Journal CMEs

Print Friendly 

Evidence-Based Psychotherapies for
Depressed Adolescents: A Review and
Clinical Guidelines

Richard Gallagher, PhD
Needs Assessment:
Adolescent depression is an important public health problem that affects up to 20% of adolescents. Depression may take a number of forms, all of which can have varied effects on personal satisfaction, family and peer relations, and school achievement. The presence of depression is correlated with teenage substance use, risky sexual activity, and dangerous behaviors. Accidents and suicide, especially, are major sources of morbidity and mortality in the teenage years. Reliance upon scientific study of child psychopathology has spawned the creation of advanced therapies that target characteristics of depression. Many of these therapies guide adolescents and their significant others to learn new skills to combat the condition. Such methods have been shown to be effective, and they hold great promise in helping adolescents recover from depression and its consequences. Primary care clinicians and mental health practitioners would benefit from becoming familiar with these therapies and methods.  

Learning Objectives:
•  Describe four evidence-based psychotherapies for adolescents.

•  Describe the interpersonal, behavioral, and cognitive skills that are the focus of change in the treatment programs.

•  Determine how to select mental health practitioners who can deliver evidencebased psychotherapy for depressed adolescents.

•  Give examples of how depressed adolescents are different from other adolescents in their responses to negative
events and interpersonal conflicts. 

Target Audience:
Primary care physicians and psychiatrists.

Accreditation Statement:
Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: September 30, 2007. The estimated time to complete all three articles and the quiz is 3 hours. 

Abstract

The last two decades have seen a dramatic change in the treatment approaches used to address adolescent depression. Research studies on the characteristics of adolescents with depression have pinpointed problems in thinking, behavior, and social interactions that are linked to the disorder and its symptoms. Clinical researchers have used this information to develop specific treatments for depression that have been put to the empirical test with good results. This article reviews the rationale, treatment content, and effectiveness of four structured and targeted treatments for depression in youth as they have been applied to adolescents. The approaches include cognitive-behavioral therapy, primary and secondary control enhancement therapy, interpersonal psychotherapy for adolescents, and systemic-behavioral family therapy. Each of these methods contributes to improvements in rates of depression and depressive symptoms for adolescents with all forms of depression, including major depressive disorder. Thus, they provide advances in the care of the depressed adolescent. Their status in relation to the use of medication and their limits are discussed. Provided is a set of guidelines for primary practitioners to facilitate teenage engagement in therapy and make selections for referrals sources.

Introduction

A major change in the psychological treatment of adolescent depression has occurred during the last 15–20 years. Methods with the greatest empirical support to date are characterized by several aspects. First, following a pattern established in the treatment of adult depression, treatments have become less focused on the past, more directive, more involved in training skills, and more involved in emphasizing current inter personal interactions and the interplay of behavior, thoughts, and mood. This shift is essential because prior efforts with nondirective therapies, supportive therapies, and general family therapies have very little documented effectiveness for depression in adolescents, especially for major depression. Second, because surveys have highlighted a high point prevalence of depressive disorders or depressive symptoms in adolescence (2% to 9%), and a high teenage lifetime inci dence (20%), the field has been spurred to find methods that go beyond simple support to provide true recovery from the condition. Next, while investiga tions also document the negative impact that depression has upon school performance, social relations, and risk for suicide, the importance of quick treatment responses has fostered the creation of relatively brief interventions. Finally, to facilitate research on effectiveness, but also to facilitate a rapid rate of learning for therapists, approaches have utilized treatment protocols with highly detailed and specific manuals. Thus, the appear ance of therapy for adolescents with depression has changed dramatically from one in which the adolescent guides therapy while a therapist listens and reflects, to one in which the therapist guides the adolescent to improve skills and coping strategies in a collaborative process. This process follows a flexible, but recommended order of steps.

 
Three forms of primarily individual treatment with some associated family involvements have been developed and evaluated in the last decades: cognitive-behavioral therapy (CBT),1 primary and secondary control enhancement training (PASCET),2 and interpersonal psychotherapy for depres sion in adolescents (IPT-A).3 A form of family therapy that contains elements of CBT, but also stresses building parenting skills and altering conflictual family relations has also been formu lated and tested.1 These approaches, described as “targeted treatments” in a more extensive review by Sherrill and Kovacs,4 have shown increased impact with depressed youth when compared to wait-list control and non specific, supportive therapies (Figure). These approaches show great promise for helping adolescents. Although recovery rates from depression are relatively high when youth are kept out of treatment or are provided with non specific therapies, the evidence-based treatments that target skills and cop ing efforts show a significant advan tage that reaches a vast majority of adolescents in immediate review and follow-ups.

This article reviews how these treatments have achieved this promise and where they stand in relation to other treatments for adolescent depression. The review describes the theoretical rationale behind each treatment package, provides a brief description of the treatment components contained in each package, and reviews the findings from controlled clinical studies.

Characteristics of Depression in Adolescence

Targeted treatments have been cre ated to address emotional, behavioral, cognitive, and social characteristics of adolescents who suffer from depression or show depressive symptoms. These characteristics have been found in empirical studies of adolescents with depression when compared to other adolescents or generated from assumptions about functioning found in depressed adults. Among a number of documented differences between youth with and without depressive qualities, adolescents with depression are less effective than others in emo tion regulation. They have trouble managing tension and anxiety; have weak problem-solving skills; engage in fewer enjoyable activities and limit their social contacts; and have think ing patterns that are generally negative in viewing themselves, their surround ings, and their future prospects. They engage in rumination and do not seek out the counsel of others to challenge their thinking patterns.5 In interpersonal relationships, adolescents that are depressed are considered to be poor at resolving conflicts or obtaining full satisfaction in relationships. This leads to them being distressed, unsup ported, and unhappy about their social circumstances. Poor social relations or problems in an important social relation are assumed to contribute to the emergence of depression, but are alsobelieved to persist during the course of the illness.6 The treatments that are evidence based may emphasize one of these characteristics, but usually these treatments incorporate interventions that address several characteristics.

Cognitive-Behavioral Therapy

Several forms of CBT recognize that adolescents who are prone to depression or are experiencing depression have a characteristic set of distortions in thinking and a diminished set of effective behaviors for coping with stress and seeking pleasant experiences. Compared to other youth who are not depressed or who are less likely to have depressive reactions to stress, adoles cents with depression are more likely to have negative beliefs about themselves, view their surroundings as being harsh, unfulfilling, or unaccepting, and con sider their prospects for future change to be minimal if not worse than they already are. This negative cognitive triad was formulated by Beck and colleagues7 in studies of depressed patients, and has been confirmed in numerous studies of adults, adolescents, and children as being highly associated with depression and depressive symptoms.8 For example, a depressed adolescent may make a mistake in school and conclude that the mistake reflects his or her status as “a total failure who will never get anything right.” In response to their depressed mood and lower levels of energy because of physiological changes in depression, adolescents become withdrawn. Diminished levels of activity lead to further decreases in mood and pessimism. Other data sug gest that adolescents with depression experience limited positive reinforce ment. This occurs because of the limited energy depressed adolescents have for activities when the physical components of the illness strike, or because of reduced resilience following stressful life events. Depressed adolescents are also less effective at obtaining positive responses from people and their envi ronment because they are less skilled in problem solving and managing their reactions.9,10 Based on effective methods used with depressed adults, treat ments have been developed to help adolescents learn ways to alter or, at least, review their thinking, increase their level of positive activities, and increase their social and problem-solving skills.

One form of CBT that has received considerable research review is based on Beck’s model of depression. It emphasizes increasing positive activities and altering thinking style in reac tion to negative events. In a treatment package of 12–16 sessions, adolescents and their parents are presented with psychoeducation to build their under standing of depression and the likely cognitive distortions that are present in depression. Following psychoeducation, adolescents are individually instructed in a step-wise fashion to notice their automatic negative thoughts, consider how to label the thoughts as distorted or overly pessimistic, and decide how to challenge the veracity of the thoughts they have about themselves and their surroundings. Additionally, adolescents are instructed in regulat ing their emotions by learning how to identify their feelings and how to use activities and distractions to improve their mood. Finally, adolescents are shown methods to solve problems in a logical, calm manner so that they can proactively avoid or resolve negative situations. Therapists use a flexible manual for intervention that incorporates one psychoeducational session; several sessions to learn how to notice automatic negative thoughts and chal lenge the true interpretations of events and the adolescent’s capabilities; several sessions to increase positive activities and learn to schedule them on a regular basis; and several sessions to teach emotion management and problem-solving methods. The adolescent is actively engaged in using methods between sessions so that he or she is able to provide “self-directed” therapy for more effective coping.

Tests of the impact of this treatment compared with other interventions have shown favorable results with clinic-referred cases. Adolescents were enrolled in CBT or a form of family therapy designed to address problems found in the families of depressed adolescents (systemic-behavioral fam ily therapy [SFBT]) or nondirective supportive therapy (NST). The thera pies are carried out for 12–16 sessions over 12 weeks with opportunity for up to four booster sessions after imme diate follow-up assessment. At the end of the initial treatment program, CBT showed substantial advantage in reducing the rate of major depressive disorder (MDD) when compared to NST, (17% versus 42%) and helped those with MDD at the beginning of the trial to recover from the condition. Adolescents with MDD who were treat ed with CBT had a recovery rate of 65% while those in SBFT and NST had simi larly lower rates of recovery (38% and 39% respectively).11 Less effective out comes were predicted by the presence of anxiety disorders in conjunction with depression, a high level of cogni tive distortions, and a stronger sense of hopelessness at the beginning of treatment.12 At 2-year follow-up there were no statistically significant differences among the treatment groups in the rates of MDD, even though the numbers favored CBT (6% compared to 23% for SBFT and 26% for NST). Conclusively, CBT was perhaps effec tive in helping adolescents during the episode even though adolescents in other conditions showed some recovery in the long term. Considering the nega tive impact that depression has upon school performance, social adjust ment, and substance use, reducing the length of depressed episodes is a con siderable benefit.1

Another form of CBT that has been developed and carefully scrutinized has stressed combat of diminished posi tive experiences by helping adolescents engage in an increased number of pos itive activities and interactions. The treatment takes the form of a group psychoeducational effort entitled the Adolescent Coping with Depression Course (CWD-A). In this program, ado lescents participate in either a group of 14 sessions spread over 7 weeks (CWD A), or in a group that adds 7 sessions of parent groups to the adolescent group (CWD-A+P). The intervention seeks to teach emotion regulation by hav ing adolescents learn to monitor their mood and learn relaxation procedures. Participants expand on their behavioral repertoire by increasing pleasant activi ties and social contacts. Adolescents also practice constructive thinking strategies to counteract their negative cognitive set. To address social prob lems and possible skills deficits, ado lescents are taught specific social skills for conversations and friendship main tenance, assertive skills for problem interactions, and methods for commu nicating more effectively. They are also instructed to use logical problem-solv ing skills before selecting a choice with the the best possible outcome. This is done by expanding the number of alter native responses that they consider and by reviewing the choices for potential consequences.

A number of randomized trials of CWD have been conducted with good results. When compared to waiting list control groups, those adolescents that participated in CWD had reductions in self-reported depression and global functioning, and fewer of them met the criteria for a diagnosis of depres sion immediately after the intervention. There was no difference in these rates for adolescents that participated in the group by itself and those who par ticipated in the adolescent and parent group. The first study of this approach found recovery to occur in 46% of the CWD groups compared to 5% in the wait-list control, while a second study found rates of 67% for CWD groups and 48% for wait-list controls. Follow-up data also found no differ ences after 2 years similar to the other form of CBT discussed.13 Expansion of the program to depressed adolescents who also had conduct disorders found improved recovery at post-intervention assessment at less robust rates (26% versus 14% for a control condition).14 Thus, the program would qualify as one that is solidly efficacious because of strong results in initial tests and replications.15

Primary and Secondary Control Enhancement Therapy

PASCET shares many qualities with CBT, however, its expanded emphasis on skills building and effectiveness warrant special attention. PASCET is designed for youths between 8 and 15 years of age. Two collections of proce dures for enhanced control and cop ing are used to integrate individual, family, and school contacts to work on skills and thoughts. The basic premise is that a child or adolescent learns skills to control situations that can be influenced by another youth, as well as thinking skills for managing situations that cannot be altered. Adolescents are given extensive psychoeducation to learn and practice the skills involved. Primary skills suggest that the child “ACT” differently. Youth are directed to use Activities that solve problems; perform Activities that are enjoyed; take steps to Calm oneself; use methods that demonstrate Confidence; and build Talents to improve effectiveness in desired areas such as sports or aca demics. Children and adolescents are also directed to use THINK skills to: Think positively; obtain Help from a friend to gain perspective on problems; Identify good aspects of even difficult situations; engage in No replaying of negative events; and Keep thinking to make sure all alternatives have been considered. Imagined situations and situations from the youth’s experience are used to help determine how he or she might apply the skills. 

PASCET has been tested in school settings with good results for children and youths. The youths involved were identified as having symptoms linked to depression without necessarily meeting diagnostic criteria. On self-report measures, youths that participated in the program had decreased rates of depressive behaviors, feelings, and thoughts when compared to controls at both immediate post-evaluation and at 9 month follow-up.16 Application with a clinical sample of youths from mental health clinics that meet diagnostic criteria is being conducted currently.  This study does not focus exclusively on adolescents, so its application to adolescents by themselves and with older adolescents will have to be surmised.

Interpersonal Therapy for Depressed Adolescents

IPT-A is an adaptation of interper sonal therapy (IPT), which is a highly effective method for treating adult depression. IPT and IPT-A are based on the idea that interpersonal conflicts or problems in managing transitions in relationships maintain depression even if that depression is initially caused by physical factors. Short-term focused therapy uses psychoeducation and an extensive analysis of an adolescent’s interpersonal relationships to explore sources of conflict or stress.  The heavy emphasis that adolescents place on their peer and family relationships makes the treatment particularly important for this phase of development. Since adolescents find the method highly relevant and practical, engagement may be easier than other forms of evidence based treatment. 

In treatment, adolescents can be seen individually, in meetings with their parents, or in groups. Adolescents are asked to consider five areas of interpersonal interactions, including separation from parents, authority problems with par ents, developing dyadic relationships, loss of relatives and friends, and rela tionships in single-parent families. Each area is explored for problems, and one area about which the adolescent feels most distressed is selected for the focus of a 12-session program. In each ses sion, adolescents are asked to provide indications of their mood, report on the status of the relationship area, and engage in active problem solving to find alternative means of resolving conflict and obtaining satisfaction in the area of concern. When indicated, adolescents may be provided with social skills training to improve their negotiation, communication, and relationship main tenance skills.

Tests of IPT-A have found good results when conducted in the setting in which treatment was created. In a controlled clinical trial with random assignment, IPT-A in comparison to clinical monitor ing (CM)—operationalized as monthly 30-minute meetings with a therapist to review symptoms and functioning—was much more effective in contributing to remission from depression. More ado lescents completed the course of IPT-A (88%) than the CM condition (46%). Additionally, at the end of the treatment period 88% of adolescents in IPT-A no longer met the criteria for depression, against 58% from the CM group. A second use of IPT-A, with a sample of adolescents enrolled in treatment in Puerto Rico using a Spanish-language version, found that IPT-A resulted in significantly diminished depressive symptoms when compared to a wait list control group, but no difference when compared to an equally effective course of CBT.17 However, those in IPT-A reported higher levels of self-esteem and social functioning when compared to the CBT group. Extending the approach for use in school mental health clinics, Mufson and colleagues18 reported rates of recovery between 50% and 75% depending on the measure used for students that participated in IPT-A, in comparison to rates of 10% to 25% recovery for adolescents that received treatment with a usual, typically sup portive and nondirective approach. This study was conducted with experi enced therapists who received a relatively brief round of training in IPT-A, suggesting that the program has much promise for dissemination. Thus, IPT-A is another form of treatment that has good empirical standing. 

Systemic-Behavioral Family Therapy

Family therapy designed specifically for depressed adolescents emphasizes the repair of inappropriate interactions between the adolescent and his or her parents, poor communication among the parties, and weak problem-solving skills for the conflicts encountered as adolescents move to independence. Adolescents and their parents meet together and learn how to describe their problems with one another in open non-aggressive fashions. The family is directed to use careful, active listening skills with one another so that they can become supports for each other. Additionally, family mem bers are directed to negotiate problems using calm, logical problem-solving approaches. If there are changes that parents wish to see in their adolescent’s actions, contracts and use of rewards are developed and monitored by thera pists. As noted above, the effectiveness of SBFT is not distinctly different from NST in contributing to recovery from MDD at post-intervention assessment. However, SBFT has been found to have a positive affect on improving family relations and diminishing conflict, so it may offer assistance in those cases in which family conflict is the main source of stress in a adolescent’s life.11,12 

Comparative Studies Among Evidence-Based Therapies and Status in Relation to Medication

Comparisons between evidence based approaches are limited. As noted above, CBT and SBFT show a similar impact on rates of depression, but they also demonstrate specific effects and may be used to match the refer ring circumstances. Adolescents who have participated in CBT report fewer cognitive distortions in their analysis of stressful events, while adolescents treated with SBFT report less family conflict and distress in family interactions.15 A single study that compared CBT to IPT-A found that both were equally effective in reducing depres sion in relation to a wait-list control.17

Only recently has one of the evidence based therapies been studied in relation to the most effective class of medi cations, the selective serotonin reup take inhibitors. In a comprehensive study conducted in several research centers, four conditions were randomly compared to one another with 439 adolescents who met the criteria for MDD. During 12 weeks of treatment, adolescents were randomly assigned to either placebo medication, CBT alone, fluoxetine alone, or CBT in combina tion with fluoxetine. Fluoxetine was administered in doses from 10–40 mg/ day depending on clinical response and side effects. Placebo doses were also advanced from 10–40 mg/day in a simi lar pattern. CBT was provided in 50–60 minute sessions at a rate of 15 sessions during the 12-week treatment phase. Most CBT sessions were individual, but two parent-only sessions emphasized psychoeducation about depression, and between 1 and 3 conjoint adoles cent and parent sessions were held to address conflicts or concerns.19

The results found that both medica tion conditions (alone and in combination with CBT) were superior to CBT alone and to placebo in facilitating clinical improvement. Statistically, CBT was not significantly different in comparison to placebo, while the combined treat ment and fluoxetine alone were significantly different than placebo in facilitat ing improvement on a broad range of depressive symptoms. CBT, when used in combination as well as alone, was better at reducing suicidality than were the two conditions in which CBT was lacking (fluoxetine alone and placebo). Rates of improvement for the four conditions were as follows: fluoxetine and CBT combined, 71%; fluoxetine alone, 61%; CBT alone, 43%; and placebo, 35%.  

The results strongly suggest that the combined use of medication and CBT should be provided to adolescents with MDD, especially if there is significant suicidality present. CBT alone does not seem warranted for adolescents that meet the criteria for MDD, although it did reduce suicidality. It did not have a significantly different impact on other depressive symptoms. Further research with a long-term follow-up is being conducted with the sample to determine if CBT reduces or delays relapse when it is part of the package, as opposed to medication alone. This is feasible as CBT has been shown to have a significant impact in delaying relapse and enhancing recovery from a second episode of depression in adolescents.14

Despite the low level of recovery documented for CBT in relation to the placebo condition, the use of CBT may still be necessary. Although careful study has suggested that increases in suicidality with the use of medication in the early phases of treatment is man ageable with close monitoring,20 many parents and adolescents are reluctant to utilize medications for depression. CBT may provide benefits during the time that reluctance to participate in medication therapy is addressed, through careful discussions of the risks and benefits. It can be implied that CBT may also benefit from further development, as would medication efforts for severe forms of adolescent MDD, because even at their best the combined treatments left over 25% of adolescents with limited improvement.

Guidelines

The data indicate that forms of CBT and IPT are more effective than non specific forms of supportive therapy, generic family therapy, and relaxation treatments. These latter therapies are in turn more effective than no treatment at all for varied forms of depression in adolescents. Neither CBT nor interpersonal psychotherapy have been tested against medication alone for these varied forms of depression. However, in the case of MDD, it appears that CBT alone is not any more effective than placebo responses and is less effective than medication alone or medication in combination with CBT. CBT in conjunction with medication seems to provide a boost in impacting suicidal ideation after short-term follow-up. Its impact in long-term responsivity and diminishing relapse effects is yet to be determined.

Recommended Guidelines for Primary Care Practitioners

The collected data suggest that the targeted psychotherapies described in this article show more promise than generic or supportive therapy in helping adolescents recover from depres sion. Yet, instruction and experience in these forms of therapy is not wide spread. No form of these therapies have been developed for pediatricians or family medical practitioners, even though advanced experience in CBT has been shown to have a signifi cant affect in depression treatment.21 However, there are guidelines for two groups of primary practitioners that can be suggested based on the review. These guidelines are for practitioners with psychotherapy training and expe rience, or for practitioners who wish to facilitate treatment referrals and help adolescent patients get engaged in mental health care.

If done with diligence and care, practitioners with psychotherapy expe rience can add treatment components that are part of the effective packages. Workshops, training books, and super vision in these methods are becoming more widely available. For example, the manuals and training materials for coping with depression are avail able on a dissemination Web site22 that is intended to expand the use of this approach. Treatment approaches that are supported have characteristic components that can be incorporated in care. Candidates for inclusion are listed for critical review in the guide lines and summarized in the Table. In considering these elements of treat ment, however, it must be clear that only the full treatment packages have been tested and the impact of any component by itself is unknown.

Activity Level

The depressed adolescent can be helped by taking a more active approach. An increase in activities in general and an increase in activities that in the past had provided the adolescent with pleasure and a sense of mastery should be negotiated and scheduled.

General Interpersonal Interactions

In interpersonal relations, the adolescent can also be encouraged to become more communicative, more assertive, and more active in solving problems that are present. Efforts to build communication skills, assertiveness skills, and interpersonal problem-solving and negotiation skills can be incorporated through practice in therapy sessions.

Emotion Management

Methods to improve emotion man agement with a particular focus on anxiety and despondency can be taught and applied so that the adolescent is able to cope more effectively. The goal of diminishing the number of episodes of unresolved negative emotions is central to most approaches.

Cognitive Components

Adolescents can be directed to notice the content and style of their cognitive reactions to events. Their reactions are likely to be inaccurately pessimistic or critical. A systematic means of noting those reactions, critically reviewing their accuracy, and learning to question and replace them is essential for decreasing depressive experiences. Guided instruction in doing this can be provided.

Problem-solving Skills

Instruction and practice in problem solving skills helps the adolescent alter outcomes and can provide hope. The depressed adolescent can be taught to approach difficult situations more effectively by learning to generate alter native ideas, evaluate their potential consequences, and implement solutions that seem most desirable. 

Family Relations

Family support can be fostered through psychoeducation to help parents and others recognize that depression is an illness, not a choice. Family members can be directed to be calmer and less critical in interactions while they support application of the behaviors that are likely to diminish depression. Contracts for change with the use of rewards for altered response can be negotiated and implemented to diminish family conflict and improve functioning.

For practitioners interested in referring patients to others for treatment, several steps are useful: Actively help the adolescent enroll in therapy. Adolescents in general, depressed adolescents in particular, and even adolescents who have made injuri ous suicide attempts are notoriously difficult to engage in therapy. Direct guidance for the adolescent and demys tification of the therapy process may facilitate participation in treatment.

Consider several different steps:

1.  Explore options at the adolescent’s school. Getting help in-house is often the easiest step for an adoles cent to take. Many school health clinics have added mental health components in the last decade and they are often informed of recent treatment developments.

2.  Provide easy to read literature that explains therapy to adolescents. The American Psychological Association, the American Academy of Child and Adolescent Psychiatry, and the Association for the Advancement of Cognitive and Behavior Therapies have brief booklets and Web site information directed toward adolescents. Help the adolescent under stand that there will be talking in sessions, but practical steps are likely to be used to improve the adolescent’s situation.

3.  Attempt to have a therapist meet the adolescent in your office. It may be easier for the adolescent to have contact on neutral ground. This may give the adolescent a chance to ask questions without committing to a “therapy” contact. Some practitioners may be willing to do this or be supported by their agencies to engage in such outreach.

Question your referral sources on their therapy practices. Expect your referral sources to obtain continuing education so that they are informed and trained in the most effective methods available. With the growth of empirically tested methods during the last decades, strictly adhering to a particular orientation to treatment is no longer acceptable. Expect to hear a clear outline of treatment plans for depression in adolescents before using the source for assistance.

Turn to careful and guided use of medi cations if the adolescent and the parents are interested in that route and if no viable therapy options are readily avail able. This recommendation is especially important for those suffering from MDD.

Conclusion

Even at their best, the application of targeted therapies over a relatively short period of time results in recovery of between 70% and 87% of adoles cents who participate. It is possible that a substantial minority of adolescents with depression require longer care. This is also true for medication treat ments. Persistent follow-up and evaluation of an adolescent’s status following a bout with depression is required. Despite advances, the field has far to go to meet the needs of the large number of adolescents (20%) who will suffer from depression. PP

References

1. Weersing VR, Brent DA. Cognitive-behavioral therapy for adolescent depression: Comparative efficacy, mediation, moderation and effectiveness. In: Kazdin AE, Weisz JR, eds. Evidence-Based Psychotherapies for Children and Adolescents. New York, NY: Guilford Press; 2003:148-164.

 2.  Weisz JR, Southam-Gerow MA, Gordis EB, Connor-Smith J. Primary and secondary control enhancement training for youth depression: Applying the deployment-focused model of treat ment development and testing. In: Kazdin AE, Weisz JR, eds. Evidence-Based Psychotherapies for Children and Adolescents. New York, NY: Guilford Press; 2003:165-183.

 3.  Mufson L, Dorta KP. Interpersonal psychother apy for depressed adolescents. In: Kazdin AE, Weisz JR, eds. Evidence-Based Psychotherapies for Children and Adolescents. New York, NY: Guilford Press; 2003:148-164.

 4.  Sherrill JT, Kovacs M. Special articles: treatment of mood disorders in children and adolescents: nonsomatic treatment of depression. Psychiatr Clin North Am. 2004;27(1):139-154.

 5.  Hammen C, Rudolph KD. Childhood depres sion. In: Mash EJ, Barkley RA, eds. Child Psychopathology. New York, NY: Guilford Press; 1996:153-195.

 6.  Stader SR, Hokanson JE. Psychosocial ante cedents of depressive symptoms: an evaluation using daily experiences methodology. J Abnorm Psychol. 1998;107(1):17-26.

 7.  Beck AT, Rush AJ, Shaw BF, Emery G. Cognitive Therapy of Depression. New York, NY: Guilford Press; 1979.

 8.  Gladstone TR, Kaslow NJ. Depression and attributions in children and adolescents: A meta-analytic review. J Abnorm Child Psychol. 1995;23(5):597-606.

 9.  Lewinsohn PM, Steinmetz JL, Antonuccio D, Teri L. Group therapy for depression: the coping with depression course. Int J Ment Health. 1985;13(3-4):8-33.

 10.  Clarke GN, DeBar LL, Lewinsohn PM. Cognitive behavioral group treatment for adolescent depression. In: Kazdin AE, Weisz JR, eds. Evidence-Based Psychotherapies for Children and Adolescents. New York, NY: Guilford Press; 2003:120-134.

 11.  Brent DA, Holder D, Kolko D, et al. A clinical psychotherapy trial for adolescent depression com paring cognitive, family, and supportive therapy. Arch Gen Psychiatry. 1997;54(9):877-885.

 12.  Brent DA, Kolko DJ, Birmaher B, et al. Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. J Am Acad Child Adolesc Psychiatry. 1998;37(9):906-914.

 13.  Clarke GN, Rohde P, Lewinsohn PM, Hops H, Seely JR. Cognitive-behavioral treatment of adolescent depression: efficacy of acute group treatment and booster sessions. J Am Acad Child Adolesc Psychiatry. 1999;38(3):272-279.

 14.  Rohde P, Clarke GN, Mace DE, Jorgensen JS, Seely JR. An efficacy/effectiveness study of cognitive-behavioral treatment for adolescents with comorbid major depression and conduct disorder. J Am Acad Child Adolesc Psychiatry. 2004;43(6):660-668.

 15.  Curry JF. Specific psychotherapies for childhood and adolescent depression. Biol Psychiatry. 2001;49(12):1091-1100.

 16.  Weisz JR, Thurber CA, Sweeney L, Proffitt VD, LeGagnoux GL. Brief treatment of mild to-moderate child depression using primary and secondary control enhancement training. J Consult Clin Psychol. 1997;65(4):703-707.

 17.  Rossello J, Bernal G. The efficacy of cognitive-behavioral and interpersonal treatments for depression in Puerto Rican adolescents. J Consult Clin Psychol. 1999;67(5):734-745.

 18.  Mufson L, Dorta KP, Wickramaratne P, Nomura Y, Olfson M, Myrna M. Randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry. 2004;61(6):577-584.

 19. March J, Silva S, Petrycki S. Treatment for Adolescent Depression Study (TADS) team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807-820.

 20. March JS. Adolescents with depression. JAMA. 2004;292:2578-2579.

 21. DeRubeis RJ, Hollon SD, Amsterdam JD, Shelton RC, Young PR, Salomon RM et al. Cognitive therapy vs medications in the treat ment of moderate to severe depression. Arch Gen Psychiatry. 2005;62(4):409-416.

 22. Download Site for Youth Depression Treatment and Prevention Programs. Available at: www.kpchr.org/public/acwd/acwd.html. Accessed August 22, 2005.


Dr. Gallagher is assistant professor of psychiatry and director of cognitive behavior therapy training in the Division of Child and Adolescent Psychiatry at New York University (NYU) School of Medicine in New York City.

Disclosure: Dr. Gallagher recieved grant support from McNeil Pharmaceuticals.

Please direct all correspondence to: Richard Gallagher, PhD, NYU Child Study Center, 215 Lexington Ave, 13th Floor, New York, NY 10016; Tel: 212-263-5840; Fax: 212-263-3690; E-mail: richard.gallagher@med.nyu.edu.


Articles

Print Friendly 

Trichotillomania:
Apparent CYP 2D6 Interaction
with Amphetamine and Paroxetine

Nathaniel W. Parker, BA, and Charles E. Parker, DO

Focus Points

• Trichotillomania may present as an unusual iatrogenic condition secondary to specific drug-drug interactions.

• Depression and attention-deficit/hyperactivity disorder often present as comorbid conditions, and the medications used to treat those comorbid conditions may interact through the cytochrome P450 (CYP) 2D6 pathway.

• Understanding the pharmacology of this dramatic presentation of trichotillomania may alert the clinician to more subtle manifestations of this important CYP 2D6 interaction.

Abstract

Although pharmacotherapy is intended to resolve clinically relevant symptoms, unpredictable side effects may occur, especially when polypharmacy is initiated. This report details a drug-drug interaction between paroxetine and mixed amphetamine salts that manifested as iatrogenic trichotillomania. Mild amphetamine toxicity may result in irritability, psychomotor agitation, restlessness, insomnia, tremor, hypervigilance, hal lucination, anxiety, and stereotypical repetitive motor activity. Trichotillomania, within the spectrum of anxiety disorders, may be described as having a repetitive motor com ponent of hair pulling, which serves as an anxiolytic to patients with trichotillomania. In this report, the onset of trichotillomania appears to have been initiated by long-term adjunctive treatment of amphetamine salts in a patient receiving paroxetine. Symptoms of trichotillomania in this patient abated with a reduction in the amphetamine salts and a discontinuation of paroxetine.

Introduction

With the high comorbid incidence of attention-deficit/hyperactivity disorder (ADHD) and depression the poten tial for using antidepressants concur rently with stimulants is abundant and potentially problematic. Most relevant regarding the possibility of drug inter actions is the use of antidepressant medication that significantly inhibits cytochrome P450 (CYP) 2D6 while given simultaneously with stimulant medications that are substrates of CYP 2D6. This case report demonstrates an unusual but graphic patient reaction, in the form of trichotillomania, to such a CYP 2D6 interaction between parox etine and mixed amphetamine salts.

  Noteworthy with similar CYP 2D6 interactions and important to take into account is the length of time necessary for this type of interaction to appear, sometimes presenting clinically up to ≥3 months after starting the two inter active medications. Noting that the CYP 2D6 inhibition is often not abso lute and therefore not complete, these interactions take some time to appear and are often overlooked in their more clinically subtle manifestations.

Case Report

Ms. A is a single 19-year-old female with dysthymic disorder and ADHD, inattentive type. She has no history of tic disorder or other significant medical his tory. Two years prior to her recent presen tation she began taking mixed amphet amine salts 20 mg QAM for ADHD and, at the same time, paroxetine 20 mg QAM for comorbid anxiety and depression. Ms. A reported taking her medication as prescribed with no self regulation of her dosage. The combination of medications was initially effective for both conditions, but the patient began noticing difficulty sleeping, agitation, and anxiety. After 6 months the patient began to report sores on her scalp and was seen by a number of dermatologists who were unable to diagnose the lesions (Figure). Some dos age adjustments of mixed amphetamine salts were made with no clear response. Approximately 6 months ago her cur rent dermatologist ultimately diagnosed the loss of hair as trichotillomania and referred the patient to our office for a second psychiatric opinion. Her dose of mixed amphetamine salts was immedi ately reduced while slowly and simultaneously she was titrated off of paroxetine and venlafaxine extended release 150 mg QAM was added. On 21-day follow-up, the patient reported feeling “much better,” had improved sleeping patterns, and had significant hair re-growth.

Discussion

Metabolically, paroxetine is a CYP 2D6 substrate and potently inhibits CYP 2D6, even in extensive metabolizers.1 Using the popular technique of measuring blood levels of desipramine (a CYP 2D6 substrate) metabolites, patients showed a 3-fold increase in desipramine levels when administered with paroxetine.2 Regarding the metabolism of the mixed amphetamine salts, there is no evidence that amphetamines cause CYP 2D6 inhibition.3 A literature review of amphetamine metabolism describes a complex process where a portion of the oral dose is renally excreted by “oxidative deamination forming the inactive metabolites benzoic acid and hippuric acid.”4  The remaining amphetamine is converted by aromatic hydroxylation via 2D6 to three active metabolites: p-hydroxyamphetamine, phenylpropanolamine and p-hydroxynorephedrine.5-7

Additional studies used a potent CYP 2D6 inhibitor, quinidine, on rat CYP 2D1, (rat CYP 2D1 is equivalent to human CYP 2D6) which resulted in a decrease in the amount of active metabolite p-hydroxyamphetamine that was excreted.8 Other research demonstrated a 2-fold increase in plasma concentration of amphetamine in rats treated with quinidine.9

Further rat studies reported increased amphetamine concentrations in the brains of rats treated with similar potent CYP 2D6 inhibitor, fluoxetine.10,11 Based on well-documented research of rat metabolism of amphetamines on CYP 2D1, and on this clinical presentation, one is lead to the conclusion that amphetamine salts are metabolized to some extent by CYP 2D6. This report demonstrates what appears to be a significant drugdrug interaction due to enzymatic inhibition of metabolic clearance by paroxetine, which caused a relative accumulation of amphetamines and resulted in trichotillomania. A resolution of symptoms was seen when an antidepressant that does not significantly inhibit CYP 2D6 was combined with a lower dose of mixed amphetamine salts. The duration of use of the two interacting medications and the presence or absence of medication self-regulation are important factors to consider in the clinical setting when evaluating whether pharmacokinetic interactions are taking place.

Conclusion

This unusual case is only one example of a drug-drug interaction with amphetamines based upon the described CYP 2D6 interaction. This report illuminates a metabolic pathway along CYP 2D6 for amphetamines, one of the oldest psychiatric medications, and warrants ongoing clinical vigilance when administering amphetamines with medications that inhibit CYP 2D6. PP

References

1. Hardman JG, Limbird LE, Gilman AG, Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill Professional; 2001.
2. Alderman J, Preskorn SH, Greenblatt DJ, et al. Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol. 1997;17(4):284-291.
3. Markowitz JS, Morrison SD, DeVane CL. Drug interactions with psychostimulants. Int Clin Psychopharmacol. 1999;14(1):1-18.
4. Dring LG, Smith RL, Williams RT. The metabolic fate of amphetamine in man and other species. Biochem J. 1970;116(3):425-435.
5. Patrick KS, Straughn AB, Jarvi EJ, Breese GR, Meyer MC. The absorption of sustainedrelease methylphenidate formulations compared to an immediate-release formulation. Biopharm Drug Dispos. 1989;10(2):165-171.
6. Bach MV, Coutts RT, Baker GB. Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999;29(7):719-732.
7. Wu D, Otton SV, Inaba T, Kalow W, Sellers EM. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol. 1997;53(11):1605-1612.
8. Moody DE, Ruangyuttikarn W, Law MY. Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine. J Anal Toxicol. 1990;14(5):311-317.
9. Tomkins DM, Otton SV, Joharchi N, et al. Effect of CYP2D1 inhibition on the behavioural effects of d-amphetamine. Behav Pharmacol. 1997;8(2-3):223-235.
10. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction. Psychopharmacology (Berl). 1999;141(4):421-427.
11. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Subchronic fluoxetine treatment induces a transient potentiation of amphetamineinduced hyperlocomotion: possible pharmacokinetic interaction. Behav Pharmacol. 2000;11(2):109-116.


Mr. N.W. Parker is a fourth year medical student at Eastern Virginia Medical School.

Mr. C.E. Parker is chief psychiatrist of Amen Clinic in Washington, DC.

Disclosure: Mr. N.W. Parker reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Mr. C.E. Parker is on the speaker’s bureaus of Sanofi-Aventis, Shire, and Wyeth.

Please direct all correspondence to: Nathaniel W. Parker, BA, 545 Warren Crescent #9, Norfolk, VA 23507; Tel: 757-285-5467; Fax: 757-473-3768; natparker@cox.net.


Journal CMEs

Print Friendly 

When to Use Antidepressant
Medication in Youths

Raul R. Silva, MD, Vilma Gabbay, MD, Haruka Minami, BA,
Dinohra Munoz-Silva, MD, and Carmen Alonso, MD
Needs Assessment:
Recent actions taken by regulatory bodies in the United States and abroad have raised the level of alertness and concern regarding the use of antidepressants in children. Antidepressants are only Food and Drug Administration approved for two indications in children, yet they represent the second most frequently prescribed group of agents for child psychiatric illness. Physicians need to understand the extent of the methodologically sound literature regarding the efficacy of these agents in different conditions.

Learning Objectives:
•  Identify reasons why regulatory agencies have issued warnings regarding antidepressant use in youths.

•  Describe cardiac issues related to the use of tricyclic antidepressants.

•  Numerate conditions and antidepressants that have proven efficacy in well controlled studies in this age group.

Target Audience:
Primary care physicians and psychiatrists.

Accreditation Statement:
Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: September 30, 2007. The estimated time to complete all three articles and the quiz is 3 hours.

Abstract

The development of antidepressant agents has been underway since their first use in the 1950s. Types of agents include monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs). The utility of these agents in adult populations has led to multiple approved indications by the Food and Drug Administration. Although there are only two approved indications in pediatric age groups—major depressive disorder (MDD) and obsessive-compulsive disorder (OCD)—physicians have been prescribing antidepressants to children and adolescents in increasing numbers. In previous years, the TCAs had documented cardiotoxic potential, and there were several sudden unexpected deaths associated with their administration in youths. In December 2003, Great Britain’s drug regulatory agency contraindicated the use of four SSRIs in childhood populations. This decision was based on the increased rates of developed suicidal thinking or gestures observed in the pooled data of >4,000 pediatric aged subjects treated with an antidepressant versus placebo. In October 2004, after careful consideration, the FDA placed a black box warning on all antidepressants, alerting clinicians to the potential of developing similar behaviors upon receiving these agents. These findings underscore the importance of using the increasing evidence base of well-designed, doubleblind studies to guide the usage of these antidepressants in conditions where efficacy is established. This article reviews that body of literature in conditions such as MDD, OCD, attention-deficit/ hyperactivity disorder, selective mutism, and anxiety disorders.

Introduction

Antidepressants are considered among the most effective somatic interventions. They are approved by the Food and Drug Administration in adults for the treatment of disorders including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), panic, generalized anxiety disorder (GAD), premenstrual dysphoria, posttraumatic stress disorder (PTSD), bulimia nervosa, and social anxiety disorder.1 There are several groups of agents included in this broad psychopharmacologic category. Among them are the monoamine oxidase inhibitors (MAOIs), which in the 1950s were the first antidepressant medications available on the market.2 Later, both the secondary and tertiary amine forms of the tricyclic antidepressants (TCAs) gained popularity. Several heterocyclic compounds, such as trazodone, bupropion, and maprotiline, were introduced along the way. The development and release of the benzenepropanamine compounds, also known as the selective serotonin reuptake inhibitors (SSRIs), revolutionized the prescribing habits of psychiatrists around the world.3

MAOIs work by inhibiting monoamine oxidase (MAO), an enzyme found on the outer membrane of mitochondria. There are two types of MAO. MAO-A deaminates norepinephrine, serotonin, and dopamine, while MAOB deaminates only dopamine. MAOIs inhibit either or both of these two types of enzymes, which consequently elevate the involved neurotransmitters. MAOIs are classified by their selectivity for inhibition of MAO-A or MAO-B, as well as the reversibility of the bond between the enzyme and the agent.4

TCAs received their name because they have a three-ring structure bound to an amine group. Secondary amines have two methyl groups, and tertiary amines have three methyl groups. In both cases these groups are attached to a nitrogen molecule.5 Functionally, TCAs block the norepinephrine reuptake transporter protein. Presynaptically, they increase release of norepinephrine into the synapse and decrease serotonin reuptake. Postsynaptically, they increase noradrenergic and serotonergic activity.6

The SSRIs have a variety of chemical structures, but essentially the mechanism of action is to increase serotonin by inhibiting reuptake at presynaptic neurons. SSRIs vary in their selectivity for serotonergic receptor types, which can yield differential effects on sleep, appetite, and libido.7 Antidepressant prescriptions in children and adolescents have increased considerably over the last few decades. This phenomenon was highlighted in one study that examined the use of psychotropic medications in youth.8 The study reported on prescription patterns at three healthcare sites. Included were approximately 1 million patients 5–20 years of age between 1987 and 1996. Antidepressants were the second most frequently prescribed group of medication in this age group. A majority of the growth was largely attributable to the increasing rates of SSRI use, but the prevalence of TCA use   persisted during the observed time period. On average, across the three sites, there was a six-fold increase in the use of antidepressants during that 10-year period. Overall, the 1996 annual prevalence of antidepressant prescriptions averaged 19% of prescribed psychotropic agents in this age group.

Despite the regularity with which these agents have been prescribed for children and adolescents in the past, a recent set of regulatory actions has altered the way many physicians may ultimately use these agents in the future. This article reviews those events. Various ways to approach these findings are presented, as are other seminal issues related to the safety and efficacy of antidepressants in youth. Proposed is an evidence-based approach concerning the psychiatric conditions that may be most amenable to treatment with these agents. A review of the relevant literature to substantiate their use is provided.

The Advisories

In June 2003, the FDA issued an advisory raising concern about the use of paroxetine in children. This advisory was on the heels of a decision made by the Department of Health in the United Kingdom that essentially put a stop to paroxetine use for depressed individuals <18 years of age. The decision was based on the safety data of three controlled trials involving youths with a diagnosis of MDD. Apparently, the paroxetine-treated group had experienced higher rates (3% versus 1%) of suicidal thoughts and attempts than the placebo-treated group, although no one died during the trials.9

In December 2003, authorities in Great Britain officially labeled sertraline, citalopram, escitalopram, and fluvoxamine as contraindicated for the treatment of MDD in children. By October 2004 the FDA directed the manufacturers of all antidepressants to include a black box warning and expanded warning statements regarding increased risk of suicidality (suicidal thinking and behavior). The FDA based their findings on the combined analysis of 24 short-term studies which included >4,400 youths with various disorders. The increased risk of suicidal thinking or behaviors from the antidepressants was twice that of placebo (4% versus 2%). No suicides occurred during these trials.10 

Risk of Suicidal Thoughts

Most of the turmoil regarding suicidal thoughts in youths treated with antidepressants emanates from data available on the SSRIs. It is important to characterize the magnitude of the problem. In the United States there are nearly 500,000 adolescent suicide attempts yearly, and 2,000 successful completions.11–13 Suicide is the  fourth leading cause of death among adolescents 10–14 years of age and the third leading cause in individuals 15–19 years of age.14 The results of a large scale, multi-site study helped make sense of the findings that led to the regulatory changes. March and colleagues15 recruited 439 subjects 12–17 years of age, who met criteria for MDD. The treatments in this study were administered over the course of 12 weeks, and subjects received  either fluoxetine alone 10–40 mg/day, cognitive-behavioral treatment (CBT) alone, CBT with fluoxetine, or placebo. Placebo and fluoxetine alone were administered in a double-blind fashion, while the CBT arm and CBT with fluoxetine were administered nonblinded. The results demonstrated a number of important findings. The combination of fluoxetine and CBT was significantly better than placebo according to the Children’s Depression Rating Scale-Revised.16 The combination of fluoxetine and CBT was superior to either treatment alone. Fluoxetine was superior to CBT alone. March and colleagues17 further clarified that fluoxetine was superior to CBT on all measures and it was also superior to placebo on three of five comparisons. Suicidal thoughts, which were present in 29% of the sample at baseline, decreased significantly in all treatment arms. The combination of fluoxetine and CBT showed the greatest reduction in suicidal thoughts as rated by the Suicidal Ideation Questionnaire.18 Alone, the impact of fluoxetine and CBT did not differ significantly from placebo on this measure. Seven of the 439 patients in the trial attempted suicide, but there were no completed suicides. In examining this more closely four attempts had been on the combination of fluoxetine and CBT, two on fluoxetine, and one on CBT alone. This sample was too small to be subjected to statistical analysis. However, this study was included in the FDA review of the antidepressant’s link to suicidal thoughts.

Olfson and colleagues19 helped establish a balanced perspective of how SSRIs affect suicidal thinking and behaviors. They investigated changes in the rates of adolescent suicide in large geographic regions within the US from 1990 to 2000, and examined how these rates related to antidepressant use. The study integrated information from prescription data, national suicide mortality files from the Centers for Disease Control, and regional geographic characteristics from the US Census Bureau. The study also examined how each class of antidepressants fared. The authors reported that the rate of adolescent prescriptions for TCAs were relatively low in 1990 and decreased by one third in 2000. The study found that for every 1% increase in use of antidepressants by adolescents, there was a decrease of .23 suicides per 100,000 adolescents per year. More notably, the changes in suicide rates were not significantly attributable to changes in the rates of TCA treatment.

Leon and colleagues20 examined the relationship between suicide and SSRIs from a slightly different perspective. They looked at a sample of 66 completed suicides in youth <18 years of age in New York City between 1993 and 1998. Toxicology testing from the New York City Medical Examiner’s Office was available in 58 individuals and of these only 4 had detectable levels (2 imipramine, 2 fluoxetine) of antidepressants. Strikingly, 54 of the youth suicides lacked any evidence of antidepressant use prior to death. In another report, Gray and colleagues21 examined 151 completed youth suicides consecutively from 1996 to 1999 in Utah. Toxicology reports from the Medical Examiner’s Office were available on 137 individuals. Only 4 (3%) of them had detectable levels of psychotropic agents, which included antidepressants, antipsychotics, or mood stabilizers. In these two samples only 7 of the 195 youth suicides had detectable levels of psychiatric medications in their system. These findings failed to address the possibility that these individuals may not have taken their medication in recommended therapeutic fashion, and thus may not have received optimal therapeutic effect for their conditions.  In these combined samples, the ratio of suicide completers for medicated versus unmedicated individuals was 7:188. This ratio is a strikingly different outcome than that noted earlier by regulatory agencies for developing suicidal thinking when comparing antidepressants to placebo.

Nevertheless, other reports have called attention to the potential dangers of some of the other antidepressants when used to treat children and adolescents. There have been at least eight sudden deaths reported in children who were receiving TCAs (six receiving desipramine, two receiving imipramine). Though not conclusively established, most of these deaths are considered cardiac in nature. The arrhythmogenic properties of these particular agents have been implicated as one potential explanation.22 As a result of the cardiovascular impact of these agents, some authors have made monitoring recommendations when considering the use of the TCAs in children. Elliot and Popper23 suggest performing electrocardiograms (EKG) at baseline and when doses are increased to approximately 3 mg/kg/day, with the highest dose not to exceed 5 mg/kg/day. The American Heart Association has recommended cardiovascular monitoring for youths receiving TCAs in order to modify treatment if any of the following parameters occur: sustained resting heart rate >130 beats/minute, the PR interval >200 ms, QRS >120 ms, QTc >460 ms, or if symptoms such as palpitations, near syncope, or syncope develop.24 Alternative therapy may need to be considered along with pediatric cardiology consultation. It had been speculated that children may be more vulnerable than adults to the toxic cardiac effects of TCAs. One theory is that this may be related to children’s ability to convert TCAs to their more cardiotoxic 2-OH metabolites. This particular question was addressed by Wilens and colleagues.25 The group examined the steady-state serum concentrations of desipramine and 2-OH-desipramine in a sample of 40 children and 36 adolescents, and contrasted them to 27 adult patients. Strikingly, the findings demonstrated that youths required higher doses per kg to achieve similar blood levels of both desipramine and its 2-OH metabolite than the adult subsample.

The issue of cardiotoxicity and TCAs were further examined by Walsh and colleagues.26 In their study of 42 individuals, which included youths (n=12) and adults, 24-hour EKGs were done while subjects were receiving clinically optimal doses. Findings revealed that desipramine was associated with increased heart rate and decreased RR interval variability, which met the threshold for statistical significance.

In an effort to put these issues in perspective, Biederman and colleagues27 compared the risk of exposure to desipramine between 1986 and 1992 to the rates of unexplained death for similar aged children during a post 1987 period, as reported by the National Center for Health Statistics. Though not statistically significant, the relative risk of sudden death with desipramine exposure was reported to be between 2.1 and 3.1 of the contrast group. When the American Academy of Child and Adolescent Psychiatry looked at this phenomenon, they concluded the risk of sudden death for similarly aged untreated children in the general population was very similar and ranged between 1.5 and 4.2 million/year.28

Approved Usage of Antidepressants

Antidepressants are used effectively in a broad array of adult psychiatric conditions.  Unfortunately, in children, studies and indications lag behind their adult counterparts. The FDA has approved use of this class of agents in children and adolescents for the treatment of OCD and MDD. Sertraline received approval for OCD in youths ≥6 years of age, fluoxetine for youth >7 years of age, fluvoxamine for children 8 years and beyond, and clomipramine for children ≥10 years of age. Of all the antidepressants for MDD, only fluoxetine is indicated for children ≥8 years of age.

For many years, physicians prescribing medications to youths for psychiatric conditions have largely done so beyond the boundaries of FDA approval and indication. However, the evidence base has increased in this field, especially with agents such as the antidepressants. A growing number of welldesigned double-blind studies have contributed greatly to our knowledge base. As a result, the recommended approach for antidepressant usage in our field should be dictated first by applying those agents that have received formal FDA approval for a specific indication in given disease state, when there are no contradictory mitigating circumstances for their use. This is especially prudent given the regulatory warnings, restrictions, and potentially serious consequences. When that is not viable, treating physicians should rely on agents that have demonstrated efficacy in double-blind trials for identified conditions. Table 1 summarizes the antidepressants and conditions they are effective in, as reported in the child psychopharmacologic literature. The following section briefly reviews those studies by disease states.28-53


Anxiety Disorders

Anxiety disorders are fairly common in the pediatric age range and are seen in up to 17.3% of samples.54 This group of illnesses is characterized by excessive and persistent worries, occasionally accompanied by physical symptoms such as headaches or stomach aches. In the past, there was little evidence to support the role of pharmacologic interventions in children with anxiety disorders based upon randomized controlled trials, but there are now two trials with SSRIs that demonstrate their efficacy. Rynn and colleagues30 compared the safety and efficacy of sertraline to placebo in the treatment of GAD in subjects 5–17 years of age, during a 9week randomized, double-blind trial. Significant differences favored sertraline according to the Hamilton Rating Scale for Anxiety total scores, and  the severity and improvement subscales of the Clinical Global Impressions (CGI) scale, which were first evident at week 4.55,56 In a second study, Walkup and colleagues29 recruited 128 children 6–17 years of age. Subjects met criteria for a number of anxiety disorders including social phobia, separation anxiety disorder, and GAD. Under double-blind conditions for 8 weeks, the children were randomly assigned to either fluvoxamine or placebo. The fluvoxamine group registered significant improvement on the Pediatric Anxiety Rating Scale when compared to the placebo group. 

Attention-Deficit/ Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood, affecting up to 10% of school-aged children. If left untreated, it can lead to problems with self-esteem as well as academic and interpersonal difficulties.57 The hallmark of this illness is a triad of symptoms which can be broadly generalized as motoric overactivity, impulsive behaviors, and problems related to inattentiveness. As many as half the children with this diagnosis may experience the persistence of symptoms into adolescence.58 Though the stimulants have been the mainstay of pharmacologic treatment of ADHD for >60 years, there are numerous individuals that either do not respond optimally to these drugs or develop intolerable side effects in response to them.57,59 Until the launch of atomoxetine there were no other FDA-approved agents for the treatment of ADHD, and numerous antidepressants had been studied to establish efficacy.

Since the 1990s there has been a noticeable reduction in the use of TCAs in children.19 Issues related to sudden death and other potential cardiotoxic complications are probably responsible for this phenomenon. Predating this change, the tertiary amine TCAs, imipramine and amitriptyline, had been systematically studied. In a randomized 2week trial, Yepes and colleagues31 compared amitriptyline, methylphenidate, and placebo in 50 children diagnosed with hyperkinetic reaction of childhood. Amitriptyline was comparable to methylphenidate in terms of reducing hyperactivity and aggression. Rapoport and colleagues37 compared the efficacy of imipramine to methylphenidate in a double-blind, placebo-controlled study. The sample consisted of 76 hyperactive males. Both agents were superior to placebo. In another double-blind, placebo-controlled, crossover study with 30 hyperactive children, Werry and colleagues38 found that imipramine was superior to methylphenidate in its overall therapeutic effect.

The secondary amine TCAs, nortriptyline, and desipramine, also had well-designed studies examining their efficacy. Prince and colleagues41 conducted a two-phase, 9-week, study of 35 subjects diagnosed with ADHD. Twenty-five of the 29 responders of the first phase participated in the 3week double-blind discontinuation phase wherein they received either placebo or nortriptyline. At the end of the study those who were still on nortriptyline performed better on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD checklist. Biederman and colleagues39 studied the efficacy of desipramine in treating 62 children and adolescents diagnosed with attention deficit disorder (ADD). This was a randomized 6-week, double-blind, placebo-controlled, parallel-groups design study. Subjects treated with desipramine significantly improved on the Conners Abbreviated Parent and Teacher Questionnaires when compared to placebo, although this statistically significant improvement required 3–4 weeks of treatment.60

However, in another double-blind, placebo-controlled, crossover trial, desipramine was compared to methylphenidate and clomipramine in 12 males with ADD.40 Unlike the results of the trial conducted by Werry and colleagues,38  the patients  on methylphenidate had scores on the Conners Teacher’s Scale that were significantly better than those noted on the other two antidepressants.61

There have been at least four doubleblind studies of bupropion for this condition. Clay and colleagues32 studied 30 children with ADHD, who were enrolled in a placebo-controlled study. Optimal doses of bupropion ranged from 100–250 mg/day. Bupropion treatment was associated with significant improvement on the two subscales, improvement and severity, of the CGI scale.32 In two other doubleblind, placebo-controlled,  parallel-group design  studies of children with ADHD, both  Casat and colleagues33 and Conners and colleagues35 reported that  bupropion was associated with significant reductions in hyperactivity scores. In terms of onset of action, Conners and colleagues35 described improvements noted by teachers after the third day of treatment.

Barrickman and colleagues34 conducted a 16-week, double-blind, crossover study comparing bupropion to methylphenidate in 15 subjects with ADHD. Both treatments were associated with significant reductions in parent and teacher ratings, and there were no significant differences in efficacy between the two agents.

There are two compelling reasons why the use of nonselective MAOIs for the treatment of youths may not be recommended.62 The first reason is the lack of data from rigorously controlled trials. The second reason has to do with the dietary restrictions required for the safe administration of these agents, which may be especially difficult for some teenagers. Nevertheless, there is at least one study that compared the utility of dextroamphetamine versus placebo to that of either clorgyline (a selective MAOI-A), or tranylcypromine (a nonselective MAOI-A and B) versus placebo.36 A 12-week, double-blind, random order, crossover study was conducted in 14 males with ADHD 8–12 years of age. It was noted that both of these MAOIs had significant effects at the first time point of ratings (1 week). The degree of improvement between the MAOIs and dextroamphetamine were comparable in terms of ratings on the Conners Parent and Teacher scales.60

Major Depressive Disorder

Depression has long been considered one of the most pressing mental healthcare issues facing the US. The illness is characterized by the presence of sadness (and irritability in children), loss of interest in daily activities, decreased self worth, problems with sleep and appetite, and the development of suicidal ideations and/or behaviors. The point prevalence of depression in adults has been identified to occur in 5% to 9% of women and 2% to 3% of men; up to 15% of those with severe MDD may commit suicide.63 Although the average age of onset for MDD is in the mid twenties, the prevalence of depression in youth increases with age. The estimated prevalence in preschoolers is 0.8%, which increases to 2% during the latency years and reaches 4.5% in adolescents.7 According to the US Department of Health and Human Services, in 2002 there were >72 million individuals >18 years of age.64 This translates to well over 1 million youths suffering from MDD.

Given the magnitude of the problem and the established effectiveness of antidepressants in treating MDD in adults, it is striking that there are relatively few well-controlled studies that corroborate antidepressant utility in children and adolescents. Preskorn and colleagues,42 in a report that included three studies, described a double-blind, placebo-controlled, randomized trial of 22 depressed subjects 6–12 years of age. There was a 4–7 day placebo baseline assessment period followed by a 2-week initial treatment period where doses were adjusted. This was followed by another 4-week study period. Doses of imipramine were titrated at 25–150 mg/ day in order to achieve plasma levels in the range of 125–250 ng/mL for imipramine and its metabolite, desipramine. The authors described that the children on imipramine did statistically better than those on placebo as measured on the Children’s Depressive Rating ScaleRevised,16 and the CGI56 but not on the Children’s Depression Inventory.65 It was noted that these changes could be evidenced  within  3 weeks.

In the first study to identify superiority of an SSRI over placebo in youths with MDD, Emslie and colleagues44 reported on an 8-week, randomized, double-blind, placebo-controlled study of 96 children and adolescents diagnosed with MDD. There was a 1-week, single-blind, placebo lead-in period. Fluoxetine was dosed at 20 mg/day. Fluoxetine was statistically superior to placebo on the CGI56 scale, with 56% of the fluoxetine group rated as much or very much improved as compared to 33% of the placebo group.

In another report, Wagner and colleagues45 chronicled a pooled data analysis of two 10-week multi-site, randomized, double-blind, placebocontrolled, parallel-group design studies of sertraline in 376 children and adolescents with depression. Dosages of sertraline ranged from 50–200 mg/day. The sertraline group demonstrated significantly greater improvement on the primary efficacy variable (Children’s Depression Rating Scalerevised16) than the placebo group over the course of the study. In this study there were no significant differences in rates of suicidal ideation between the sertraline and placebo groups.

In a multi-site study that looked at another SSRI, paroxetine, Keller and colleagues43 recruited 275 adolescents who met criteria for MDD. Subjects were randomized to 8 weeks of doubleblind paroxetine (20–40 mg/day), imipramine (up to daily doses of 200–300 mg), or placebo. Only subjects on paroxetine demonstrated significantly greater improvement when compared to placebo on the Hamilton Rating Scale for Depression55 total score and CGI56 scores of 1 or 2. Of concern was that patients receiving paroxetine and imipramine did not do significantly better than those on placebo on any of the parent- or selfrating measures.  Another limitation of this study was that although mention was made about the development of suicidal ideation/gestures, the specific frequencies for this particular problem across the three-study treatment arms were not clearly reported.

Obsessive-Compulsive Disorder

The prevalence of OCD in the pediatric age group may be as high as 3%.49 Patients with OCD frequently present with recurrent thoughts and behaviors which are intended to reduce distress. The need for rapid identification and treatment must be underscored, as prolonged duration of OCD symptoms is reported to be associated with functional impairment and increased morbidity.66 In adults, the SSRIs are considered the first line of treatment. In the pediatric age group, antidepressants have the most studies substantiating their efficacy in OCD compared to other psychiatric disorders. In fact, as previously mentioned, four different agents have FDA approval for this indication (Table 1) and there is a positive double-blind, placebo-controlled trial substantiating the efficacy of paroxetine as well. In that study, Geller and colleagues49 randomized 207 subjects between 7 and 17 years of age, giving them paroxetine (10–50 mg/day) or placebo for 10 weeks. Paroxetine significantly outperformed placebo on the Children’s Yale-Brown Obsessive-Compulsive Scale.67

Posttraumatic Stress Disorder

By definition, posttraumatic stress disorder (PTSD) requires exposure to a serious event, which must be outside the range of normal human experience. In children, the exposure to high index stressors increases the risk for developing PTSD, and repeated exposure to these stressors further increases the risk of PTSD.68,69 The clinical presentation includes the development of features such as re-experiencing, avoidance, and hyperarousal. In children, reports of these phenomena date back to the 1930s.70 A variety of serious stressors have been linked to the development of PTSD, including sequestration, crime, and burns. Fitzpatrick and Boldizar71 and Silva and colleagues72 have reported that 59% to 70% of youth in their inner city samples were exposed to at least one of the serious stressors described in the DSM. Rates of youth who go on to develop full PTSD criteria after experiencing such a stressor vary from 22% to 27%.71,72 In children, although CBT is the most effective empirically based treatment for this disorder, many physicians use psychopharmacologic agents as adjuncts.73 The only doubleblind trial in children published to date employed an antidepressant. Robert and colleagues51 conducted a randomized, double-blind study, comparing imipramine to chloral hydrate on 25 survivors (2–19 years of age) of burn wounds who developed symptoms consistent with acute PTSD (ASD). ASD symptoms are similar to PTSD symptoms and include anxiety, nightmares, agitation, and sometimes depression but last for ≤4 weeks.74 In this study, patients received up to 100 mg/day of imipramine or a maximum of 500 mg/ day of chloral hydrate at night. Results indicated an 83% response rate to imipramine as compared to a 38% response to chloral hydrate. 

Selective Mutism

Dummit and colleagues75 assert that historically selective mutism has been associated with pathological shyness, anxiety, oppositionality, and language dysfunction. In actuality, these patients seem to have normal language skills, with the exception that a small percentage of patients display delayed language development and difficulties with articulation. It has been observed that the disorder begins during the preschool years. In the DSM-IV the name was changed from “elective mutism” to “selective mutism” to highlight that this condition usually represents an abnormal behavior which is selectively dependent on social context, rather than a volitional choice to remain silent. Only two double-blind trials document the effectiveness of any pharmacologic agent on this disorder. In the first, Black and Uhde52 conducted a 12-week study comparing fluoxetine to placebo in 15 subjects who had been nonresponders to placebo during a 2week single-blind period. During the ensuing 10-week double-blind period, significant improvements were noted on ratings of elective mutism, anxiety, and social anxiety, as rated by clinicians, parents, and teachers, in both fluoxetineand placebo-treated subjects. Those subjects treated with fluoxetine were rated by parents as having improved significantly more than the placebo-treated groups. However, these differences were not noted by teachers. In another study, Carlson and colleagues53 treated five outpatients with selective mutism in a 16week, double-blind trial of sertraline versus placebo. There were four randomly ordered treatment phases. In four of five outpatients, improvement was noted in each of their speaking within a few days of starting sertraline. Two of the five subjects began speaking in school, and within 10 weeks these subjects no longer met criteria for the disorder.

Special Considerations

It is evident that the number of studies on antidepressant use in children and adolescents are increasing. When possible, clinicians should be guided in their treatment selection by evidencebased practices. This article provides physicians with the rationale and evidence to inform the selection of antidepressants for different disease states.

In practice, some practitioners  use other agents in addition to the antidepressants.3 This may ultimately increase the risk of drug interactions.  Much insight has been gained into drug interactions by our understanding of the cytochrome P450 (CYP) system. The CYP system is a family of proteins located primarily in the liver. This system is responsible for metabolizing drugs so they can be excreted. The first step of the process is oxidative metabolism, while phase two is one of conjugation  through the  transferase enzyme systems.76 The nomenclature of the CYP system is followed by a number which identifies the family, then a letter which represents the subfamily, and finally another number which refers to the specific isoenzyme. Many of the antidepressants serve as substrates for these cytochromes to work on and are also inhibitors of various CYP systems (Table 2).  In the latter case, when these antidepressants are added to another drug that is metabolized by the specific cytochrome system, blood levels of the other medication may increase.

Important examples of the effects of inhibition on medication groups include the Type 1C antiarrhythmics and antipsychotics which are metabolized by the CYP 2D6 isoenzymes, or the benzodiazepines which are metabolized by the CYP 2C family.

To date, antidepressants are not considered inducers of any of the cyto-chrome systems that affect drug degradation. Physicians should familiarize themselves with other medications that may  serve as inducers or inhibitors of different antidepressants which may ultimately lead to serious drug interactions.7,76 Another cautionary note should be made about the use of TCAs. Despite their demonstrated efficacy, especially in the realm of ADHD, there are a number of agents with safer side-effect profiles that are not quite as cardiotoxic. Because of the potential cardiac problems especially, these agents should not be considered firstline treatments in children or adolescents. Caution should be used whenever employing TCAs, and clinicians should adhere to monitoring parameters listed by the American Heart Association.24 Clinicians should be aware of the monitoring guidelines issued by the FDA in 2004 when prescribing any antidepressants to a child or adolescent.10 The physician should arrange for weekly visits during the first month of treatment. Thereafter, visits can be reduced to every 2 weeks between weeks 5 and 12 of treatment, unless more frequent visits are clinically indicated. Physicians should document the assessment of mood, suicidality, functional impairment, treatment response, and side effects. The minimum number of pills required prior to the next visit should be prescribed. There should be communication between sessions with the patient. Finally, guardians should also be aware of the potential for suicide and understand the need for close monitoring and supervision.

Conclusion

Antidepressants are primarily indicated for MDD and OCD, psychiatric conditions associated with significant morbidity and/or mortality. Although antidepressants have not been studied in the pediatric population as extensively as in adults, there are several randomized controlled trials demonstrating their efficacy in children and adolescents when dosed and monitored appropriately. The recent controversy regarding increased suicidal ideation and/or behavior during some of these trials has led to increased caution in the use of these agents.  However, physicians must educate their patients and the public about the significant short- and longterm risks of inadequately treating MDD and OCD, with their potentially devastating impact on a child’s development, education, and future adjustment.

Available evidence suggests that antidepressants should be used for the treatment of pediatric psychiatric disorders with appropriate psychoeducation, informed consent, and monitoring of response and side effects. These are prudent recommendations for the use of any medication in all age groups.  PP

References

1. Chiu S, Henrietta LL. Antidepressants I: Selective serotonin reuptake inhibitors. In: Martin A, Scahill L, Charney DS, Leckman JF, eds. Pediatric Psychopharmacology: Principles and Practice. New York, NY: Oxford University Press; 2002:274-283.

2. Schoonover SC. Depression. In:  Bassuk EL, Schoonover SC, Gelenberg AJ, eds.  The Practitioner’s Guide to Psychoactive Drugs. New York, NY: Plenum Publishing Corporation, 1983:19-77.

3. Safer DJ. Changing patterns of psychotropic medication prescribed by child psychiatrists in the 1990s. J Child Adolesc Psychopharmacol. 1997;7(4):267-274.

4. Walkup J, Ritter-Welzant J, Kastelic E, Joshi N, Frosch E. Antidepressants III: Other agents. In: Martin A, Scahill L, Charney DS, Leckman JF, eds. Pediatric Psychopharmacology: Principles and Practice. New York, NY: Oxford University Press; 2003:295-308.

5. Gundersen K, Geller B. Antidepressants II: Tricyclic agents. In: Martin A, Scahill L, Charney DS, Leckman JF, eds. Pediatric Psychopharmacology: Principles and Practice. New York, NY: Oxford University Press; 2003:284-294.

6. Sugrue MF. Chronic antidepressant therapy and associated changes in central monoaminergic receptor functioning. Pharmacol Ther. 1983;21(1):1-33.

7. Viesselman, JO. Antidepressant and antimanic drugs. In: Werry JS, Aman MG, eds. Practitioner’s Guide to Psychoactive Drugs for Children and Adolescents. New York, NY: Plenum Publishing Corporation; 1999:249-296.

8.  Zito JM, Safer DJ, DosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med. 2003;157(1):17-25.

9. Silva RR. Psychopharmacology News. J Child Adolesc Psychopharmacology. 2003;13:409-410. 10. Silva RR. Psychopharmacology News. J Child Adolesc Psychopharmacology. 2005;15(1):1-2.

11. Arias E, MacDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics 2002. Pediatrics. 2003;112(6 pt 1):1215-1230.

12. Gould MS, King R, Greenwald S, et al. Psychopathology associated with suicidal ideation and attempts among children and adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37(9):915-923.

13. Shaffer D, Gould MS, Fisher P, et al. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry. 1996;53(4):339-348.

14. Anderson RN. Deaths: leading causes for 2000. Natl Vital Stat Rep. 2002;50(16):1-85.

15. March J, Silva S, Petrycki S, et al; Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807-820.

16. Poznanski EO, Freeman LM, Mokros HB. Children’s Depression Rating Scale-Revised. Psychopharmacol Bull. 1985;21:979-989.

17. March JS; TADS Group. Authors of TADS study reply to letter raising concerns. BMJ. 2005;330(7493):730-731.

18. Reynolds WM. Professional Manual for the Suicidal Ideation Questionnaire. Odessa, FL: Psychological Assessment Resources Inc; 1987.

19. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry. 2003;60(10):978-982.

20. Leon AC, Marzuk PM, Tardiff K, Teres JJ. Paroxetine, other antidepressants, and youth suicide in New York City: 1993 through 1998. J Clin Psychiatry. 2004;65(7):915-918.

21. Gray D, Achilles J, Keller T, et al. Utah youth suicide study, phase I: government agency contact before death. J Am Acad Child  Adolesc Psychiatry. 2002;41(4):427-434.

22. Green WH. Child and Adolescent Clinical Psychopharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:150-160.

23. Elliot GR, Popper CW. Tricyclic antidepressants: the QT interval and other cardiovascular parameters [editorial]. J Child Adolesc Psychopharmacol. 1990/1991;1:187-189.

24. Gutgesell H, Atkins D, Barst R, et al. AHA Scientific Statement: cardiovascular monitoring of children and adolescents receiving psychotropic drugs. J Am Acad Child Adolesc Psychiatry. 1999;38(8):1047-1050.

25. Wilens TE, Biederman J, Baldessarini RJ, Puopolo PR, Flood JG. Developmental changes in serum concentrations of desipramine and 2-hydroxydesipramine during treatment with desipramine. J Am Acad Child Adolesc Psychiatry. 1992;31(4):691-698.

26. Walsh BT, Giardina E-GV, Sloan RP, Greenhill L, Goldfein J. Effects of desipramine on autonomic control of the heart. J Am Acad Child Adolesc Psychiatry. 1994;33(2):191-197.

27. Biederman J. Thisted RA. Greenhill LL, Ryan ND. Estimation of the association between desipramine and the risk for sudden death in 5- to 14-year-old children. J Clin Psychiatry. 1995;56(3):87-93.

28. American Academy of Child and Adolescent Psychiatry. Desipramine and sudden death. Topic presented at an ad hoc committee at the American Academy of Psychiatry Meeting in Washington, DC; 1992.

29. Walkup JT, Labellarte MJ, Riddle MA, et al. Fluvoxamine for the treatment of anxiety disorder in children and adolescents. N Engl J Med. 2001;344(17):1279-1285.

30. Rynn MA, Siqueland L, Rickels K. Placebocontrolled trial of sertraline in the treatment of children with generalized anxiety disorder. Am J Psychiatry. 2001;158(12):2008-2014.

31. Yepes LE, Balka EB, Winsberg BG, Bialer I. Amitriptyline and methylphenidate treatment of behaviorally disorders children. J Child Psychol Psychiatry. 1977;18(1):39-52.

32. Clay TH, Gualtieri CT, Evans RW, Gullion CM. Clinical and neuropsychological effects of the novel antidepressant bupropion. Psychopharmacol Bull. 1988;24(1):143-148.

33. Casat CD, Pleasants DZ, Schroeder DH, Parler DW. Bupropion in children with attention deficit disorder. Psychopharmacol Bull. 1989;25(2):198-201.

34. Barrickman LL, Perry PJ, Allen AJ, et al. Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995;34(5):649-657.

35. Conners CK, Casat CD, Gualtieri CT, et al. Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry. 1996;35(10):1314-1321.

36. Zametkin A, Rapoport JL, Murphy DL, Linnoila M, Ismond D. Treatment of hyperactive children with monoamine oxidase inhibitors. I. Clinical efficacy. Arch Gen Psychiatry. 1985;42(10):962-966.

37. Rapoport JL, Quinn PO, Bradbard G, Riddle D, Brooks E. Imipramine and methylphenidate treatment of hyperactive boys. A double-blind comparison. Arch Gen Psychiatry. 1974;30(6):789-793.

38. Werry JS, Aman MG, Diamond E. Imipramine and methylphenidate in hyperactive children. J Child Psychol Psychiatry. 1980;21(1):27-35.

39. Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS. A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy. J Am Acad Child Adolesc Psychiatry. 1989;28(5):777-784.

40. Garfinkel BD, Wender PH, Sloman L, O’Neill I. Tricyclic antidepressant and methylphenidate treatment of attention deficit disorder in children. J Am Acad Child Adolesc Psychiatry. 1983;22(4):343-348.

41. Prince JB, Wilens TE, Biederman J, et al. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2000;10(3):193-204.

42. Preskorn SH, Weller EB, Hughes CW, Weller RA, Bolte K. Depression in prepubertal children: dexamethasone nonsuppression predicts differential response to imipramine vs. placebo. Psychopharmacol Bull. 1987;23(1):128-133.

43. Keller MB. Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2001;40(7):762-772.

44. Emslie GJ, Rush AJ, Weinberg WA, et al. double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry. 1997;54(11):1031-1037.

45. Wagner KD, Ambrosini P, Rynn M, et al. Sertraline Pediatric Depression Study Group. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA. 2003; 290(8):1033-1041.

46. Leonard HL, Swedo SE, Rapoport JL, et al. Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents: a double-blind crossover comparison. Arch Gen Psychiatry. 1989;46(12):1088-1092.

47. Physician’s Desk Reference. 58th ed. Montvale, NJ: Thomson PDR; 2004.

48. Riddle MA, Scahill L, King RA, et al. Doubleblind, crossover trial of fluoxetine and placebo in children and adolescents with obsessivecompulsive disorder. J Am Acad Child Adolesc Psychiatry. 1992;31(6):1062-1069.

49. Geller DA, Wagner KD, Emslie G, et al. Paroxetine treatment in children and adolescents with obsessive-compulsive disorder: a randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2004;43(11):1387-1396.

50. March JS, Biederman J, Wolkow R, et al. Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA. 1998;280(20):1752-1756.

51. Robert R, Blakeney P, Villareal C, Rosenberg L, Meyer WJ 3rd. Imipramine treatment in pediatric burn patients with symptoms of acute stress disorder; A pilot study. J Am Acad Child Adolesc Psychiatry. 1999;38(7):873-882.

52. Black BN, Uhde TW. Treatment of elective mutism with fluoxetine: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1994;33(7):1000-1006.

53. Carlson JS, Kratochwill TR, Johnston HF. Sertraline treatment of 5 children diagnosed with selective mutism: a single-case research trial. J Child Adolesc Psychopharmacol. 1999;9(4):293-306.

54. Kashani JH, Orvaschel H. Anxiety disorders in mid-adolescence: a community sample. Am J Psychiatry. 1988;145(8):960-964.

55. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

56. Guyu W. Clinical Global Impressions Scale. ECDEU Assessment Manual for Psychopharmacology. Washington, DC: US Department of Health, Education and Welfare Publication (ADM): 76-338. National Institute of Mental Health; 1976:218-222.

57. Liu F, Muniz R, Minami H, Silva RR. Review and comparison of the long acting methylphenidate preparations. Psychiatr Q. 2005;76(3):259-269.

58. Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M. Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry. 1998;155(4):493-498.

59. Bradley C. The behavior of children receiving benzedrine. Am J Psychiatry. 1937;94:577-585.

60. Goyette CH, Conners CK, Ulrich RF. Normative data on revised Conners Parent and Teacher Rating Scales. J Abnorm Child Psychol. 1978;6(2):221-236.

61. Conners CK, Barkley RA. Rating scales and checklists for child psychopharmacology. Psychopharmacol Bull. 1985;21(4):809-843.

62. Findling RL, Feeny NC, Stansbrey RJ, DelPorto-Bedoya D, Demeter C. Somatic treatment for depressive illnesses in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2002;11(3):555-78.

63. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. text rev. Washington, DC: American Psychiatric Association; 2000.

64. DHHS. Maltreatment. Washington, DC: Department of Health and Human Service; 2002.

65. Kovacs M. Children’s Depression Inventory manual. North Tonawanda, NY: Multi-Health Systems; 1992.

66. Hanna GL. Demographic and clinical features of obsessive-compulsive disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1995;34(1):19-27.

67. Scahill L, Riddle MA, McSwiggin-Hardin M et al. Children’s Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997:36(6):844-852.

68. March J. What constitutes a stressor? The “criterion A” issue. In: Davidson JRT, Foa EB, eds. Posttraumatic Stress Disorder: DSMIV and Beyond. Washington, DC: American Psychiatric Press, Inc; 1992.

69. Kilpatrick DG, Resnick HS, Saunders BE, Best CL. Rape, other violence against women and posttraumatic stress disorder: Critical issues in assessing the adversity-stress-psychopathology relationship. In: Dohrenwend BP ed. Adversity, Stress, and Psychopathology. New York, NY: Oxford University Press; 1998:161-176.

70. Bender L, Blau A. The reaction of children to sexual relations with adults. Am J Orthopsychiatry. 1937;7:500-518.

71. Fitzpatrick KM, Boldizar JP. The prevalence and consequences of exposure to violence among African-American Youth. J Am Acad Child Adolesc Psychiatry. 1992;32(2):424-430.

72. Silva RR, Alpert M, Munoz DM, Kim JI, Matzner F, Dummit S. Stress and vulnerability to posttraumatic stress disorder in children and adolescents. Am J Psychiatry. 2000;157(8):1229-1235.

73. Silva, RR, Cloitre M, Davis L, et al. Early intervention with traumatized children. Psychiatr Q. 2003;74(4):333-337.

74. Sadock BJ, Sadock VA. Kaplan and Sadock’s Concise Textbook of Clinical Psychiatry. 2nd ed. New York, NY: Lippincott Williams & Wilkins; 2003. 

75. Dummit ES 3rd, Klein RG, Tancer NK, Asche B, Martin J. Fluoxetine treatment of children with selective mutism: an open trial. J Am Acad Child Adolesc Psychiatry. 1996;35(5):615-621.

76. Flockhart DA, Oesterheld JR. Cytochrome P450-mediated drug interactions. Child Adolesc Psychiatr Clin N Am. 2000;9(1):43-76.


Dr. Silva is associate professor of psychiatry, Dr. Gabbay and Dr. Alonso are assistant professors of psychiatry, and Ms. Minami is a research assistant in the Department of Psychiatry at New York University School of Medicine, in New York City.

Dr. Munoz-Silva is in private practice in Tenafly, New Jersey.

Disclosure: Dr. Silva is a consultant to Novartis; is on the speakers bureaus of AstraZeneca, Novartis, and Ortho-McNeil; and receives grant support from the New York City Department of Mental Health, the New York State Office of Mental Health, the Red Cross, the Research Foundation for Mental Hygiene, and Substance Abuse and Mental Health Services Administration. Dr. Gabbay is funded by the American Foundation for Suicide Prevention and the Tourette Syndrome Association. Ms. Minami and Dr. Munoz-Silva report no affiliations with or financial interest in any organization that may pose a conflict of interest. Dr. Alonso is funded by the American Foundation for Suicide Prevention and the Tourette Syndrome Association.

Please direct all correspondence to: Raul R. Silva, MD, NYU School of Medicine, Department of Psychiatry, 550 First Ave, NB21S6, New York, NY 10016;  Tel: 212-263-6602; Fax: 212-263-0202; E-mail: raul.silva@med.nyu.edu.


Journal CMEs

Print Friendly 

Structural and Functional
Neuroimaging of Pediatric Depression

Vilma Gabbay, MD, Raul R. Silva, MD, F. Xavier Castellanos, MD,
Beth Rabinovitz, BA, and Oded Gonen, PhD
Needs Assessment:
Neuroimaging technology has been increasingly used to investigate the underlying neurobiology of psychiatric disorders such as pediatric depression. As this field is rapidly progressing, it is difficult to stay abreast with new developments. Our goal is to provide clinicians with current knowledge regarding the structural and functional neuroimaging findings in pediatric depression. This information will allow medical professionals to view neuroimaging data critically and to understand methodological concerns in neuroimaging research involving pediatric depression.  

 Learning Objectives:
 •  Identify suitable neuroimaging methods for the study of major depressive disorder in the pediatric population.

 •  Critically evaluate studies of neuroimaging in pediatric depression.

 •  List major brain structures implicated in pediatric depression.

 •  Identify functional correlates of pediatric depression.

 Target Audience:
Primary care physicians and psychiatrists.

 Accreditation Statement:
Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

 Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

 It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

 To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: September 30, 2007. The estimated time to complete all three articles and the quiz is 3 hours.

Abstract

Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidity and mortality. Newly available noninvasive neuroimaging techniques provide unique opportunities to illuminate the underlying neurobiological factors of MDD. This article reviews structural and functional neuroimaging data in pediatric MDD. In general, neuroimaging studies in pediatric MDD tend to confirm findings in adult depression implicating the prefrontal cortex, amygdala, and hippocampus. These brain regions are linked and believed to be critical in modulating emotional responses. However, neuroimaging research in pediatric MDD is still in its infancy, and inconsistencies are rife. These inconsistencies are largely due to the small samples and lack of agreement regarding methodology in ascertainment as well as in imaging. Greater focus on careful delineation of clinically and neurobiologically defined subgroups will likely lead to improved understanding of the pathophysiology of MDD.

Introduction

Major depressive disorder (MDD), a serious public health concern, affects both pediatric and adult populations. This common psychiatric ailment has an estimated lifetime prevalence of approximately 15% for adolescents 15–18 years of age.1 Pediatric MDD has serious consequences, including social and academic impairment. Most critically, attempted and completed suicides are the third leading cause of death among youths 15–19 years of age.2-7 Pediatric MDD is also a strong predictor of MDD in adulthood, which carries its own burden of disadvantage.8,9 The importance of specific neurobiological research in pediatric MDD has been increasingly recognized over the past decade. Neuroimaging technology has provided unique tools for direct structural and functional imaging of the working human brain. In adult MDD, neuroimaging research has implicated specific brain regions, including the anterior cingulate cortex, orbital cortex, basal ganglia, amygdala, and hippocampus, as well as disturbances in pathways linking cortical, subcortical, and limbic sites.10

Safety concerns regarding radiation exposure have limited the use of neuroimaging techniques such as computerized tomography (CT), positron emission tomography (PET), or singlephoton emission computed tomography (SPECT) in pediatric populations. Fortunately, noninvasive imaging techniques such as structural magnetic resonance imaging (MRI), functional MRI (fMRI), proton magnetic resonance spectroscopy (1H-MRS), and diffusion tensor imaging (DTI) do not involve radiation exposure, nor do they require injections, thus alleviating safety concerns.

Neuroimaging research in pediatric MDD is still in its initial stages, and inconsistencies among different research groups are not uncommon. However, the field is rapidly progressing and has the potential to contribute to our understanding of the underlying pathophysiological processes of pediatric MDD. This type of research could potentially foster preventive therapeutic options and contribute to the identification of at risk individuals. This article reviews structural and functional neuroimaging data in pediatric MDD.

Critical Assessment of Neuroimaging Findings

Despite commendable advances in pediatric neuroimaging research, particularly in the past decade, several limitations require mention. First, small sample sizes are still the rule, and these yield insufficient statistical power. Second, comparison of results across studies is constrained by variability in subject selection. This is especially problematic in a heterogeneous clinical syndrome such as pediatric MDD that most likely reflects a common final clinical pathway of multiple etiologies.11 For example, limiting adult MDD samples to patients with familial MDD yields relatively more informative neuroimaging findings in specific brain regions.10,12 In addition, because pediatric MDD is associated with significant morbidity and mortality, recruiting medication-naïve patients in North America has become more challenging. Studies often include children and adolescents who are currently taking antidepressants, who have been exposed previously to medications, and who have never been medicated. This may further complicate comparisons across studies. Finally, the field has not yet adopted standard quantitative analytical methods that allow direct comparisons across studies. Current methods include handtracing of individual regions of interest, fully automated methods, and semiautomated methods. Fully automated methods maximize test-retest reliability but are best applied to large well-defined brain regions. Semi-automated methods combine the strengths and weaknesses of the other two alternatives.

Neuroanatomical Correlates of Pediatric Major Depressive Disorder

Structural MRI allows the assessment of neuromorphology and neuromorphometry in pediatric MDD. Most structural MRI studies in pediatric MDD have focused on the frontal cortex, the hippocampus, and the amygdala. The corpus callosum, the pituitary gland, and white matter abnormalities have also been examined. These findings are discussed in turn.

Frontal Cortex

Anatomic hypotheses of the substrates of MDD have generally focused on the role of the frontal brain, particularly on the prefrontal cortex (PFC) (Figure 1A). Evidence based on animal and adult studies suggests that the PFC acts  as the executive branch of emotions.13,14 Neuroimaging studies have confirmed the role of the frontal lobe/PFC in adult MDD.10


There are several structural studies of frontal cortex in pediatric MDD (Table 1).15-18 In a retrospective chart review study, structural MRI images of 65 hospitalized children and adolescents with depressive disorders (56 with MDD, 9 with dysthymia) were compared to 18 non-depressed psychiatric controls.15

Psychiatric diagnoses among the controls included conduct/oppositional defiant disorder (n=11), attention-deficit/ hyperactivity disorder (n=2), posttrau matic stress disorder (PTSD; n=3), and adjustment disorder (n=2). As the original digital MRI data were not available for analysis, results are based on redigitization of brain images from films. The researchers discovered decreased frontal lobe/cerebral volume ratios and increased lateral ventricle/cerebral volume ratios in the hospitalized pediatric MDD group compared to psychiatric controls. These results should be viewed with caution in light of several design limitations, including the lack of structured diagnostic measures, the lack of a healthy control group, and an inherently less sensitive method of image analysis. In addition, medication history, which may affect imaging findings, was not documented.

A later study by the same group supported the involvement of the frontal lobe in pediatric MDD16 by examining frontal lobe morphometry in adolescents with MDD (n=19) versus healthy comparisons (n=38). Three MDD subjects were treated in the past with antidepressants, but were antidepressant free for at least 3 months at the time of the scan. The authors found significantly smaller whole brain volumes in the pediatric MDD group, as well as significantly smaller frontal white matter, compared to the healthy comparison group. It is noteworthy that 73% of MDD subjects and 16% of the controls had a first-degree relative with a mood disorder. However, an effect for familial loading was not found.

Nolan and colleagues17 focused on the PFC in 22 psychotropic-naïve children and adolescents 9–17 years of age with MDD, and 22 healthy comparisons. Twelve MDD subjects had familial MDD (with at least one first-degree relative with MDD), but none had a familial history of bipolar disorder. While the intracranial PFC volumes did not significantly differ between the MDD and control groups, the nonfamilial MDD subjects were found to have larger leftsided total PFC volumes and larger prefrontal white matter, compared to familial MDD subjects and healthy comparisons. Familial MDD subjects were found to have smaller left-sided gray matter volumes compared to subjects with nonfamilial MDD. These findings are intriguing in light of similar findings in adult MDD in which striking reductions in mean gray matter volumes of the subgenual PFC (sgPFC; located ventral to the genu of the corpus callosum, Figure 1A) were demonstrated only in familial MDD12 and in familial bipolar disorder.19 These gray-matter reductions were attributed to reduced glial cell density in the sgPFC in postmortem study.20

Botteron and colleagues18 examined sgPFC volumes in thirty young women (17–23 years of age) with adolescent onset MDD compared to eight matched controls. Females with adolescent onset MDD compared to normal controls had reduced left sgPFC volumes.

These studies support the view that regions of the frontal cortex play a role in the pathophysiological mechanisms underlying adult and pediatric MDD.

Amygdala and Hippocampus

The temporo-limbic structures comprising the amygdala and hippocampus (Figures 1B and 1C) are also critical in emotional regulation processes.13,21 Excitatory projections enable the amygdala to directly activate the PFC. Current evidence suggests that the amygdala is critical in the reception and production of emotional responses and in the establishment of conditioned fear.14

The amygdala and hippocampus have been the focus of many structural and functional imaging studies in adult MDD. Several structural studies have examined these brain regions in pediatric MDD (Table 2).2224 MacMillan and colleagues22 examined the amygdala and hippocampus volumes in antidepressant-naïve MDD children and adolescents (n=23; 8–17 years of age) and case-matched healthy comparisons (n=23). No significant group differences in amygdala and hippocampus volumes were found. However, significantly larger left (14%; P=.004) and right (11%; P=.026) amygdala:hippocampal volume ratios were found in the MDD group compared to control.22


In a later study focusing only on hippocampal volumes in adolescents with MDD (n=17, ages=13–18) and matched comparisons (n=17), relatively smaller hippocampus volumes were found in the MDD group.23 This difference was more significant in the left hippocampus (17%; P=.001) compared to the right hippocampus (P=.047). Two MDD subjects had comorbid substance abuse disorder and three were on antidepressants. Small left hippocampal volumes were confirmed when analyses were repeated using only the medication-naïve subjects (n=14). In addition, duration of MDD episode was found to be correlated with left hippocampal volume.23

In a recent study, Rosso and colleagues24 examined amygdala and hippocampal volumes in children and adolescents (n=20) with MDD and in healthy controls (n=24). They reported decreased amygdala volumes in the MDD group compared to controls. No significant difference in hippocampal volumes was found between the two cohorts. In a study of children and adolescents with PTSD, of whom half had MDD, no hippocampal volumes reductions were found either.25 In adult MDD, smaller hippocampal volumes have been reported in some but not all studies. In two adult studies, hippocampal atrophy was found to be correlated with the duration of MDD, suggesting that these changes are secondary to recurrence or chronicity of the illness.26,27 Conflicting results may also be related to difficulties in determining the precise boundaries of these structures, spatial resolution limits, and sample differences (ie, age, comorbid disorder, medication history).  

Corpus Callosum

Lyoo and colleagues28 examined corpus callosum (Figure 1A) structure in females with early onset minor depression (n=40; 18–25 years of age) and in healthy comparisons (n=42). The authors found that the genu of the corpus callosum in the depression group was significantly smaller compared to the healthy controls. The corpus callosum was also found to be smaller in offspring of mothers with a history of MDD.29 If confirmed, this finding may represent a developmental marker of premorbid risk for MDD.

Pituitary Gland

The role of the pituitary gland in MDD has been inferred from evidence of abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis in individuals with MDD. MacMaster and Kusamaker30 measured pituitary volumes in adolescents with MDD (n=17, 14–17 years of age), and age- and sex-matched controls (n=17). Larger pituitary volumes were found in the MDD group (P=.02) even when MDD subjects treated with medications were excluded.

White-Matter Hyperintensities

White matter signal hyperintensities (WMH), detected by T2-weighted clinical MRI, reflect brain regions with increased water density. The clinical importance of these white-matter lesions has not been determined. Neuroimaging studies have examined the prevalence of WMH in adults with several psychiatric disorders. There are also two studies that were conducted in children and adolescents with MDD. Lyoo and colleagues examined WMH in children and adolescents admitted to inpatient psychiatric units compared with nonpsychiatric patients. The pediatric MDD group (n=94, 7–17 years of age) was found to have significantly greater numbers of WMH compared to subjects without a psychiatric diagnosis (n=83).30 WMH were mainly located in frontal lobes. As noted, small whitematter volumes were also found in adolescents with MDD.16 The same group conducted a retrospective study in which prevalence and severity of WMH were compared to history of suicidal attempts among  inpatients with a variety of psychiatric disorders for whom an MRI scan had been performed as part of the medical work-up.32 WMH were found to be associated with a history of suicide attempts only in the pediatric MDD group (n=48, 12–17 years of age). These findings are interesting in light of decreased oligodendrocyte density found in the amygdala of patients with MDD. Oligodendrocytes play the key role in myelination. Although there is no clear evidence of a myelin disorder in mood disorders, myelin basic protein is decreased in PFC in adults with MDD and schizophrenia.33

Functional Neuroimaging Studies in Pediatric Major Depressive Disorder

Functional neuroimaging techniques such as PET and SPECT, which provide information on brain function in specific brain regions, are widely used in adult populations. These techniques allow the measurement of neurotrans mitters, specific brain receptors, as well as blood flow and perfusion. The use of these technologies has been limited in pediatric MDD due to safety and ethical concerns (ie, even minimal radiation exposure and the requirement to inject radioactive isotopes). We know of only two studies that have used SPECT in pediatric MDD. Tutus and colleagues34 examined medication-free adolescents with MDD (n=13; 11–15 years of age) and comparisons (n=11; 12–15 years of age) using SPECT. The authors found reduced perfusion in the left anterolateral and left temporal cortical areas in the MDD group compared to controls. These abnormalities were not found in follow-up scans after depressive symptoms had subsided, suggesting that abnormalities may be a state-related marker for this disorder.34 Another small study conducted by Kowatch and colleagues,35 using SPECT (seven subjects per group), found regional hyperperfusion in the right mesial temporal lobe, and hypoperfusion in the parietal lobe, thalamus, and caudate. Above all, the authors emphasized the need for replication with larger samples prior to reaching firm conclusions. However, such larger samples are unlikely, particularly in the United States. Instead, the noninvasive neuroimaging techniques fMRI and 1H-MRS have been used in pediatric MDD.

Functional Magnetic Resonance in Pediatric Major Depressive Disorder

fMRI allows for the identification of specific brain regions which are activated during the performance of various cognitive tasks by the subtle change in their hemodynamics. Investigating pediatric MDD, Thomas and colleagues36 examined amygdala activity in five girls with MDD (8–16 years of age), five girls with anxiety disorders, and five healthy comparison girls matched for age. Two of the MDD girls had a comorbid disorder of generalized anxiety disorder. Girls with MDD were found to have reduced amygdala activation when processing fearful or neutral faces compared with the anxious and healthy comparison girls, suggesting amygdala involvement in pediatric MDD. This small but pioneering study is consistent with structural data implicating the amygdala in pediatric MDD, but clearly calls for more and larger studies.

Proton Magnetic Resonance Spectroscopy in Pediatric Major Depressive Disorder

Regional reductions in numbers of glia and neurons, increased WMH, and abnormalities of cerebral blood flow and metabolism have been well documented in MDD. These findings suggest that impaired cellular resilience may underlie MDD.10,12,37 1HMRS allows the in vivo non-invasive assessment of a variety of neurochemicals which reflect neuronal and glia integrity (Figure 2). These qualities make 1H-MRS ideally suited for use in pediatric MDD since it allows the early detection of neurochemical alterations and may contribute to the identification of at risk individuals. Among the metabolites that 1H-MRS quantifies are choline (Cho, reflects membrane lipid breakdown), N-acetylaspartate (NAA, associated with neuronal integrity and viability), creatine (Cr, may indicate abnormal energy metabolism and decreased overall cell density), γ-aminobutyric acid (GABA), and glutamine. There are discrepancies among 1 H-MRS studies of MDD as to whether absolute metabolite levels and/or ratios are higher or lower in pediatric and adult MDD. Conflicting results have been attributed to methodological differences in imaging technique (single voxel versus multivoxel; voxel size), medication history at time of scan, and the heterogeneous nature of MDD samples.

The few 1H-MRS studies on pediatric MDD in the current literature are in general agreement with structural neuroimaging studies, suggesting the role of PFC38-42 and the amygdala42 in pediatric MDD (Table 3).38,39,41-45

The Frontal Lobe in Proton Magnetic Resonance Spectroscopy Studies of Pediatric Major Depressive Disorder

Steingard and colleagues38 examined the orbitofrontal cortex in adolescents with MDD (n=17) and healthy comparisons (n=28). Four MDD subjects were treated with medication at the time of the scan. Significantly higher ratios of Cho/Cr (P=.032) and Cho/ NAA (P=.04) in the left orbitofrontal cortex were found in adolescents with MDD compared to healthy comparisons. Farchione and colleagues39 examined the dorsolateral PFC (DLPFC) in children and adolescents with MDD (n=11, 10–16 years of age) and matched healthy comparisons (n=11). All MDD subjects were psychotropic naïve. Higher absolute Cho levels were found in the left DLPFC in the MDD group compared to healthy comparisons. These findings contrast a recently published study in which Cho was lower in the left DLPFC in children and adolescents with MDD (n=14, 9–17 years of age, including six treated with psychotropic medications at the time of the scan), when compared to healthy controls (n=22, 8–17 years of age).42 1H-MRS can quantify GABA and glutamine, amino acids which have been increasingly implicated in MDD. 1H-MRS provides only limited ability to assign unequivocal resonance peaks to these amino acids. The fitted combination of glutamine, glutamate, GABA, and homocarnosine are often referred to as Glx. Two 1 H-MRS studies from the same group examined Glx levels in the anterior cingulate cortex in pediatric MDD and controls.41,43 Both studies found decreased Glx levels in the anterior cingulate in the pediatric MDD group compared to healthy comparisons.

The Amygdala in Proton Magnetic Resonance Spectroscopy Studies of Pediatric MDD

Kusumakar and colleagues44 examined the neurochemistry of the amygdala in adolescents with MDD (n=11, 14–18 years of age), and in age and sex matched comparisons (n=11). Significantly decreased Cho/Cr ratios were found in the MDD group in the left amygdala region.

The Thalamus in Proton Magnetic Resonance Spectroscopy Studies of Pediatric Major Depressive Disorder

Smith and colleagues45 compared thalamic Cho levels in psychotropicnaïve children and adolescents with MDD (n=18, 9–17 years of age) and 18 matched comparisons. No differences were reported between the two groups.

Diffusion Tensor Imaging

DTI is a recently developed MRI method that measures the directionality of self-diffusion of water molecules. DTI allows the quantification of correlates of myelination (ie, white matter), one of the key components of neuronal maturation which continues through adolescence and which may be impaired and/or delayed in pediatric MDD. This possibility is especially relevant in light of structural neuroimaging studies which found white matter abnormalities in pediatric MDD.

Conclusion

Consistent with neuroimaging research in adult MDD, the current structural and functional neuroimaging literature implicates several key brain structures involved in pediatric MDD, including the prefrontal cortex, amygdala, and the hippocampus. There has been almost a complete lack of neuroimaging research that examines the basal ganglia in pediatric MDD, a brain region which is suggested to play a possible role in adult MDD. Methodological inconsistencies and low statistical power limit current neuroimaging findings. Extrapolating from the adult literature, future studies should strive to focus on specific clinical subgroups. Inclusion criteria such as familial MDD, psychotropic-naïve status, and specific age of onset (adolescent onset versus childhood onset) may improve the detection of neurobiological findings by decreasing phenotypic heterogeneity.10,46  Such refinements in study design should improve the yield of the powerful noninvasive functional neuroimaging technologies such as fMRI, MRS, and DTI, that can now be applied to pediatric MDD. PP

References

1. Kessler RC, Walters EE. Epidemiology of DSMIII-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety. 1998;7(1):3-14. 

2. Kutcher SP, Marton P. Parameters of adolescent depression. A review. Psychiatr Clin North Am. 1989;12(4):895-918.

3. Fleming JE, Offord DR. Epidemiology of childhood depressive disorders: a critical review. J Am Acad Child Adolesc Psychiatry. 1990;29(4):571-580.

4. Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA. 1999;281(18):1707-1713.

5. Lewinsohn PM, Hops H, Roberts RE, Seeley JR, Andrews JA. Adolescent psychopathology: I. Prevalence and incidence of depression and other DSM-III-R disorders in high school students. J Abnorm Psychol. 1993;102(1):133-144.

6. Rao U, Weissman MM, Martin JA, Hammond RW. Childhood depression and risk of suicide: a preliminary report of a longitudinal study. J Am Acad Child Adolesc Psychiatry. 1993;32(1):21-27.

7. Ryan ND, Puig-Antich J, Ambrosini P, et al. The clinical picture of major depression in children and adolescents. Arch Gen Psychiatry. 1987;44(10):854-861.

8. Pine DS, Cohen P, Gurley D, Brook J, Ma Y. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry. 1998; 55(1):56-64.

9. Harrington R, Fudge H, Rutter M, Pickles A, Hill J. Adult outcomes of childhood and adolescent depression. I. Psychiatric status. Arch Gen Psychiatry. 1990;47(5):465-473.

10. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry. 2000;48(8):813-829.

11. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004;29(10):1765-1781.

12. Drevets WC, Price JL, Simpson JR Jr., et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386(6627):824-827.

13. Davidson RJ, Irwin W. The functional neuroanatomy of emotion and affective style. Trends Cogn Sci. 1999;3(1):11-21.

14. Davidson RJ. Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry. 2002; 51(1):68-80.

15. Steingard RJ, Renshaw PF, Yurgelun-Todd D, et al. Structural abnormalities in brain magnetic resonance images of depressed children. J Am Acad Child Adolesc Psychiatry. 1996;35(3):307-311.

16. Steingard RJ, Renshaw PF, Hennen J, et al. Smaller frontal lobe white matter volumes in depressed adolescents. Biol Psychiatry. 2002;52(5):413-417.

17. Nolan CL, Moore GJ, Madden R, et al. Prefrontal cortical volume in childhood-onset major depression: preliminary findings. Arch Gen Psychiatry. 2002;59(2):173-179.

18. Botteron KN, Raichle ME, Drevets WC, Heath AC, Todd RD. Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biol Psychiatry. 2002;51(4):342-344.

19. Hirayasu Y, Shenton ME, Salisbury DF, et al. Subgenual cingulate cortex volume in first-episode psychosis. Am J Psychiatry. 1999;156(7):1091-1093.

20. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290-13295.

21. Lane RD, Reiman EM, Bradley MM, et al. Neuroanatomical correlates of pleasant and unpleasant emotion. Neuropsychologia. 1997;35(11):1437-1444.

22. MacMillan S, Szeszko PR, Moore GJ, et al. Increased amygdala: hippocampal volume ratios associated with severity of anxiety in pediatric major depression. J Child Adolesc Psychopharmacol. 2003;13(1):65-73.

23. MacMaster FP, Kusumakar V. Hippocampal volume in early onset depression. BMC Med. 2004;2:2.

24. Rosso IM, Cintron CM, Steingard RJ, Renshaw PF, Young AD, Yurgelun-Todd DA. Amygdala and hippocampus volumes in pediatric major depression. Biol Psychiatry. 2005;57(1):21-26.

25. De Bellis MD, Keshavan MS, Clark DB, et al. A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development. Biol Psychiatry. 1999;45(10):1271-1284.

26. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157(1):115-118.

27. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93(9):3908-3913.

28. Lyoo IK, Kwon JS, Lee SJ et al. Decrease in genu of the corpus callosum in medication-naive, early-onset dysthymia and depressive personality disorder. Biol Psychiatry. 2002;52(12):1134-1143.

29. Martinez P, Ronsaville D, Gold PW, Hauser P, Drevets WC. Morphometric abnormalities in adolescent offspring of depressed mothers. Abstr Soc Neurosci. 2002;498:4.

30. MacMaster FP, Kusamaker V. MRI study of the pituitary gland in adolescent depression. J Psychiatr Res. 2004;38(3):231-236.

31. Lyoo IK, Lee HK, Jung JH, Noam GG, Renshaw PF. White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders. Compr Psychiatry. 2002;43(5):361-368.

32. Ehrlich S, Noam GG, Lyoo IK et al. White matter hyperintensities and their associations with suicidality in psychiatrically hospitalized children and adolescents. J Am Acad Child Adolesc Psychiatry. 2004;43(6):770-776.

33. Honer WG, Falkai P, Chen C, Arango V, Mann JJ, Dwork AJ. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience. 1999;91(4):1247-1255.

34. Tutus A, Kibar M, Sofuoglu S, Basturk M, Gonul AS. A technetium-99m hexamethylpropylene amine oxime brain single-photon emission tomography study in adolescent patients with major depressive disorder. Eur J Nucl Med. 1998;25(6):601-606.

35. Kowatch RA, Devous MD, Sr., Harvey DC et al. A SPECT HMPAO study of regional cerebral blood flow in depressed adolescents and normal controls. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23(4):643-656.

36. Thomas KM, Drevets WC, Dahl RE, et al. Amygdala response to fearful faces in anxious and depressed children. Arch Gen Psychiatry. 2001;58(11):1057-1063.

37. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7(5):541-547.

38. Steingard RJ, Yurgelun-Todd DA, Hennen J, et al. Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biol Psychiatry. 2000;48(11):1053-1061.

39. Farchione TR, Moore GJ, Rosenberg DR. Proton magnetic resonance spectroscopic imaging in pediatric major depression. Biol Psychiatry. 2002;52(2):86-92.

40. Mirza Y, Tang J, Russell A, et al. Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. J Am Acad Child Adolesc Psychiatry. 2004;43(3):341-348.

41. Rosenberg DR, Mirza Y, Russell A, et al. Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. J Am Acad Child Adolesc Psychiatry. 2004;43(9):1146-1153.

42. Caetano SC, Fonseca M, Olvera RL, et al. Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients. Neurosci Lett. 2005;384(3):321-326.

43. Mirza Y, Tang J, Russell A, et al. Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. J Am Acad Child Adolesc Psychiatry. 2004;43(3):341-348.

44. Kusumakar V, MacMaster FP, Gates L, Sparkes SJ, Khan SC. Left medial temporal cytosolic choline in early onset depression. Can J Psychiatry. 2001;46(10):959-964.

45. Smith EA, Russell A, Lorch E, et al. Increased medial thalamic choline found in pediatric patients with obsessive-compulsive disorder versus major depression or healthy control subjects: a magnetic resonance spectroscopy study. Biol Psychiatry. 2003;54(12):1399-1405.

46. Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry. 1998;3(3):190-191;220-226.


Dr. Gabbay is assistant professor in the Department of Psychiatry at New York University School of Medicine in New York City.

Dr. Silva is associate professor of psychiatry and the deputy director of the Division of Child and Adolescent Psychiatry at New York University School of Medicine/Bellevue Hospital Center.

Dr. Castellanos is the Brooke and Daniel Neidich Professor of Child and Adolescent Psychiatry, director of research, and director of the Institute for Pediatric Neuroscience in the Department of Psychiatry at New York University School of Medicine.

Ms. Rabinovitz is a research assistant in the Department of Psychiatry at New York University School of Medicine.

Dr. Gonen is professor of radiology, and physiology and neuroscience in the Department of Radiology at New York University School of Medicine.

Disclosure: Dr. Gabbay has received funding from the American Foundation for Suicide Prevention and the Tourette Syndrome Association. Dr. Silva is a consultant to Novartis; is on the speakers bureau for AstraZeneca, Novartis, and Ortho-McNeil; and receives grant support from the New York City Department of Mental Health, the New York State Office of Mental Health, the Red Cross, the Research Foundation for Mental Hygiene, and the Substance Abuse and Mental Health Services Administration. Dr. Castellanos receives grant support from the Stavros S. Niarchos Foundation, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Alliance for Research in Schizophrenia and Affective Disorders, the National Institute for Neurological Disorders and Stroke, and McNeil Consumer & Specialty Pharmaceuticals Division of McNeil-PPC. Ms. Rabinovitz reports no affiliations with or financial interest in any organization that may pose a conflict of interest. Dr. Gonen serves on several National Institute of Health (NIH) review panels and currently holds two NIH R01 grants.

Please direct all correspondence to: Vilma Gabbay, MD, 577 First Ave, New York, NY 10016; Tel: 212-263-2731; Fax: 212-263-8662; Email: vilma.gabbay@med.nyu.edu.


Journal CMEs

Print Friendly 

Differential Diagnosis and Treatment of Excessive Daytime Sleepiness

Scott M. Leibowitz, MD, and Jed E. Black, MD
Needs Assessment:
Excessive daytime sleepiness (EDS) is an extremely common complaint in the general medical and psychiatric population. In this light, physicians should have a solid working knowledge of the differential diagnosis, preliminary evaluation, and range of treatment options for this complaint. Despite the enormous impact of EDS and its varied causes on productivity, quality of life, and overall health, there is a surprising deficit in knowledge in many general medical practitioners. A more thorough understanding of EDS and its attendant causes should be part of the knowledge base of all general medical personnel.  

Learning Objectives:
• List the primary causes of excessive daytime sleepiness (EDS).
• Generate a differential diagnosis of
diseases causing EDS.
• Understand the causes of fragmented sleep.
• Differentiate between primary disorders of hypersomnolence.
• Understand the appropriate treatment options available for the various causes of EDS.

Target Audience:
Primary care physicians and psychiatrists.
Accreditation Statement: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

To receive credit for this activity:
Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: August 31, 2007. The estimated time to complete all three articles and the quiz is 3 hours. 

Primary Psychiatry. 2005;12(8):57-66

 

Dr. Leibowitz is a fellow in sleep medicine at the Stanford Sleep Disorders Center at Stanford University in California.

Dr. Black is the director of the Stanford Sleep Disorders Center and assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University.

Disclosure: Dr. Leibowitz has received research support from GlaxoSmithKline. Dr Black has received research support from Cephalon, GlaxoSmithKline, and Orphan Medical.

Please direct all correspondence to: Jed E. Black, MD, 401 Quarry Road, #3301 Stanford, CA 94305; Tel: 650-723-6601; E-mail: jedblack@stanford.edu.


 

Abstract

Excessive daytime sleepiness (EDS) is a common problem plaguing society’s health, well-being, and productivity. While insufficient sleep is the most common cause of EDS, there are many pathologic disorders which, despite sufficient sleep quantity, produce ongoing EDS. Disorders that cause sleep fragmentation, such as obstructive sleep apnea and periodic limb movement disorder, can cause significant EDS despite adequate hours of sleep. Additionally, there are several primary disorders of somnolence that arise from central nervous system dysfunction. Narcolepsy is one such disorder that is well known to clinicians but frequently misunderstood. Idiopathic hypersomnia, the recurrent hypersomnias, and EDS associated with central nervous system disorders must also be considered in the differential of EDS to provide appropriate evaluation and patient management. EDS associated with psychiatric disorders is less common than often presumed, but still should be a consideration in the work-up. This review summarizes the various clinical syndromes of primary EDS and provides an overview of evaluation and management of the patient suffering from EDS.

 

Introduction

The sleep-wake system is a complex and dynamic system which governs the general states of arousal or somnolence at all times. These dynamic and interrelated states predispose the individual either to wakefulness or sleep. An individual’s degree of somnolence may be impacted by multiple determinants, including quantity or quality of sleep, circadian clock time, concentration, motivation, environmental influences, medications, primary sleep disorders, acute or chronic medical conditions, and/or acute and chronic psychiatric conditions. “Pathologic” sleepiness or excessive daytime sleepiness (EDS) is a complaint found in patients who experience somnolence at unwanted times which adversely affects their daytime function.

A distinction should be noted between EDS and fatigue, although these descriptors are frequently used interchangeably in clinical practice. The patient with EDS will often struggle to maintain wakefulness in monotonous situations while the patient with the complaint of fatigue may have EDS, but may as readily have no feeling of sleepiness and may be experiencing listlessness or lethargy rather than a tendency to fall asleep. While there is considerable overlap between these two complaints, and both complaints may be indicative of a significant problem, the former is a more specific symptom complex, usually indicative of a specific physiologic state, while the latter is a nonspecific complaint which may represent any number of chronic or acute physiologic or psychological processes.

The American Academy of Sleep Disorders defines EDS in the International Classification of Sleep Disorders1 (ICSD) as “a complaint of difficulty in maintaining desired wakefulness or a complaint of excessive amount of sleep.” The ICSD elucidates that excessive sleepiness (also referred to as somnolence or hypersomnia) is a subjective report of difficulty maintaining the alert awake state, usually accompanied by a rapid entrance into sleep when the person is sedentary. The severity criteria for sleepiness in the ICSD are based on frequency and degree of associated daytime impairment. This review summarizes the clinical presentation, the differential diagnosis, diagnostic armamentarium, and treatment options for the patient complaining of EDS.

 

Epidemiology of Sleepiness  

There is considerable variability in the literature in terms of the prevalence of reported EDS. This variability is likely due to the inconsistent measures of EDS and subsequent differences in investigation, definition, and classification of the complaint. A review by Partinen and Hublin2 of 24 epidemiologic studies conducted from 1976–1997 found a range of .03% to 36% across studies, depending on how EDS was defined.2 While the prevalence of “sleeping too much” fell in the range of .03% to 4%, the prevalence of “perceived sleepiness” ranged from 10% to 15%.2 The largest and most comprehensive representative population survey was performed across four Western European countries (the United Kingdom, Germany, Spain, and Italy). Substantial EDS, defined by meeting three parameters of marked sleepiness during >3 days/week, was reported in 15% of this combined population.3 In the United States, smaller population surveys have been conducted. Two recent polls4,5 suggested that 15% to 16% of the US population over 18 years of age may experience EDS that interferes with daily activities a few days a week or more; they did not differentiate between causes of EDS.

 

Evaluation of the Patient with Excessive Daytime Sleepiness  

Of key importance in evaluating the patient complaining of EDS is a detailed history and physical exam. Obtaining a detailed sleep history in addition to a medical history is essential. Documentation of total daily 24-hour sleep time and daily sleep pattern, number of nocturnal awakenings, prolonged sleep latencies, snoring, witnessed apneas, symptoms of restless legs syndrome (RLS), periodic limb movements, and restless sleep are highlights of the sleep history that should be covered at minimum. Medical conditions and alcohol or drug abuse can be significant contributors to EDS and, if suspected, appropriate evaluation should ensue. Special note should also be made of chronic sedating medications.

Sleep history should be supplemented with questionnaires evaluating degree of sleepiness and impact on daily living. These questionnaires include, but are not limited to, the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, and the Sleep-Wake Activity Inventory. The ESS is the most commonly used questionnaire due to its ease of use and small, but statistically significant, correlation with sleepiness measured by an objective test of sleepiness known as the multiple sleep latency test (MSLT).6,7 While a normal value of the ESS is considered to be <10, this test is neither highly specific nor sensitive for the existence of pathological sleepiness and these values are not entirely representative of true level of sleepiness; however, the ESS serves as a useful screen for those who are severely sleepy.8 With the ease of use of the ESS and the high prevalence of sleepiness in the general public, we advocate the administration of this tool to all adult patients in any clinical practice. To further characterize a patient’s sleep, nightly sleep logs can be helpful in establishing circadian tendencies and patterns of sleep. If the patient is unable to give a reliable history or nightly sleep times are in question, several days of actigraphy monitoring, a device that registers movement by the patient, may be a useful tool in evaluating patterns of waking and sleep.

Once a thorough history and physical are performed, if a physical sleep problem is considered, the primary diagnostic tool available is the nocturnal polysomnogram (PSG). The PSG is used to evaluate sleep disturbances leading to sleep fragmentation, including sleep-related breathing disorder (SRBD), periodic limb movement of sleep (PLMS), rapid eye movement (REM)-sleep behavior disorder, and/or, more rarely seen, nocturnal seizures.

To objectively evaluate the degree of sleepiness of an individual, the MSLT can be used. The MSLT consists of four or five 20-minute polysomnographically monitored daytime nap opportunities separated by 2-hour intervals wherein the patient is placed in a sleep laboratory bed in a dark room with instructions to fall asleep. The primary assessments made by the MSLT are the rapidity of sleep onset, which correlates to degree of sleepiness, and to establish the presence of REM sleep, if sleep occurs during the nap opportunity. REM sleep episodes (a period of sleep during which dreams occur) at or close to sleep onset are known as sleep-onset rapid eye movement (SOREM) periods.

Typical sleep latencies in the normal adult are 10–20 minutes while pathological sleepiness is manifested by a latency of <5–6 minutes.9 The MSLT should be performed immediately following a nocturnal PSG in order to exclude other causes of EDS due to either sleep fragmentation or insufficient sleep. If the PSG is positive for other causes of EDS, these conditions should be adequately treated before an evaluation of EDS with an MSLT is pursued.  

The maintenance of wakefulness test (MWT) is another diagnostic test used in the sleep laboratory. Rather than evaluate the tendency to fall asleep, as the MSLT does, the MWT assesses the capacity to maintain wakefulness in a sedentary setting during the patient’s regular waking hours and is often used to evaluate impact of treatment for obstructive sleep apnea (OSA)-related EDS in heavy equipment operators and/or airline pilots.

 

Syndromes of Sleepiness

Insufficient Sleep

Insufficient sleep is the most common cause of EDS in western culture. Although the exact prevalence is unclear, Sleep in America polls conducted by the National Sleep Foundation in 2002 found that 37% of adults reported sleeping <7 hours/night and 68% of adults reported sleeping <8 hours/night.4 Although sleep requirements vary between individuals, it was found in these same polls that total weeknight sleep times averaged 6.9 hours, compared to 7.5 hours on weekends. This discrepancy in weeknight versus weekend sleep times implies ongoing voluntary sleep restriction during the week with compensation on the weekends through sleep time extension.

The number of hours of experimental sleep loss in normal volunteers is directly proportional to the degree of increased daytime sleepiness, as assessed by the MSLT.10 The effects of sleep deprivation may be cumulative,9 but this accumulated sleep debt may be countered by extending sleep time over several days.11 Insufficient sleep may be due to voluntary lifestyle choices, job or school demands, shift work, or poor sleep hygiene.  

Shift work comprises as much as 16% of the workforce in the US.12  Some research has suggested that despite subjectively experiencing adequate daytime sleep, shift workers lose an average of 5–7 hours of sleep/ week, compared to diurnal workers.13 Additionally, studies have consistently shown that individuals who engage in regular night shift work experience more disrupted sleep as well as sleepiness during waking hours, compared to day workers.14,15

Insufficient sleep is expected to lead to frank EDS, however a constellation of other subjective complaints are more commonly seen. These include complaints of tiredness, lack of energy, or fatigue. Additionally, decrements in attention, learning capacity, short-term memory, and/or psychomotor performance, with or without EDS, may be present. Moreover, irritability, poor impulse control, or other forms of mood instability may exist alone or in concert with the above-noted features in individuals with insufficient sleep.

 

Circadian Influences

The body’s sleep/wake cycle is controlled or influenced by an internal pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus that provides regulatory signaling which oscillates on a circadian or approximately 24-hour pattern. This internal “clock” is influenced by a number of external factors called zeitgebers. Zeitgebers regulate and synchronize circadian rhythms; the strongest zeitgeber is sunlight. The SCN facilitates potent central nervous system (CNS) alerting activity during the day and activity that promotes sleep at night. Light and other zeitgebers reset the timing or “phase” or the SCN when we travel to a new time zone. Additionally, genetically determined individual variability in circadian phase exists resulting in some individuals manifesting “night owl” sleep-wake behavior while others are “morning larks.” If an individual’s circadian phase does not coordinate with social or work demands, sleep time may be curtailed and residual EDS may occur.

Circadian rhythm disorders are chronic conditions that occur when sleeping patterns are not synchronized with environmental cues for sleep and wakefulness. These disorders manifest when a patient cannot sleep at a suitable time or desires to sleep at an unsuitable time. Examples of these disorders include, but are not limited to, advanced sleep phase syndrome, which is characterized by propensity to fall asleep in the early evening with subsequent early morning awakening; delayed sleep phase syndrome, characterized by inability to fall asleep at traditional evening times with subsequent difficulty arising in the morning; jet lag, where an individual’s internal circadian rhythm is desynchronized with the external environment due to travel across multiple time zones; and shift work sleep disorder (SWSD), where work demands the constant adjustment and readjustment of the sleep phase resulting in EDS during work hours and curtailed, fragmented sleep in off-hours.

 

Fragmented Sleep

Several physical conditions may lead to fragmented sleep, predominately in the form of microfragmentation. Microfragmentation is seen on an electroencephalogram (EEG) as cortical microarousals typically originating from a disturbance in breathing (eg, OSA, central sleep apnea [CSA], mixed apneas, upper airway resistance syndrome [UARS], or snoring), or a disturbance due to abnormal movements during sleep, most commonly in the form of periodic limb movements of sleep (PLMS). These microarousals may lead to awakenings from sleep at various times during the sleep period, but often the patient is unaware of these problems. Microarousal activity has been postulated to disrupt the normal restorative processes of sleep and has been demonstrated to produce sleepiness and/or daytime performance deficits when induced by various sensory stimuli in normal subjects.16,17

Fragmented sleep in adults, and especially in children, however, may not lead to EDS. While children with sleep-related breathing disorders (SRBD) are generally sleepier than normals, children with SRBD more often tend to display inattention, irritability, and/or hyperactivity,18-20 and their degree of sleepiness tends to increase with severity of SRBD,  as opposed to EDS.21,22 In addition, recent evidence strongly suggests that children with primary snoring in the absence of OSA suffer significant neurobehavioral deficits compared to children who do not snore, probably in part due to increased susceptibility to sleep fragmentation.23 The link between sleep fragmentation and attention-deficit/hyperactivity disorder (ADHD) in children has also been found in children with PLMS. A surprising percentage of children diagnosed with ADHD have been found to have PLMS, and conversely, a substantial number of children with PLMS were also found to have ADHD.24,25

 

Sleep-Related Breathing Disorder

SRBD is highly prevalent in North America with an estimated 20% of adults with mild to asymptomatic disease and at least 5% of adults with significant disease.26 In children, studies have shown a prevalence of primary snoring to be between 10% and 25% in children 3–12 years of age,27,28 while the prevalence of OSA has been found to be between 1% and 3% in the general pediatric population.29

OSA is a condition where cyclical or repetitive obstructive respiratory events occur during sleep with microarousals occurring at the termination of a respiratory event.30,31 In addition to the increased occurrence of micro-arousal activity, alterations in the pattern of sleep stage activity, known as “sleep architecture,” are commonly observed. Specifically, reductions in slow-wave sleep (stages 3 and 4) and REM sleep percentages, with corresponding increases in lighter sleep, typify these changes. Sleep-related EEG alterations, however, do not consistently correlate with measures of sleepiness severity.32 Additionally, it was demonstrated that patients with OSA will complain more often of fatigue and “lack of energy” than of frank sleepiness.33    

In addition to OSA, two other types of apneas have been described: CSA and mixed sleep apnea.34 CSA occurs when the drive to breathe during sleep is intermittently absent, while mixed sleep apnea begins as a central event but changes to an obstructive event as respiratory effort begins in the midst of airflow cessation. While CSAs appear to be a unique physiologic event, mixed apneas appear to be essentially obstructive events in which respiratory effort is undetected at the beginning of the apnea. Both apneas are associated with arousals and fragmented sleep with resultant EDS; however, patients with pure CSA less commonly complain of this problem, compared to those with OSA.35,36 CSA may be seen in infants with immature central respiratory control systems, while in adults it may occur with cerebrovascular or neuromuscular disease, hypoventilation syndromes, or in association with the Cheyne-Stokes breathing. CSA is notably present in patients with low cardiac output heart failure.37

UARS is a sleep breathing disorder in which there is increased breathing effort during periods of increased upper airway resistance but in the absence of hypopneas or apneas.38  UARS patients have frequent micro-arousals associated with increased respiratory effort and possibly suffer from EDS. Snoring is often the first symptom reported by patients (or more commonly bedpartners or room/housemates) later diagnosed with OSA or UARS. Snoring alone implies increased resistance of the upper airway during sleep, although data are mixed regarding the true consequences of snoring with regard to EDS.

 

Periodic Limb Movement Disorder   

PLMS are repetitive flexions of the toes, feet, legs, thighs, and/or the arms during sleep, lasting 0.5–5 seconds in duration, recurring every 5–90 seconds. Intermittently, cortical microarousals will occur with movements. Cross-sectional studies predict PLMS occurs in approximately 3.9% to 5% of the adult population39 and approximately 1.2% of children40 in the absence of other sleep disorders. Some controversy exists regarding the impact of PLMS on sleep disturbance and subsequent daytime functioning in adults. When PLMS occur at rates of >5/hour of sleep, they may be associated with EDS. Periodic limb movement disorder (PLMD) may also be diagnosed.41  Several studies have shown no positive correlation of EDS with the number of PLM-arousal complexes per hour of sleep as measured by MSLT.42,43 Based on conflicting data, the significance of PLMS and associated arousals remains poorly understood and clinical correlation is required to understand the significance of each individual case.

 

Restless Legs Syndrome

A separate but related disorder from PLMD is RLS, a syndrome consisting of an uncomfortable or unpleasant feeling; that occurs predominately in the legs, but may involve the arms: it occurs more often in the evening time and usually relieved by moving or stretching.  While PLMD is a PSG diagnosis, RLS is, by definition, a subjective diagnosis based on the patient’s report. While 80% to 85% of all patients with RLS have PLMS, as few as 18% of patients with PLMD experience RLS symptoms.44 Although the mechanism of both disorders likely involves problems with dopamine production and/or utilization, these are distinctly different disorders as classified by the ICSD.1 While RLS is predominately a waking phenomenon, patients do report significantly interrupted sleep and sleep curtailment, often reporting as little as 4 hours of sleep/night due to these uncomfortable sensations.45

 

Primary Disorders of Excessive Daytime Sleepiness

Many disorders are regarded as primary disorders of EDS. Considered in this review are narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, and posttraumatic hypersomnia.1 Similar to patients with disorders of EDS, individuals with these CNS-mediated EDS syndromes are commonly misdiagnosed as suffering a mood disorder and inappropriately treated with antidepressant therapy.

 

Narcolepsy

Narcolepsy is the most well-known and well-studied of the primary disorders of EDS. Epidemiologic studies46,47 have shown that narcolepsy has a prevalence of approximately 1 in 2,000, worldwide, but may have significant variability based on ethnic background. Narcolepsy is characterized by EDS with an increased propensity to fall asleep throughout the day. When in sedentary situations, patients will need to exert an extra effort to avoid nodding or dozing. This tendency toward sleep often manifests as the irresistible or uncontrollable urge to sleep, described as “sleep attacks.” Contrary to popular belief, “sleep attacks” are not sudden lapses into sleep, but rather represent episodes of profound sleepiness similar to that experienced by those with marked sleep deprivation or other severe sleep disorders. ESS scores of >15 are common in untreated patients.48,49 In addition to frank sleepiness, the EDS of narcolepsy, as in other sleep disorders, can cause related symptoms, including poor memory, reduced concentration or attention, and irritability.

Because narcolepsy likely represents a disorder of sleep-state boundary control, patients with narcolepsy will often present with other symptoms in addition to EDS including cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis, all of which manifest features that create the appearance of REM-sleep phenomena intruding into wakefulness. Patients with narcolepsy may also report automatic behaviors and up to 90% of patients will complain of disrupted nocturnal sleep.50 Symptom onset typically begins during adolescence or young adulthood; however, narcolepsy has been seen to occur in early childhood as well into the third or fourth decade of life, or later. The impact of narcolepsy on the individual is dramatic; studies have shown that effect on quality of life is equal to that of Parkinson’s disease.51 Diagnosis of narcolepsy may be elusive as no symptom or sign of narcolepsy is specific to it; cataplexy unrelated to narcolepsy may occur, although rarely, either as an isolated symptom or in conjunction with other conditions.

Cataplexy is the partial or complete loss of bilateral voluntary muscle tone in response to strong emotion. The range of severity of cataplectic events is broad. Reduced muscle tone may be minimal, occurring only in a few muscle groups, causing minimal symptoms such as bilateral ptosis, head drooping, slurred speech, or dropping things from the hand. On the other extreme, cataplexy can be so severe that total body paralysis occurs, resulting in complete collapse of the affected individual. Cataplectic events usually last from a few seconds to 2 or 3 minutes, but occasionally will continue longer.52 During an event, patients are usually alert and oriented despite the inability to respond. Any strong emotion is a potential trigger for cataplexy; although, laughter and other positive emotions are a more common trigger for cataplexy than negative emotions.53 Startling stimuli, stress, physical fatigue, or sleepiness may also be important triggers or factors that exacerbate cataplexy.

Based on epidemologic studies, it appears that patients with narcolepsy experience cataplexy 60% to 100% of the time, depending on how cataplexy is defined. Typically, patients will begin to experience cataplexy either simultaneously or within a few months of developing EDS, but in some cases, cataplexy may not develop until many years after initial onset of EDS.52

Hypnagogic or hypnopompic hallucinations occur at the transition from wakefulness to sleep (hypnagogic) or from sleep to wakefulness (hypnopompic). These hallucinations exist in many forms; they may be visual, tactile, auditory, or multi-sensory, and are usually brief in duration but will occasionally continue for a few minutes. Hallucinations may simultaneously contain a combination of elements from both dream sleep and consciousness; and are often bizarre or disturbing to patients. Patients who experience these episodes have occasionally been misdiagnosed with a psychotic syndrome and inappropriately treated with antipsychotics. Antipsychotics provide no benefit to these patients.

Sleep paralysis is the inability to move during the transition from sleep to wakefulness or from wakefulness to sleep, which may last from a few seconds to minutes. This phenomenon, like hypnogogic hallucinations, appears to be an intrusion of a component of REM-sleep, specifically REM-sleep atonia, into wakefulness. Episodes of sleep paralysis can be quite alarming to patients, especially if combined with a hypnogogic event. Often, patients will report a terrifying experience of the sensation of being unable to breathe. Accessory muscle activity is absent during these episodes, however, diaphragmatic activity continues and air exchange remains adequate, in the same way that air-exchange continues during the atonia of REM-sleep.

Fragmented nocturnal sleep is another “hallmark” symptom of narcolepsy. Patients with narcolepsy have many more and longer nocturnal awakenings than controls, a seemingly paradoxical finding.54 However, narcolepsy is a condition of disrupted continuity of both wakefulness and sleep, with intrusion of each of these states into the other at various inappropriate times. Another symptom commonly reported in narcolepsy patients are automatic behaviors; “absent-minded” behavior or speech that is often nonsensical and that the patient does not remember. Hypnogogic hallucinations, sleep paralysis, and automatic behavior are seen in healthy individuals as well as patients with narcolepsy; however, these symptoms are far more common and occur with much greater frequency in patients with narcolepsy.

 

Diagnosis of Narcolepsy

The diagnosis of narcolepsy is dependent on clinical history, coupled with confirmatory diagnostic testing. The primary diagnostic tool used to confirm the diagnosis of suspected narcolepsy is the MSLT. The MSLT usually demonstrates substantially reduced sleep latency and SOREMs in patients with narcolepsy. In normal controls with adequate, non-fragmented nocturnal sleep, REM sleep does not occur during daytime naps. During nocturnal sleep, the first REM period will usually not occur until at least 90 minutes after sleep onset. Average MSLT sleep latencies for untreated narcolepsy with cataplexy is approximately 2–3 minutes48; however, substantial variability across patients and within patients can, at times, be seen. SOREM periods are not specific for narcolepsy. Sleep deprivation, REM-suppressant medication rebound, altered sleep schedule, OSA, or delayed sleep-phase syndrome are a few circumstances where SOREMs will be commonly seen on the MSLT. However, the occurrence of >2 of these events during the MSLT, in the setting of objective marked sleepiness and without another explanation for their occurrence is suggestive of narcolepsy.

When cataplexy accompanies EDS, a straightforward diagnosis of narcolepsy can be made. In these cases, nocturnal PSG is not an essential diagnostic tool; however, it still remains an important part of the evaluation process. The nocturnal PSG is used in this setting primarily to exclude other conditions that occur in narcolepsy at a higher than normal rate (OSA, PLMD, and REM-sleep behavior disorder) and could add to the sleepiness or nocturnal sleep disruption and daytime sleepiness the patient may be experiencing.55

In addition to the MSLT, a number of adjunctive tests exist which may help to confirm the diagnosis of narcolepsy in the patient with a confusing clinical presentation. Hypocretin, an excitatory, wake-promoting neurotransmitter produced in the hypothalamus, is found to be low or undetectable in the cerebrospinal fluid (CSF) of many, but not all, patients with narcolepsy.56,57 Such low levels of CSF hypocretin are not specific for narcolepsy. However, when used to assess patients for narcolepsy, low CSF hypocretin is a more specific test than the MSLT and may be more sensitive as well.

A very strong, but incomplete correlation exists between narcolepsy (with cataplexy) and the HLA subtype DQB1* 0602. Unfortunately, this subtype is very common in the general population (approximately 20% in the combined US population) and as a result, not at all specific or sensitive for narcolepsy.47 HLA testing should be reserved for the sleep physician evaluating the possibility of narcolepsy in a patient with a high degree of clinical suspicion.  

 

Idiopathic Hypersomnia

Idiopathic hypersomnia (previously labeled “idiopathic CNS hypersomnia”), is another important primary disorder of EDS that should be considered in the patient complaining of sleepiness. This diagnosis has historically been given to individuals who complain of EDS when other disorders causing hypersomnolence have not been found or clearly characterized. There are numerous documented cases of patients having been misdiagnosed with idiopathic hypersomnia when in fact; they suffered from other disorders causing EDS, such as narcolepsy without cataplexy, DSPS, or upper airway resistance syndrome.58      

True idiopathic hypersomnia is believed to be less common than narcolepsy, but estimation of prevalence is difficult because there are no strict diagnostic criteria and specific biological markers have not yet been definitively identified. The first symptoms tend to occur in late adolescence or early adulthood. No cause for idiopathic hypersomnia has been clearly identified, but viral illnesses, including those that may lead to Guillain-Barre syndrome, hepatitis, mononucleosis and atypical viral pneumonia may be a harbinger of the onset of sleepiness in a subset of patients. EDS may occur as part of the acute illness but persist after the other symptoms subside. HLA-Cw2 and HLA-DR11 have occurred with increased frequency in some rare familial cases.59 However, most patients with idiopathic hypersomnia have neither a family history nor an obvious associated viral illness. Autonomic nervous system dysfunction has been associated with some of these cases, including orthostatic hypotension, syncope, vascular headaches and peripheral vascular complaints. Little is known about the pathophysiology of idiopathic hypersomnia. No animal model is available for study. Neurochemical studies using CSF have suggested that patients with idiopathic hypersomnia may have altered noradrenergic system function.60-62

Clinically, symptoms of idiopathic hypersomnia vary in presentation among individuals. It is not uncommon for idiopathic hypersomnia to be mistaken for narcolepsy. Because the predominant symptom in both disorders is EDS and both diseases have similar age of onset, it is understandable that one may be mistaken for the other. However, with careful history taking and diagnostic testing, essential differences between the disorders become apparent. Patients with idiopathic hypersomnia present with EDS but without cataplexy or significant nocturnal sleep disruption.63 The sleepiness of which they complain will typically interfere with normal daily activities. Occupational and social functioning may be severely impacted by sleepiness. Nocturnal sleep time tends to be long and unrefreshing, and patients are usually difficult to awaken in the morning. They may become irritable or even abusive in response to the efforts of others to rouse them. In some patients, this difficulty may be substantial and include confusion, disorientation, and poor motor coordination, a condition called “sleep drunkenness.”64 These patients often take naps, which may be prolonged but again, usually non-refreshing. No amount of sleep ameliorates EDS. “Microsleeps,” with or without automatic behavior, may occur throughout the day.

PSG studies of patients with idiopathic CNS hypersomnia usually reveal shortened initial sleep latency, increased total sleep time and normal sleep architecture (in contrast to narcoleptic patients, who exhibit significant sleep fragmentation). Mean sleep latency on MSLT is usually reduced, often in the 8–10 minute range, but sometimes dramatically shorter. Also in contrast to narcolepsy, SOREMs are not typically seen.

As with narcolepsy, other disorders producing EDS (such as insufficient sleep, sleep-related breathing disorders, PLMDs, other sleep fragmenting disorders, psychiatric diseases, or circadian rhythm disorders) must be ruled out before the diagnosis of idiopathic hypersomnia is made. Treatment of idiopathic CNS hypersomnia is often difficult and poorly responsive to medications. Lifestyle and behavioral modifications, including good sleep hygiene, are appropriate, but treatment with stimulant or wake-promoting medication, as with narcolepsy, is usually necessary.51

 

Recurrent Hypersomnias

Another group of disorders to consider in the differential diagnosis of a patient who presents with EDS, although somewhat rarer, are the recurrent hypersomnias. The Kleine-Levin syndrome is a form of recurrent hypersomnia, which occurs primarily in adolescents.65 There is a male preponderance. It is characterized by the occurrence of episodes of EDS, and frequently, but not always, accompanied by hyperphagia, aggressiveness and hypersexuality. These episodes may last days to weeks and be separated by asymptomatic periods of weeks or months. During symptomatic periods, individuals sleep up to 18 hours/day and are usually drowsy (often to the degree of stupor), confused and irritable the remainder of the time. Additionally, during these episodes, PSG studies will show long total sleep time with high sleep efficiency and decreased slow-wave sleep. MSLT studies demonstrate short sleep latencies and SOREMs.66 The etiology of this syndrome remains obscure. Symptomatic cases of Klein-Levin syndrome associated with structural brain lesions have been reported, but most cases are idiopathic. Single-photon emission computed topography studies have demonstrated hypoperfusion in the thalamus in one patient and in the nondominant frontal lobe in another.67 Treatment with stimulant medication is usually only partially effective. Effects of treatment with lithium, valproic acid, or carbamazepine have been variable, but generally unsatisfactory. Fortunately, in most cases, episodes become less frequent over time and eventually subside.

Another form of recurrent hypersomnia is menstrual-related periodic hypersomnia, in which EDS occurs during the several days prior to menstruation.68,69 The prevalence of this syndrome has not been well characterized. Likewise, the etiology is not known, but presumably the symptoms are related to hormonal changes. Some cases of menstrual-related hypersomnia have responded to the blocking of ovulation with estrogen and progesterone (birth control pills).70

Another less commonly seen form of the recurring hypersomnias is idiopathic recurring stupor. There have been numerous cases reported in which, in the absence of obvious cause, individuals are subject to stuporous episodes lasting from hours to days. This syndrome affects predominantely middle-aged males. The individuals are normal between episodes, which occur unpredictably. Elevated plasma and CSF levels of endozepine-4, an endogenous ligand with affinity for the benzodiazepine recognition site at the γ-aminobutyric acidA receptor, has been found in several of these patients.71 EEG data collected during symptomatic episodes have shown fast background activity in the 13–16 Hz range. Administration of flumazenil, a benzodiazepine antagonist, has produced transient awakening with normalization of the EEG.72 In some cases, the episodes resolved spontaneously after several years. Similar cases have been reported in children.73

 

Nervous System Disorders and Eexcessive Daytime Sleepiness     

Patients with disorders of the central or peripheral nervous systems will often complain of EDS as well. In some chronic diseases of neurological origin, EDS may be the predominate complaint. It may be a dominant clinical feature in many toxic or metabolic encephalopathic processes. Structural brain lesions, including strokes, tumors, cysts, abscesses, hematomas, vascular malformations, hydrocephalus, and multiple sclerosis plaques are known to produce EDS. It appears that in these patients, somnolence may result either from direct involvement of discrete brain regions or due to effects on sleep continuity (for example, nocturnal seizure activity or secondary SRBD).

Patients who experience a head trauma or have been afflicted with encephalitis may have the chronic sequela of EDS. Victims of “encephalitis lethargica,” described by Von Economo in the early 20th century, were found to have lesions in the midbrain, subthalamus and hypothalamus. Additionally, posttraumatic narcolepsy with cataplexy is well documented.74 EDS may be seen in patients with epilepsy, due to medication effects or nocturnal seizure activity.75 EDS may be associated with numerous infectious agents affecting the central nervous system, including bacteria, viruses, fungi and parasites. Perhaps the best known is trypanosomiasis, which is called “sleeping sickness” because of the prominent hypersomnia. Certain inflammatory mediators have been shown to cause sleepiness. These agents have been hypothesized to be the origin of EDS in acute infectious illness, where EDS occurs without direct invasion of the central nervous system. These mediators include cytokines, interferon, interleukins, and tumor necrosis factor.76 EDS may also persist chronically after certain viral infections.77

Various neurodegenerative disorders, including Parkinson’s disease, Alzheimer’s disease, other dementias of varied causes, and multiple system atrophy all have been shown to commonly have sleep disruption and EDS.78-80 Patients with neuromuscular disorders or peripheral neuropathies have an increased incidence of SRBD (CSA or OSA), pain and PLMS, and may develop EDS due to disrupted sleep of these origins.81 Patients with myotonic dystrophy often suffer from EDS, even in the absence of SRBD.82

 

Chronic Medical Conditions and Excessive Daytime Sleepiness

Chronic medical conditions may also cause significant sleep disturbance and manifest clinically as either EDS or fatigue. Patients with fibromyalgia frequently characterize their sleep as being restless, light, and unrefreshing.83 These patients often have a characteristic EEG finding during sleep of alpha-frequency activity intrusion during delta-frequency activity or “alpha-delta” sleep.84 Alpha activity is characteristic of the EEG pattern seen during quiet wakefulness with the eyes closed and does not occur during the deep sleep (wherein delta activity occurs) in normal controls. This EEG finding has been reported to also occur in rheumatoid arthritis and chronic fatigue syndrome.84-86 Researchers have found a positive correlation between the frequency of alpha-delta sleep and severity of overnight pain in patients with fibromyalgia  and a inverse correlation between frequency of alpha-delta sleep and subjective sleep depth and refreshing sleep.87,88

Other chronic medical conditions may have a significant impact on sleep continuity and on daytime function. Patients with severe congestive heart failure have highly fragmented sleep, with frequent arousals and sleep changes.89 Additionally, >50% of patients with heart failure suffer from SRBDs.90 A recent study has shown that at least 21% of patients with CHF complained of EDS and 48% of patients complained of being awake more than 30 minutes during the course of the night.91

Patients with cancer also have increased reports of EDS.  Prevalence rates of 54% to 68% for “feeling drowsy” and 21% to 40% for being “overly sleepy” have been found in studies of this population.92,93 Causes of EDS reported in this population may be related to increased risk of primary sleep disorders due to age alone (average age of onset of cancer is 55 years old); insufficient sleep due to insomnia, depression, or pain; disruption or erratic hormone secretion due to the malignancy or chemotherapy, with subsequent sleep disruption or shortened sleep periods; effects of cytokines and inflammatory mediators induced by cancer cells, biotherapy, or radiotherapy; and/or side effects from chemotherapy or other adjunctive medications.94

Endocrine disorders comprise another chronic disease group wherein patients may complain of EDS. It has long been observed that sleepiness is a symptom of hypothyroidism. Additionally, there are considerable data to show that hypothyroidism is a risk factor for the development of OSA.95 It is not clear whether the sleepiness that hypothyroid patients experience is due to a direct effect of the hypothyroid state on sleep or to coexisting SRBD. Patients with acromegaly have also been shown to have an increased prevalence of sleep apnea, with rates between 39% and 58.8% in various studies.96,97 On the other hand, patients with growth hormone deficiency consistently report a reduced level of energy, fatigue, and impaired sleep quality.98

Psychiatric illness, especially depression, has been thought to be a significant cause of EDS. While it is true that tiredness, fatigue and/or lack of energy are reported by an overwhelming majority of patients with major depression, evaluation of true EDS with subjective rating scales and objective measures suggests that frank sleepiness or a high sleep propensity may be much less common than the complaint of fatigue or lack of energy.99 There are only a few studies evaluating objective measures of sleepiness, such as MSLT, in depression, but these studies suggest that only a minority of these patients suffer EDS that is clinically relevant and that the majority are actually in the normal range of alertness.100

 

Treatment of Excessive Daytime Sleepiness

Depending on the etiology of EDS, treatment modalities differ greatly. Typically, regardless of the cause, appropriate behavioral interventions should be introduced. These include extension of the nocturnal sleep period, structured bedtimes and/or wake times, appropriate timing of light therapy in the case of circadian rhythm disorders, and scheduled naps. Risks of driving while sleepy should be explained to patients with EDS and these patients should be instructed to take appropriate measures to eliminate driving risks (eg, avoid driving while sleepy; if driving and sleepy, pull-over and take a short nap; use appropriate alerting agents when indicated).  

 

Circadian Rhythm Disorders

Patients with advanced sleep phase syndrome and delayed sleep phase syndrome may effectively shift their biological clock by the use of bright light therapy (phototherapy) either in the evening or in the morning, respectively, and avoidance of bright light in the morning and the evening, respectively.101 The use of properly timed melatonin administration appears to have an impact on phase-shifting as well, although not as greatly as phototherapy.102 Regular, fixed wake times with fixed daytime and nighttime routines helps to reinforce the phase shift as well.

 

Sleep-Related Breathing Disorders

Continuous positive airway pressure (CPAP) is the first-line therapy for treatment of SRBD. CPAP acts as a “pneumatic splint” to brace open the airway via a nasal or nasal-oral interface, providing continuous positive pressure to the upper airway while sleeping. By stabilizing the airway walls, the tendency for the upper airway to collapse is alleviated, breathing disturbances are ameliorated, and sleep continues much less interrupted. Studies have shown that CPAP therapy significantly improves subjective and objective measures of daytime sleepiness in patients with OSA.103,104 Alternatives to CPAP for the treatment of OSA include a variety of soft tissue and/or maxillary-mandibular surgical interventions. These procedures address the various points of obstruction in the upper airway and/or any anatomic variants that predispose an individual to SRBD. Additionally, mandibular advancing dental devices are a third-line treatment option for mild to moderate OSA in patients intolerant of CPAP who are not candidates for surgery. A discussion of these interventions is beyond the scope of this paper.

 

Periodic Limb Movement Disorder

The pathophysiology of PLMS is not well understood but evidence exists that both an alteration in brain iron metabolism and central dopaminergic dysfunction may play a role.105 The use of dopaminergic agents has been found to be remarkably effective in treating PLMS. Thus, dopamine agonists have become first line agents for the treatment of PLMS in terms of tolerability, efficacy, and continuity of sleep.106,107

 

Narcolepsy

In treating the primary disorders of EDS, pharmacotherapy, in addition to behavioral interventions, provides the mainstay of treatment. Clearly, before initiation of pharmacotherapy is begun, a definitive diagnosis of the cause of EDS is essential. The most significant impact on the treatment of narcolepsy in recent history has been the full characterization of the use of sodium oxybate (the sodium salt of γ-hydroxybutyrate) and its effect on cataplexy, daytime sleepiness, and nocturnal sleep fragmentation. While sodium oxybate’s sleep-promoting effect appears to be largely mediated via GABAB receptor agonism, the mechanism whereby it improves cataplexy and EDS is unknown. Low dose sodium oxybate (50 mg/kg [Scrima]; 60 mg/kg) in narcolepsy has been studied in some capacity for 35 years; however, not until the last 10 years have thorough investigations in the form of multi-center trials been conducted. These trials have extensively characterized the dose-response impact of sodium oxybate on the enhancement of nocturnal sleep, on improvement of cataplexy, and improvement of EDS.108,109 These findings support the view that sodium oxybate is the optimal first-line agent for the treatment of narcolepsy.

While sodium oxybate has demonstrated its efficacy in treating all symptoms of narcolepsy, alerting agents provide a critical adjunctive component in the treatment of patients with narcolepsy, specifically for the treatment of EDS. Once considered first-line agents for the treatment of patients with narcolepsy, it is now considered a useful addition to the use of sodium oxybate in our clinical practice. Clinically, common practice is to combine two agents when one does not adequately ameliorate symptoms. The use of modafinil as an adjunct to sodium oxybate has been shown to provide significantly greater improvement in measures of EDS than either agent alone. While some patients may wish to avoid medications and attempt to take extra naps during the day, it is rarely successful in alleviating EDS to the degree that these patients function at or near normal capacity. While alerting agents may not eliminate daytime symptoms, they have been shown to produce substantial improvement in EDS associated with narcolepsy.110

Modafinil is a novel alerting agent whose mechanism of action is not fully characterized. Its therapeutic effect of promoting wakefulness appears to be largely dopaminergic. Similar to traditional stimulants, modafinil appears to function as a dopamine transporter inhibitor, but unlike the amphetamines, it does not induce dopamine release. This difference in activity may account for the improved tolerability of modafinil over traditional stimulants, as well as its almost complete lack of street use, abuse, or addiction by illicit users.111 In addition to its use in narcolepsy, after multiple trials regarding safety and efficacy, it has been approved by the Food and Drug Administration for use in SWSD and in the residual sleepiness associated with fully treated OSA. Of course in these conditions, adequate compliance with optimal CPAP or other primary airway treatment, as well as structured and adequate sleep, are of paramount importance before the initiation of pharmacotherapy.

In addition to modafinil, commonly used stimulants include methylphenidate, dextroamphetamine, and methamphetamine.110 Side effects are not uncommon with any alerting agent. Agitation, anxiety, tremor, and palpitations are just a few of the commonly reported side effects associated with traditional stimulants. Some patients may report a rebound hypersomnia as the dose wears off and/or tolerance (tachyphylaxis) may occur with time. Traditional stimulants are still an important resource in the arsenal of medications for the treatment of narcolepsy, but in our clinical practice, have become second-line agents behind sodium oxybate and/or modafinil for treatment of EDS associated with narcolepsy.

Cataplexy is an important aspect to address in the treatment of narcolepsy; however, the various agents and modes of action implicated in this aspect of narcolepsy expand beyond the scope of this paper.

 

Conclusion

EDS is an important problem in our society and produces significant decrements in quality of life and productivity. There are many causes of EDS that must be considered by the clinician before contemplating diagnostic testing and treatment. Patterns of sleepiness and chronicity of the complaint should be well established before initiating a diagnostic work-up and treatment plan. Insufficient sleep, chronic medical problems, and medications are all confounding variables that may contribute to EDS and may be a primary cause of EDS or may exacerbate a primary sleep disorder or primary disorder of hypersomnolence. Despite the development of several methods to diagnose and quantify EDS, each has its limitations. Fortunately, in most cases of EDS, treatment options exist to ameliorate symptoms and improve quality of life.  PP

 

References

1. International Classification of Sleep Disorders: Diagnostic and Coding Manual. Revised.  Rochester, Minn:  American Sleep Disorders Association; 1997.

2. Partinen M, Hublin C. Epidemiology of sleep disorders. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practices of Sleep Medicine. 3rd ed.  Philadelphia, Pa: Saunders; 2000:558-575.

3. Ohayon MM, Priest RG, Zulley J, et al. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology. 2002;58(12):1826-1833.

4. National Sleep Foundation: Sleep in America Poll, 2002. Available at: http://www.sleepfoundation.org/_content/hottopics/2002SleepInAmericaPoll.pdf. Accessed May 30, 2005.

5. National Sleep Foundation: Sleep in America Poll, 2003. Available at: http://www.sleepfoundation.org/_content/hottopics/2003SleepPollExecSumm.pdf. Accessed May 30, 2005.

6. Chua LWY, Yu NC, Golish JA, et al. Epworth sleepiness scale and the multiple sleep latency test: dilemma of the elusive link. Sleep. 1998;21(Suppl):184.

7. U.S. Modafinil in Narcolepsy Multicenter Study Group.  Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43:88-97.

8.  Johns MW, Hocking B. Daytime sleepiness and sleep habits of Australian workers. Sleep. 1997;20:844-849.

9.  Carskadon MA, Dement WC. Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology. 1981;18:107-113.

10. Rosenthal L, Roehrs TA, Rosen A, Roth T.  Level of sleepiness and total sleep time following various time in bed conditions.  Sleep. 1993;16:226-232.

11.  Roehrs TA, Shore E, Papineau K, et al. A two-week sleep extension in sleepy normals. Sleep Res. 1994;23:142.

12. Beers T. Flexible schedules and shift work: replacing the ‘9-to-5’ workday? Monthly Labor Rev. 2000;33-40.

13. Monk TH. Shift work. In: Kryger MH, Roth T, Dement WC, eds. Priniciples and Practices of Sleep Medicine. 3rd ed. Philadelphia, PA: Saunders; 2000:602-603.

14. Akerstedt T. Sleepiness as a consequence of shift work. Sleep. 1988;11:17-34.

15. Budnick LD, Lerman SE, Baker TL, Jones H, Czeisler CA. Sleep and alertness in a 12-hour rotating shift work environment. J Occup Med. 1994;36:1295-1300.

16.  Philip P, Stoohs R, Guilleminault C. Sleep fragmentation in normals. Sleep. 1994;17:242-247.

17. Chugh DK, Weaver TE, Dinges DF.  Neurobehavioral consequences of arousals.  Sleep. 1996;19(Suppl):S198-S201.

18.  Melendres CS, Lutz JM, Rubin ED, Marcus CL. Daytime sleepiness and hyperactivity in children with suspected sleep-disordered breathing. Pediatrics. 2004;114:768-775.

19. Golan N, Shahar E, Ravid S, Pillar G. Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactive disorder.  Sleep. 2004;27:261-266.

20. Gozal D, Wang M, Pope DW.  Objective sleepiness measure in pediatric obstructive sleep apnea. Pediatrics. 2001;108:693-697.

21. Rosen CL, Storfer-Isser A, Taylor HG, et al.  Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics. 2004;114:1640-1648.

22. Chervin RD, Archbold KH, Dillon JE, et al. Inattention, hyperactivity, and symptoms of sleep-disordered breathing. Pediatrics. 2002;109:449-456.

23. O’Brien LM, Mervis CB, Holbrook CR, et al. Neurobehavioral implications of habitual snoring in children. Pediatrics. 2004;114:44-49.

24. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movements disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder.  J Child Neurology. 1998;13:588-594.

25. Picchietti DL, Walters AS.  Moderate to severe periodic limb movements disorder in childhood and adolescence. Sleep. 1999;22:299-300.

26. Young T, Peppard PE, Gottlieb DJ.  Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002;165:1217-1239.

27. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4-5 year olds.  Arch Dis Child. 1993;68:360-366.

28. Castronovo V, Zucconi M, Nosetti L, et al.  Prevalence of habitual snoring and sleep-disordered breathing in preschool-aged children in an Italian community. J Pediatr. 2003;142:377-382.

29. Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems.  Am J Respir Crit Care Med. 1999;159:1527-1532.

30. Bassiri AG, Guilleminault C. Clinical features of evaluation of obstructive sleep apnea-hypopnea syndrome. In: Kryger MH, Roth T, Dement WC, eds. Priniciples and Practices of Sleep Medicine. 3rd ed.  Philadelphia, PA: Saunders; 2000;868-878.

31. Guilleminault C, Do Kim Y, Chowdhuri S, et al. Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnoea syndrome. Eur Respir J. 2001;17:838-847.

32. Guilleminault C, Stoohs R, Clark A, et al. A cause of excessive daytime sleepiness: the upper airway resistance syndrome. Chest. 1993;104:781-787.

33. Chervin RD. Sleepiness, fatigue, tiredness, and lack of energy in obstructive sleep apnea.  Chest. 2000;118:372-379.

34. Gastaut H, Tassinari CA, Duron B.  Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res. 1966;1:167-186.

35. Guilleminault C, van den Hoed J, Mitler M.  Clinical overview of the sleep apnea syndromes. In: Guillemininault C, Dement W, eds. Sleep Apnea Syndromes. New York, NY:  Alan R Liss; 1978:1-11.

36. Bradley TD, McNicholas WT, Rutherford R, et al.  Clinical physiological heterogeneity of the central sleep apnea syndrome.  Am Rev Respir Crit Care Med. 1986;134:217-221.

37. Findley LJ, Zwillich CW, Ancoli-Israel S, et al. Cheyne-Stokes breathing during sleep in patients with left ventricular heart failure.  South Med J. 1985;78:11-15.

38. Chesson AL, Wise M, Davila D, et al. Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 1999;22:961-968.

39. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res. 2002;53:547-554.

40. Kirk VG, Bohn S. Periodic limb movements in children: prevalence in a referred population.  Sleep. 2004;27:313-315.

41. American Sleep Disorders Association.  International Classification of Sleep Disorders, revised: Diagnostic and Coding Manual. American Sleep Disorders Association, Rochester, MN, 1997;1-401.

42. Mendelson WB.  Are periodic leg movements associated with clinical sleep disturbance? Sleep. 1996;19:219-223.

43. Chervin RD. Periodic limb movements and sleepiness in patients evaluated for sleep-disordered breathing. Am J Respir Crit Care Med. 2001;164:1454-1458.

44. Montplaisir J, Boucher S, Poirier G, et al.  Clinical, polysomnographic, and genetic characteristics of restless legs syndrome. Mov Disord. 1997;12:61-65.

45. Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001;18:128-147.

46. Hublin C, Kaprio J, Partinen M, et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann Neurol. 1994;35:709-716.

47. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(Suppl 1):S16-S22.

48. US Xyrem in Narcolepsy Multi-center Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25:42-49.

49. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540-545.

50. International Classification of Sleep Disorders (ICSD): Diagnostic and Coding Diagnostic Classification Steering Committee (Thorpy MJ, chairman). American Sleep Disorders Association. Narcolepsy. 1990;347:38-43.

51. Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep. 1999;22:757-765.

52. Honda Y. Clinical features of narcolepsy: Japanese experiences. In: Honda Y, Juji T, eds. HLA in Narcolepsy. Berlin: Springer-Verlag; 1988:24-57.

53. Gelb M, Guilleminault C, Kraemer H, et al. Stability of cataplexy over several months: information for the design of therapeutic trials. Sleep. 1994;17:265-273.

54. Rogers AE, Aldrich MS, Caruso CC.  Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep. 1994;17:590-597.

55. Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiological insights, and future perspectives. J Clin Neurophysiol. 2001;18:78-105.

56. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355:39-40.

57. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553-1562.

58. Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause of excessive daytime sleepiness. The upper airway resistance syndrome. Chest. 1993;104:781-787.

59. Montplaisir J, Poirier G. HLA in disorders of excessive sleepiness without cataplexy in Canada. In: Honda Y, Juji T, eds. HLA in Narcolepsy. Berlin: Springer-Verlag; 1988:186.

60. Montplaisir J, De Champlain J, Young SN, et al. Narcolepsy and idiopathic hypersomnia: biogenic, amines and related compounds in CSF. Neurology. 1982;32:1299-1302.

61. Faull KF, Guilleminault C, Berger PA, Barchas JD. Cerebrospinal fluid monoamine metabolites in narcolepsy and hypersomnia. Ann Neurol. 1983;13:258-263.

62. Faull KF, Thiemann S, King RJ, Guilleminault C. Monoamine interactions in narcolepsy and hypersomnia: a preliminary report. Sleep. 1986;9:246-249.

63. Billiard M, Dauvillies Y. Idiopathic hypersomnia. Sleep Med Rev. 2001;5(5):351-360.

64. Roth B, Nevsimalova S, Rechtschaffen A. Hypersomnia with “sleep drunkenness”. Arch Gen Psychiatry. 1972;26:456-462.

65. Critchley M. The syndrome of hypersomnia and periodical megaphagia in the adult male (Kleine-Levin): what is its natural course? Rev Neurol. 1967;116:647-650.

66. Rosenow F, Kotagal P, Cohen BH, Green C, Wyllie E. Multiple sleep latency test and polysomnography in diagnosing Kleine-Levin syndrome and periodic hypersomnia.  J Clin Neurophysiol. 2000;17:519-522.

67. Arias M, Crespo Iglesias JM, Perez J, et al. Klein-Levin syndrome: contribution of brain SPECT in diagnosis. Rev Neurol. 2003;35:531-533.

68. Billiard M, Guilleminault C, Dement WC. A menstruation-linked periodic hypersomnia. Kleine-Levin syndrome or a new clinical entity? Neurology. 1975;25:436-443.

69. Sachs C, Persson H, Hagenfeldt K. Menstruation-associated periodic hypersomnia: a case study with successful treatment. Neurology. 1982;32:1376-1379.

70. Bamford CR. Menstrual-associated sleep disorder: an unusual hypersomniac variant associated with both menstruation and amenorrhea with a possible link to prolactin and metoclopramide. Sleep. 1993;16:484-486.

71. Rothstein JD, Guidotti A, Tinuper P, et al. Endogenous benzodiazepine receptor ligands in idiopathic recurring stupor. Lancet. 1992;340:1002-1004.

72. Lugaresi E, Montagna P, Tinuper P, et al. Endozepine stupor. Recurring stupor linked to endozepine-4 accumulation. Brain. 1998;121:127-133.

73. Soriani S, Carrozzi M, De Carlo L, et al. Endozepine stupor in children. Cephalalgia. 1997;17:658-661.

74. Francisco GE, Ivanhoe CB. Successful treatment of post-traumatic narcolepsy with methylphenidate: a case report. Am J Phys Med Rehabil. 1996;75:63-65.

75. Manni R, Tantara A. Evaluation of sleepiness in epilepsy. Clin Neurophysiol. 2000;111(suppl 2):S111-S114.

76. Toth LA, Opp MR. Sleep and infection. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia, PA: Hanley & Belfus; 2002:77-83.

77. Guilleminault C, Mondini S. Mononucleosis and chronic daytime sleepiness: a long term follow-up study. Arch Intern Med. 1986;146:1333-1335.

78. Askenasy JJM. Sleep in parkinson’s disease. Acta Neurol Scand. 1993;87:167-170.

79. Chokroverty S. Sleep and degenerative neurologic disorders. Neurol Clin. 1996;14:807-826.

80. Trenkwalder C. Sleep dysfunction in parkinson’s disease. Clin Neurosci. 1998;5:107-114.

81. George CFP. Neuromuscular disorders. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd Edition. Philadelphia, PA: W. B. Saunders Co; 2000;1087-1092.

82. Gibbs JW, Ciafaloni E, Radtke RA. Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy. Sleep. 2002;25:662-665.

83. Campbell SM, Clark S, Tindall EA, et al.  Clinical characteristics of fibrositis, I: a “blinded” controlled study of symptoms and tender points. Arthritis Rheum. 1983;26:817-825.

84. Hyyppa MT, Kronhom E. Nocturnal motor activity in fibromyalgia patients with poor sleep quality. J Psychosom Res. 1995;39:85-91.

85. Modolfsky H, Saskin P, Lue FA. Sleep and symptoms in fiborsitis syndrome after a febrile illness. J Rheumatol. 1988;15:1701-1704.

86. Moldolfsky H, Lue FA, Smythe H.  Alpha EEG sleep and morning symptoms of rheumatoid arthritis. J Rheumatol. 1983;10:373-379.

87. Perlis ML, Giles DE, Bootzin RR, et al.  Alpha sleep and information processing, perception of sleep, pain, and arousability in fibromyalgia.  Int J Neurosci. 1997;89:265-280.

88. Moldolfsky H, Lue FA. The relationship of alpha delta EEG frequencies to pain and mood in “fibrositis” patients with chlorpromazine and L-tryptophan. Electroencephalogr Clin Neurophysiol. 1980;50:71-80.

89. Yamashiro Y, Kryger MH. Sleep in heart failure.  Sleep. 1993;16:513-523.

90. Javaheri S, Parker TJ, Liming JD, et al.  Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations.  Circulation. 1998;97:2154-2159.

91. Brostrom A, Stromber A, Dahlsrom U, Fridland B. Sleep difficulties, daytime sleepiness, and health-related quality of life in patients with chronic heart failure. J Cardiovasc Nurs. 2004;19:232-242.

92. Davidson JR, MacLean AW, Brundage MD, Schulze K. Sleep disturbance in cancer patients. Social Science. 2002;54:1309-1321.

93. Portenoy RK, Tahler HT, Kombilth AB, et al. Symptom prevalence, characteristics and distress in a cancer population. Quality of Life Research. 1994;3:183-189.

94. Vena C, Parker K, Cunningham M, Clark J, McMillan S.  Sleep-wake disturbances in people with cancer part I: an overview of sleep, sleep regulation, and effects of disease and treatment. Oncol Nurs Forum. 2004;31:735-746.

95. Resta O, Paanacciulli N, Di Gioia G, et al.  High prevalence of previously unknown subclinical hypothyroidism in obese patients referred to a sleep clinic for sleep disordered breathing.  Nutr Metab Cardiovasc Dis. 2004;14:248-253.

96. Blanco Perez JJ, Blanco-Ramos MA, Zamarron Sanz C, et al. Acromegaly and sleep apnea. Arch Bronconeumol. 2004;40:355-359.

97. Rosenow F, Reuter S, Deuss U, et al. Sleep apnoea in treated acromegaly: relative frequency and predisposing factors. Clin Endcroninol (Oxf). 1996;45:563-569.

98. Bjork S, Jonsson B, Westphal O, Levin JE. Quality of life of adults with growth hormone deficiency: a controlled study, Acta Paediatr Scand. 1989;356(Suppl):55–59.

99. Tylee A, Gastpar M, Lepine JP, et al. DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. DEPRES Steering Committee. Int Clin Psychopharmacol. 1999;14:139-51.

100. Reynolds CF 3rd, Coble PA, Kupfer DJ, et al. Application of the multiple sleep latency test in disorders of excessive sleepiness. Electroencephalogr Clin Neurophysiol. 1982;53:443-52.

101. Chesson AL, Jr., Littner M, Davila D, et al. Practice parameters for the use of light therapy in the treatment of sleep disorders. Standards of Practice Committee, American Academy of Sleep Medicine. Sleep. 1999;22:641-660.

102. Czeisler CA. Commentary: evidence for melatonin as a circadian phase-shifting agent. J Biol Rhythms. 1997;12:618-623.

103. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continous postitive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med. 2003;163:565-571.

104. Morisson F, Decary A, Petit D, Lavigne G, Malo J, Montplaisir J. Daytime sleepiness and EEG spectral analysis in apneic patients before and after treatment with continuous positive airway pressure. Chest. 2001;119:45-52.

105. Allen RP, Early CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001;18:128-147.

106. Allen R, Becker PM, Bogan P, et al.  Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep. 2004;27:907-914.

107. Trenwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results form the TREAT RLS1 study, a 12 week, randomized, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry. 2004;75:92-97.

108.  Mamelak M, Black J, Monplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy.  Sleep. 2004;27:1327-1334.

109. US Xyrem in Narcolepsy Multi-center Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25:42-49.

110. Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with stimulants. ASDA standards of practice. Sleep. 1994;17:352-371.

111. US Modafinil in Narcolepsy Multicenter  Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology. 2000;54(5):1166-1175.

Articles

Print Friendly 

Diagnosis, Epidemiology, and Consequences of Insomnia

Daniel J. Buysse, MD, Anne Germain, PhD, and Douglas E. Moul, MD, MPH

Primary Psychiatry. 2005;12(8):37-44

 

This CME article is expired.

 

Needs Assessment:
Psychiatrists are frequently called upon to diagnose and treat patients with insomnia, but very few psychiatrists have had any formal training in sleep medicine.  Understanding the epidemiology and consequences of insomnia are necessary for proper appreciation of this condition.  The specific techniques used to assess and diagnose insomnia differ somewhat from those used for psychiatric disorders.  Learning these techniques is an essential first step toward effective patient management.

Learning Objectives:
• Define insomnia, and distinguish between insomnia symptoms and insomnia disorder.
• Indicate the prevalence and established risk factors for insomnia.
• Recognize the consequences of insomnia.
• Describe the clinical assessment of a patient presenting with insomnia.

Target Audience:
Primary care physicians and psychiatrists.
Accreditation Statement: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.


 

Abstract

Insomnia is defined as a complaint of difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep in an individual with adequate opportunity for sleep, and is one of the most common health problems presenting to primary care and psychiatric practitioners. Insomnia symptoms are extremely prevalent, occurring in approximately 30%–40% of the adult population, whereas more narrowly-defined insomnia disorders (ie, insomnia complaint with significant distress or daytime impairment) occur in approximately 5%–10% of the population. Established risk factors for insomnia symptoms include medical and psychiatric illnesses, female gender, and lower socioeconomic status. Insomnia is associated with significant morbidity, including increased healthcare utilization and costs, decreased quality of life, and increased risk of subsequent psychiatric disorders. The evaluation of insomnia rests on a thorough clinical history, including a 24-hour history of the sleep and waking periods. Sleep-wake diaries and questionnaires can often help to establish important sleep-wake patterns relevant to insomnia. In selected cases, actigraphy (measurement of wrist movements, which correlate with sleep and wakefulness) and polysomnography (sleep studies) may also be useful. Insomnia disorders can be broadly divided into those associated with concurrent medical, psychiatric, or medication/substance use; those associated with other sleep disorders; and primary insomnias, in which insomnia is the major symptom. Primary care physicians and psychiatrists should be vigilant for symptoms of insomnia and for insomnia disorders. Accurate diagnosis and treatment can reduce distress and may lead to improved outcomes of comorbid disorders.

Introduction

Insomnia is one of the most common healthcare complaints among patients presenting to both primary care and psychiatric practitioners. For many years, insomnia was discussed almost exclusively as a symptom of other conditions.1 Logically, treatment would be directed at the “underlying” disorder, with the expectation that the insomnia would then improve. Although insomnia is indeed associated with many physical and mental health conditions, several types of evidence suggest that insomnia may not simply be a symptom of those conditions, but may warrant independent assessment and treatment. For example, insomnia has been identified as a risk factor for the development of new-onset psychiatric disorders, it is one of the most common residual symptoms in treated psychiatric disorders, and its continued presence may herald the onset of new episodes of illness. Furthermore, while some data support the belief that improvement in health conditions is associated with reduced insomnia, other data suggests that insomnia responds to different treatments than the core symptoms of mental disorders.

The symptom of insomnia is defined as a complaint of difficulty falling asleep, difficulty staying asleep, or sleep that is not refreshing in an individual who has adequate opportunity and circumstances for sleep.2 Insomnia is not defined by any specific sleep duration, nor is it currently defined by any specific laboratory or polysomnographic (PSG) finding. The presence of adequate opportunity and circumstances for sleep distinguishes insomnia from sleep deprivation, in which the individual simply does not have (or does not allow himself) adequate opportunity for sleep. Insomnia and sleep deprivation have distinct causes and consequences.

An insomnia disorder is defined by the presence of the insomnia symptom, together with either marked distress or daytime impairment.3,4 Typically, insomnia disorders are diagnosed only when symptoms have been present for most days over a minimum duration, typically 1 month. Specific insomnia disorders differ from one another by the presence of other historical or clinical features, such as evidence for learned sleep-preventing associations or hyperarousal in psychophysiological insomnia, or the presence of symptoms from childhood in idiopathic insomnia.2

Insomnia is commonly described according to its duration as being either transient, short-term, or chronic.1 However, duration-based definitions have several limitations. First, the duration of insomnia in a specific patient may be difficult to determine; a patient with transient insomnia could be in the early stages of a chronic problem. Second, these definitions are not empirically derived from actual epidemiological evidence. Indeed, most epidemiological studies suggest that 50–85% of insomnia is chronic. Empirical evidence from one longitudinal study suggested that categories of occasional insomnia, repeated brief insomnia, and chronic insomnia were better-supported by the evidence.5 Third, the duration of insomnia is only a weak proxy for the actual variable of interest, ie, the likely etiology of a particular person’s insomnia problem.

Likewise, insomnia is often described as being of sleep onset, sleep maintenance, or early morning awakening types. These classifications are not particularly useful clinically because most patients have more than one type of complaint, and the actual symptoms are not stable over time.6 Once again, type of insomnia complaint is a proxy for the more important information about etiology.

Epidemiology

The epidemiology of insomnia is complicated by the problem of distinguishing insomnia as an isolated symptom versus insomnia as a syndrome distinct from other medical and mental disorders. Epidemiological studies rely on formalized self reports rather than on open-ended clinical interviews, leading to potential biases and other limitations in epidemiological studies.7 Deciding when a complaint of poor sleep is clinically significant is a challenge both for epidemiological studies and in the clinic, as suggested by the low degree of inter-rater reliability of clinical diagnoses among sleep specialists.8 In-depth review of the epidemiology of poor sleeping and insomnia is available elsewhere,9 but the major findings are summarized here.

The 1-year prevalence of insomnia symptoms is approximately 30% to 40% in the general population, and ≤66% in primary care and psychiatric settings. The prevalence of insomnia disorders (ie, insomnia with significant distress or daytime impairment) is in the range of 5% to 10% in the general population (Figure 1).9 More recent studies have also examined the prevalence of daytime symptoms in primary insomnia, including poor concentration, fatigue, sub-clinical depression symptoms, and sleep dissatisfaction.10

Risk factors for insomnia can be grouped into predisposing, precipitating, and perpetuating categories.11 (Table 1) Predisposing factors include advancing age, female sex, being divorced or separated, unemployment, and having comorbid medical or mental illness. Genetic factors for insomnia have not yet been established, but are likely to be important. Precipitating and perpetuating factors for insomnia include psychosocial stresses and strains (eg, moves, caregiver responsibilities).12 An additional perpetuating factor that serves as the target for many behavioral interventions is the patient’s adoption of counter-productive sleep habits. While these factors are believed to be important in clinical settings, the exact magnitude of each class of risks for insomnia is difficult to estimate in the general population.

The natural history of insomnia, determined from population-based studies, has not been well described. Acute insomnia can occur with a variety of live events and stressors, including medical illnesses, accidents, occupational or family problems, loneliness, or bereavement.12-14 However, insomnia can often evolve into a chronic condition. Longitudinal and population-based studies indicate that the median duration of a more chronic insomnia ranges between 2–6 years,15-17 but can persist for 10 years or longer in 15% to 50% of patients.14,18 While follow-up studies point to insomnia severity increasing with time,5,17 remission has been described in one study of older adults,15 in apparent contradiction to the notion that sleep worsens with age. Some studies strongly relate insomnia to medical and psychiatric conditions, so that insomnia decreases when adequate treatments are provided.16 Mental disorders are also strongly associated with insomnia, and insomnia exacerbates the course and amplifies the daytime symptoms of a variety of mental illnesses.

Consequences of Insomnia

Impaired Daytime Function and Quality of Life

Chronic insomnia, whether primary or secondary, has been related to many adverse consequences aside from impairments in getting and staying asleep, having adequate sleep length, and having restorative, good quality sleep. Individuals with insomnia report daytime impairments, including fatigue, mood changes, performance decrements, memory difficulties, irritability, daytime sleepiness, increased sensitivity to environmental stimuli, and decreased ability to accomplish daily duties.10,19-22 These daytime consequences suggest that individuals with insomnia would have decreased overall quality of life (QoL). Indeed, various studies have substantiated a reduction in QoL among insomnia sufferers20,23 similar in magnitude to that among patients with congestive heart failure or major depressive disorder (MDD).24 A decrease in QoL correlates with the severity of the insomnia complaint. Among those with medical disorders, insomnia has an effect independent of the comorbid condition.25,26 The lowering of QoL is likely mediated by consequences from role impairments at work, in social life, in family life, and in other role domains.27 Among persons with severe insomnia, a sense of alienation and stigma may arise, even in relation to healthcare providers.19

Mental Health

Insomnia complaints characterize mood and substance use disorders, and are frequent in anxiety disorders as well. Several longitudinal studies have documented that insomnia is a risk factor for the later development of mood, anxiety, and substance use disorders. The most robust consequence of insomnia is an increased risk of major depression (see Riemann and Voderholzer28 for review). Specifically, longitudinal studies indicate that insomnia complaints predict onset of depression over intervals from 1–35 years. In patients with MDD, insomnia is associated with worse treatment outcomes,29 suicidal ideation,30 symptom persistence,31 and recurrence of depression.9,32 Recurrent episodes of mania in bipolar patients can also be preceded by sleep disruption and insomnia,33-35 and the severity of insomnia is related to treatment outcome. Both insomnia and hypersomnia are common symptoms during the depressive phase of bipolar disorder.34,36

Additionally, insomnia has also been associated with increased risk for anxiety and alcohol use disorders.37 Insomnia complaints characterize anxiety disorders including generalized anxiety disorders, obsessive-compulsive disorder, acute stress disorder, and posttraumatic stress disorder (PTSD). Recent longitudinal studies suggest that insomnia complaints and objective sleep disruption following exposure to traumas predict the subsequent development of PTSD.38,39 In PTSD, increased severity of insomnia complaints is associated with daytime consequences, including poor perceived health and increased alcohol use, suicidality, and depression severity.

Alcohol is commonly used as a nonprescription sleep aid in the general population.40 However, alcohol is known to cause increased sleep fragmentation and decreased deep sleep in the second half of the night, so that alcohol use may actually exacerbate insomnia. The daytime consequences of alcohol dependence are further exacerbated by insomnia.41 In addition, insomnia complaints and objective sleep disruption are associated with increased risks of relapse in recovering alcoholics (see Brower42 for review).43 Insomnia complaints may also increase the risk for alcohol-related problems in individuals with co-occurring anxiety disorders.41

Physical Health and Morbidity

Insomnia adversely affects physical health. Health complaints, healthcare utilization, and hospitalization are more frequent among individuals with insomnia as compared to good sleepers. Chronic insomnia is also associated with more specific conditions, including chronic pain,44 fibromyalgia,45 and cancer.46,47 Insomnia has been associated with increased frequency of motor vehicle and other accidents,48 as well as increased incidence of falls.49 Difficulty initiating and maintaining sleep confers increased risk for developing hypertension and cardiovascular disease.50 Immune function is impaired in patients with chronic primary and secondary insomnia.51 Finally, insomnia has been associated with increased mortality in some studies,52 but not in the majority.53-55

Healthcare Utilization and Costs

The direct and indirect costs associated with insomnia are substantial.56 Population-based studies have shown that insomniacs show increased number of medical consultations, medication use, number of medical tests performed, number of hospitalization days, and emergency visits compared to non-insomniacs.14,57 These all contribute to the approximately $14 billion  direct costs associated with insomnia.58 Indirect costs of insomnia include loss of productivity, absenteeism, and work-related accidents. Absenteeism is significantly more prevalent in insomniacs than in good sleepers.59 Workers with insomnia report more work-related injuries, and more motor vehicle accidents than good sleepers.60,61 Together, indirect costs associated with insomnia were estimated to exceed $75 billion in 1994.62 Even more conservative estimates have ranged from $30–$35 billion.63 Prospective studies are required to estimate the potential economic benefits of treating insomnia.

Assessment and Diagnosis

The diagnosis of insomnia disorders is most often based on clinical evaluation. In a smaller number of cases, actigraphy and PSG may help to establish the proper diagnosis.

History

The assessment of patients with insomnia rests on a careful clinical history, addressing specific symptoms, chronology, exacerbating and alleviating factors, and response to previous treatments. However, some aspects of a complete insomnia history differ from that of other clinical disorders and deserve special emphasis:

24-hour assessment. A thorough insomnia history should cover the patient’s usual sleep and wake periods. Starting with bedtime, the clinician should evaluate the patient’s usual activities, behaviors, and thoughts related to bedtime. Many patients with insomnia report heightened cognitive activity as bedtime approaches—an indication of conditioned arousal. Insomnia patients may also try to go to bed before they are actually sleepy, or “set up camp” in the bedroom in order to not miss any potential opportunity for sleep. Ironically, this excessive time in bed actually serves to worsen sleep further.

Environmental factors. Potential environmental factors that disrupt sleep (noise, temperature, light) should be evaluated.

Regularity. The regularity or variability of sleep hours from day to day should be discussed. Insomnia patients are often frustrated with the unpredictability of their sleep. Conversely, establishing a regular pattern may help to improve symptoms.

Other sleep disorders. Symptoms of specific sleep disorders, such as restless legs syndrome, snoring or breathing problems during sleep, pain or limitations to mobility during sleep, and the presence of abnormal behaviors should be assessed. These conditions may lead to different treatment recommendations than “primary” forms of insomnia.

Daytime activities and impairment. Particular emphasis should be placed on exercise routines, regularity of work and daytime activities, limitations in these activities, and daytime sleepiness and napping. Assessment of daytime activities helps to establish the consequences of insomnia, and may provide clues to useful interventions

Bedpartner interview. Some aspects of sleep and specific sleep disorders, such as periodic leg movements or parasomnias, may not be evident to the patient. The bedpartner may also identify additional factors that contribute to the insomnia.

A thorough medical and psychiatric history is also important in the evaluation of insomnia. Medical conditions that cause breathing difficulty, pain, or limited mobility may be especially relevant in patients with insomnia complaints. Virtually any psychiatric disorder can also be associated with insomnia, but mood disorders, anxiety disorders, and psychotic disorders are most frequently comorbid with insomnia.

Medication and substance histories are also essential, including prescription and over-the-counter medications, substances such as caffeine and alcohol, and commonly abused drugs. A list of medications that can be potentially associated with insomnia is summarized in Table 2.64


Other Assessment Tools

Although the clinical history is the key to making an insomnia diagnosis, several other tools may aid this process. A 1-week or 2-week sleep-wake diary, in which patients record their actual sleep hours and sleep experiences, can be invaluable. Diaries are useful for establishing patterns of sleep, as well as indicating the day-to-day variability in sleep hours and sleep problems. Additional information in some sleep diaries includes medication and substance use. Patients who complete a sleep diary often identify patterns to their own sleep problem, and can take corrective action. An example of a sleep diary in an insomnia patient is shown in Figure 2.

Actigraphy is an objective means of assessing rest activity patterns, and uses a motion-sensitive wrist-worn device worn on the non-dominant wrist. Commercially available software provides descriptive statistics and graphical displays of rest-activity patterns. Validation studies have shown a strong correlation between actigraphy patterns and sleep as monitored by PSG, although actigraphy tends to overestimate the actual amount of sleep.65 Similar to the sleep diary, actigraphy can be useful for examining temporal patterns, variability, and responses to treatment. However, actigraphy is not recommended for the routine evaluation of insomnia.66 Rather, it is useful for patients who may have circadian rhythm sleep disorders (eg, delayed sleep phase syndrome), or for examining longitudinal patterns, such as the response to treatment.

Polysomnography (PSG), or a sleep study, is the gold standard for identifying and quantifying sleep disturbances. However, PSG is not routinely recommended for the evaluation of chronic insomnia67 because in most cases, PSG simply confirms the patient’s subjective report without indicating a cause for awakenings. PSG may be useful in certain patients, such as those with symptoms of sleep apnea, periodic limb movements, or parasomnias. In addition, a marked discrepancy between the patient’s sleep complaints and findings on PSG serve as the basis for identifying sleep state misperception or paradoxical insomnia. Finally, patients with unusual complaints or poor response to usual treatments may be candidates for PSG.

Differential Diagnosis

As previously noted, symptom-based classifications (ie, sleep-onset, sleep maintenance, or mixed type insomnia) and duration-based classifications (e.g., acute, short-term, and chronic insomnia) are of limited value. Etiology-based classifications are the most useful for categorizing insomnia. Specific classification systems include International Classification of Diseases, Ninth Edition (ICD-9)68 and ICD-10,69 the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),4 and the International Classification of Sleep Disorders, revised (ICSD-2).3 In general, the ICD has the broadest, least well-described categories, DSM-IV has somewhat more specific categories, and ICSD has the most specific categories. However, each of the three major classification systems basically describe three major categories of insomnia, summarized in Table 3.

Primary Insomnia

The category of primary insomnia refers to disorders in which insomnia is the primary symptom, with other disorders ruled out as possible causes. DSM-IV includes a single category for primary insomnia. ICSD-2 subdivides primary insomnia into several more specific categories. For instance, psychophysiological insomnia is characterized by conditioned arousal at bedtime, learned sleep-preventing associations, and increased physiological arousal at bedtime. Idiopathic (childhood-onset) insomnia is characterized by a lifelong history, with little variation over time. Paradoxical insomnia is characterized by severe insomnia and consequences, out of proportion to objective findings.

Secondary Insomnia

The category of secondary insomnia includes insomnia associated with medical disorders, insomnia related to mental disorders, and insomnia related to the acute effects of a substance or withdrawal from a substance/medication. This is the largest single group of chronic insomnia diagnoses seen in epidemiological studies and in clinical samples.8,70 One potential concern regarding secondary insomnia disorders is that, in practice, it is often very difficult to prove that the insomnia is indeed secondary.71,72 To make a determination of true secondary insomnia would require that the other condition began before the insomnia, that the insomnia symptoms vary with the severity of the other disorder, and that treatment of the other disorder also leads to resolution of insomnia. Data regarding this type of covariation is limited. Although improvement of medical conditions and depression are associated with improvement of insomnia,24,73 sleep disturbances are also the most common residual symptom in patients being treated for depression.74 Thus, the mere presence of another medical or psychiatric disorder should not lead the clinician to conclude that insomnia is necessarily secondary to that condition.

Insomnia as a Symptom of Other Specific Sleep Disorders

This group includes the insomnia seen in restless legs syndrome (RLS), some cases of obstructive sleep apnea syndrome, and some cases of parasomnias. Insomnia, particularly difficulty falling asleep, is a very frequent symptom of RLS. The hallmark of this disorder is the urge to move the legs, temporarily relieved with movement, and accompanied by dysesthesias often described as “creepy-crawly” or “ants under my skin.” RLS symptoms follow a regular circadian pattern with worsening in the evening hours near the usual bedtime. Insomnia is somewhat less common in obstructive sleep apnea syndrome, although older adults and those with more central sleep apneas may have this presentation. Symptoms of snoring, breathing pauses, awakening with choking or gasping sensations, and daytime sleepiness should all suggest the possibility of sleep apnea. Parasomnias such as the severe nightmares of PTSD are often accompanied by significant insomnia.

A Practical Approach

In most practices, clinicians simply do not have the time to conduct a complete evaluation of all factors that may be relevant in a patient with insomnia. One approach to this quandary is to focus on areas of the evaluation with the highest yield, and to continue to evaluate over a period of time. Upon initial evaluation, the clinician should establish the duration of the problem, its severity, its consequences for daytime function, and any factors that the patient can identify as being associated with the problem. If acute and preceded by an immediate stress, instruction in good sleep habits and/or medication treatment may be appropriate. If the problem is chronic, the patient should be given a 2-week sleep diary to track their problem, and this can be briefly reviewed, together with medical and psychiatric history, upon a return visit. In particular, the clinician should look for excessive time in bed relative to actual sleep time and extreme day-to-day variability in sleep patterns; these may be amenable to behavioral recommendations. The clinician should also evaluate symptoms of other possible sleep disorders that would require more specific treatment. If symptoms or suspicion of sleep apnea or a parasomnia arise, referral to a sleep medicine center may be appropriate. RLS warrants an initial trial of pharmacotherapy, and primary insomnia warrants an initial trial of behavioral sleep recommendations and/or pharmacologic treatment.

Conclusion

Insomnia is a prevalent health problem associated with a variety of morbidities. It is a frequent “co-traveler” with other medical and psychiatric conditions, but often warrants independent treatment. Evaluation of insomnia rests on clinical history and monitoring of sleep-wake patterns. Evidence of other medical, psychiatric, and substance-induced problems should be sought. In selected cases referral for specialized evaluation and treatment may be warranted, but the majority of chronic insomnia can be managed in primary care and psychiatric settings.PP

References

1. Drugs and insomnia. NIH Consensus Development Conference. National Inst Health Consens Dev Conf Summ. 1984;4(10):1-9.

2. Edinger JD, Bonnet MH, Bootzin RR, et al. Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group. Sleep. 2004;27(8):1567-1596.

3. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

4. Diagnostic and Statistical Manual of Mental Disorders. 4th ed text rev. Washington, DC: American Psychiatric Association; 2000.

5. Vollrath M, Wicki W, Angst J. The Zurich study. VIII. Insomnia: association with depression, anxiety, somatic syndromes, and course of insomnia. Eur Arch Psychiatry Neurol Sci. 1989;239(2):113-124.

6. Hohagen F, Kappler C, Schramm E, Riemann D, Weyerer S. Sleep onset insomnia, sleep maintaining insomnia and insomnia with early morning awakening–temporal stability of subtypes in a longitudinal study on general practice attenders. Sleep. 1994;17(6):551-554.

7. Moul DE, Hall M, Pilkonis PA, Buysse DJ. Self-report measures of insomnia adults: rationales, choices, and needs. Sleep Med Rev. 2004;8:177-198.

8. Buysse DJ, Reynolds CF, Hauri PJ, et al. Diagnostic concordance for DSM-IV sleep disorders: A report from the APA/NIMH DSM-IV field trial. Am J Psychiatry. 1994;151(9):1351-1360.

9. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6(2):97-111.

10. Moul DE, Buysse DJ, Nofzinger EA, Pilkonis PA, Houck PR, Miewald JM. Symptoms reports in severe chronic insomnia. Sleep. 2002;25(8):553-563.

11. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987;10(4):541-553.

12. Kappler C, Hohagen F. Psychosocial aspects of insomnia. Results of a study in general practice. Eur Arch Psychiatry Clin Neurosci. 2003;253(1):49-52.

13. Allaert FA, Urbinelli R. Sociodemographic profile of insomniac patients across national surveys. CNS Drugs. 2004;18 (Suppl) 1:3-7.

14. Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: A placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62:453-463.

15. Chevalier H, Los F, Boichut D, Bianchi M, et al. Evaluation of severe insomnia in the general population: results of a European multinational survey. J Psychopharmacol. 1999;13(4 Suppl 1):S21-S24.

16. Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic illness. Arch Intern Med. 1998;158(10):1099-1107.

17. Mendelson WB. Long-term follow-up of chronic insomnia. Sleep. 1995;18(8):698-701.

18. Janson C, Lindberg E, Gislason T, Elmasry A, Boman G. Insomnia in men-a 10-year prospective population based study. Sleep. 2001;24(4):425-430.

19. Carey TJ, Moul DE, Pilkonis P, Germain A, Buysse DJ. Focusing on the Experience of Insomnia. Behav Sleep Med. 2005;3(2):73-86.

20. Leger D, Scheuermaier K, Philip P, Paillard M, Guilleminault C. SF-36: evaluation of quality of life in severe and mild insomniacs compared with good sleepers. Psychosom Med. 2001;63(1):49-55.

21. Ohayon MM, Lemoine P. [Daytime consequences of insomnia complaints in the French general population]. Encephale. 2004;30(3):222-227.

22. Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: Results of the 1991 National Sleep Foundation Survey. II. Sleep. 1999;22(Suppl 2):S354-S358.

23. Hatoum HT, Kong SX, Kania CM, Wong JM, Mendelson WB. Insomnia, health-related quality of life and healthcare resource consumption. A study of managed-care organisation enrollees. Pharmacoeconomics. 1998;14(6):629-637.

24. Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract. 2002;51(3):229-235.

25. Karlsen KH, Larsen JP, Tandberg E, Maeland JG. Influence of clinical and demographic variables on quality of life in patients with Parkinson’s disease [see comments]. J Neurol Neurosurg Psychiatry. 1999;66(4):431-435.

26. McCall WV, Reboussin BA, Cohen W. Subjective measurement of insomnia and quality of life in depressed inpatients. J Sleep Res. 2000;9(1):43-48.

27. Leger D, Guilleminault C, Bader G, Levy E, Paillard M. Medical and socio-professional impact of insomnia. Sleep. 2002;25(6):625-629.

28. Riemann D, Voderholzer U. Primary insomnia: a risk factor to develop depression? J Affect Disord. 2003;76:255-259.

29. Buysse DJ, Tu XM, Cherry CR,  et al. Pre-treatment REM sleep and subjective sleep quality distinguish depressed psychotherapy remitters and nonremitters. Biol Psychiatry. 1999;45:205-213.

30. Agargun MY, Kara H, Solmaz M. Sleep disturbances and suicidal behavior in patients with major depression. J Clin Psychiatry. 1997;58(6):249-251.

31. Moos RH, Cronkite RC. Symptom-based predictors of a 10-year chronic course of treated depression. J Nerv Ment Dis. 1999;187(6):360-368.

32. Perlis ML, Giles DE, Buysse DJ, Tu X, Kupfer DJ. Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Disord. 1997;42:209-212.

33. Barbini B, Bertelli S, Colombo C, Smeraldi E. Sleep loss, a possible factor in augmenting manic episode. Psychiatry Res. 1996;65(2):121-125.

34. Jackson A, Cavanagh J, Scott J. A systematic review of manic and depressive prodromes. J Affect Disord. 2003;74(3):209-217.

35. Wehr TA. The durations of human melatonin secretion and sleep respond to changes in daylength (photoperiod). J Clin Endocrinol Metab. 1991;73(6):1276-1280.

36. Nofzinger EA, Thase ME, Reynolds CF, et al. Hypersomnia in bipolar depression: A comparison with narcolepsy using the multiple sleep latency test. Am J Psychiatry. 1991;148:1177-1181.

37. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411-418.

38. Koren D, Arnon I, Lavie P, Klein E. Sleep complaints as early predictors of posttraumatic stress disorder: a 1-year prospective study of injured survivors of motor vehicle accidents. Am J Psychiatry. 2002;159(5):855-857.

39. Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B. REM sleep and the early development of posttraumatic stress disorder. Am J Psychiatry. 2002;159(10):1696-1701.

40. Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep. 1998;21(2):178-186.

41. Crum RM, Ford DE, Storr CL, Chan YF. Association of sleep disturbance with chronicity and remission of alcohol dependence: data from a population-based prospective study. Alcohol Clin Exp Res. 2004;28(10):1533-1540.

42. Brower KJ. Insomnia, alcoholism and relapse. Sleep Med Rev. 2003;7(6):523-539.

43. Clark CP, Gillin JC, Golshan S, et al. Increased REM sleep density at admission predicts relapse by three months in primary alcoholics with a lifetime diagnosis of secondary depression. Biol Psychiatry. 1998;43(8):601-607.

44. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev. 2004;8(2):119-132.

45. Harding SM. Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci. 1998;315(6):367-376.

46. Savard J, Morin CM. Insomnia in the context of cancer: A review of a neglected problem. J Clin Oncol. 2001;19(3):895-908.

47. Theobald DE. Cancer pain, fatigue, distress, and insomnia in cancer patients. Clin Cornerstone. 2004;6 (Suppl 1D):S15-S21.

48. Powell NB, Schechtman KB, Riley RW, Li K, Guilleminault C. Sleepy driving: accidents and injury. Otolaryngol Head Neck Surg. 2002;126(3):217-227.

49. Brassington GS, King AC, Bliwise DL. Sleep problems as a risk factor for falls in a sample of community- dwelling adults aged 64-99 years. J Am Geriatr Soc. 2000;48(10):1234-1240.

50. Suka M, Yoshida K, Sugimori H. Persistent insomnia is a predictor of hypertension in Japanese male workers. J Occup Health. 2003;45(6):344-350.

51. Taylor DJ, Lichstein KL, Durrence HH. Insomnia as a health risk factor. Behav Sleep Med. 2003;1(4):227-247.

52. Pollak CP, Perlick D, Linsner JP, Wenston J, Hsieh F. Sleep problems in the community elderly as predictors of death and nursing home placement. J Community Health. 1990;15(2):123-135.

53. Althuis MD, Fredman L, Langenberg PW, Magaziner J. The relationship between insomnia and mortality among community-dwelling older women. J Am Geriatr Soc. 1998;46(10):1270-1273.

54. Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry. 2002;59(2):131-136.

55. Kripke DF, Simons RN, Garfinkel L, Hammond EC. Short and long sleep and sleeping pills. Is increased mortality associated? Arch Gen Psychiatry. 1979;36(1):103-116.

56. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep. 1999;22(Suppl 2):S386-S393.

57. Novak M, Mucsi I, Shapiro CM, Rethelyi J, Kopp MS. Increased utilization of health services by insomniacs–an epidemiological perspective. J Psychosom Res. 2004;56(5):527-536.

58. Walsh JK. Clinical and socioeconomic correlates of insomnia. J Clin Psychiatry. 2004;65(Suppl 8):13-19.

59. Simon GE, Von Korff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry. 1997;154(10):1417-1423.

60. Metlaine A, Leger D, Choudat D. Socioeconomic impact of insomnia in working populations. Ind Health. 2005;43(1):11-19.

61. Nakata A, Ikeda T, Takahashi M, et al. Sleep-related risk of occupational injuries in Japanese small and medium-scale enterprises. Ind Health. 2005;43(1):89-97.

62. Stoller MK. Economic effects of insomnia. Clin Ther. 1994;16(5):873-97; discussion 854.

63. Chilcott LA, Shapiro CM. The socioeconomic impact of insomnia. Pharmacoeconomics. 1996;10:1-14.

64. Buysse DJ, Germain A, Moul D, Nofzinger EA. Insomnia. In: Buysse DJ, ed. Sleep Disorders and Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; 2005:29-75.

65. Sadeh A, Acebo C. The role of actigraphy in sleep medicine. Sleep Med Rev. 2002;6(2):113-124.

66. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. rev ed. Chicago, IL: American Academy of Sleep Medicine; 2001.

67. Sateia MJ, Doghramji K, Hauri PJ, Morin CM. Evaluation of chronic insomnia. An American Academy of Sleep Medicine review. [Review] [414 refs]. Sleep. 2000;23(2):243-308.

68. World Health Organization. International Statistical Classification of Diseases and Related health problems. 9th ed. Geneva: World Health Organization; 1977.

69. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th ed rev. Geneva: World Health Organization; 1992.

70. Ohayon MM. Prevalence of DSM-IV diagnostic criteria of insomnia: distinguishing insomnia related to mental disorders from sleep disorders. J Psychiatr Res. 1997;31(3):333-346.

71. Harvey AG. Insomnia: symptom or diagnosis? Clin Psychol Rev. 2001;21(7):1037-1059.

72. McCrae CS, Lichstein KL. Secondary insomnia: diagnostic challenges and intervention opportunities. Sleep Med Rev. 2001;5(1):47-61.

73. Rush AJ, Armitage R, Gillin JC, et al. Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biol Psychiatry. 1998;44:3-14.

74. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry. 1999;60(4):221-225.

 

 
 

Dr. Buysse is professor of psychiatry,  Dr. Germain is postdoctoral fellow, and Dr. Moul is assistant professor of psychiatry in the Department of Psychiatry at the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania.

Disclosure: Drs. Germain and Moul report no affliliations with or financial interests in any commercial organization that might pose a conflict of interest. Dr. Buysse has served as a consultant to Actelion, Cephalon, Eli Lilly, Merck, Neurocrine, Pfizer, Respironics, Sanofi-Aventis, Servier, Sepracor, and Takeda.

Funding/support: This work was suppored by National Institutes of Health grant nos. MH24652, AG00972, RR00052, and AG 29677.

Please direct all correspondence to: Daniel J. Buysse, MD; University of Pittsburgh School of Medicine; Western Psychiatric Institute and Clinic; 3811 O’Hara St.; Pittsburgh, PA 15213.


 

Articles

Print Friendly 

Mauricio Infante, MD, and Ruth Benca, MD, PhD

Primary Psychiatry. 2005;12(8):47-46

 

This CME article is expired.
 
Needs Assessment:
Insomnia is more common in psychiatric patients than in those with other medical disorders. It is possible that the higher incidence of insomnia  observed in patients with psychiatric disorders is related to the use of psychotropic drugs. Chronic insomnia in psychiatric patients does not necessarily resolve even with remission of the underlying psychiatric illness. Awareness of various treatment options, including behavioral and pharmacologic therapies, will allow for more appropriate treatment selection for patients with chronic insomnia.

Learning Objectives:
• Explain the importance of behavioral and pharmacologic approaches in the treatment of insomnia.
• Describe treatment strategies for insomnia, including sleep hygiene recommendations
• Inform the reader about FDA-approved agents to treat primary insomnia as well as other medications that may be useful in the treatment of insomnia

Target Audience:
Primary care physicians and psychiatrists.
Accreditation Statement: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.

It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.


 

 

Abstract

Chronic insomnia is a common complaint in psychiatric practice. The management of patients with insomnia should  promote sleep as well as restore normal daytime function. Most treatment modalities, including behavioral and pharmacologic approaches, have been validated in patients with primary insomnia, but may also be helpful in patients with secondary insomnia or insomnia comorbid with medical and psychiatric conditions. Behavioral therapies appear to have longer-lasting efficacy after cessation of treatment, and should therefore always be considered. Hypnotics are approved for the short-term treatment of insomnia; they are generally used in the treatment of acute or transient types of insomnia, but are increasingly being used for chronic insomnia as well. In the presence of psychiatric disorders or other sleep disorders, other options such  as antidepressants, antipsychotics, or anticonvulsants may help promote sleep.

Introduction

Chronic insomnia is a prevalent complaint in psychiatric practice, since most psychiatric disorders are characterized by sleep disturbance. Insomnia secondary to or comorbid with psychiatric illness is one of the most common forms of chronic insomnia.1 Appropriate treatment requires identification of the factors implicated in the etiology of each case of insomnia. Insomnia has traditionally been classified as primary or secondary, based on presumed etiologies. Secondary insomnia encompasses sleep disturbance caused by mental, neurological, or other medical disorders; since causality is often difficult to establish, insomnia occurring with other disorders is also referred to as comorbid insomnia. The management of patients with insomnia should aim both at promoting sleep as well as restoring normal daytime function. Management of primary medical and psychiatric (eg, mood or substance abuse disorders) disorders should be the initial target of intervention in cases of secondary insomnia. However, specific treatments to improve sleep initiation or maintenance are often required in these patients as well.

It is still not clear whether the treatment of insomnia improves the course of medical or psychiatric problems, but there is increasing evidence that treatment does not worsen disorders, such as depression.2 In fact, treating insomnia may prevent manic episodes in bipolar disorder.3 Furthermore, resolution of insomnia is associated with improvement in self-perceived health in geriatric subjects.4

Management interventions can be divided into behavioral and pharmacologic treatment approaches. Although most treatments, both pharmacologic and behavioral, have been validated in patients with primary insomnia, they are also used in patients with secondary insomnia disorders. Practice parameters for the nonpharmacologic treatment of chronic insomnia were published by the American Academy of Sleep Medicine in 1999.5 However, guidelines for the pharmacologic treatment of insomnia have not been updated in the last 20 years and no guidelines exist for chronic treatment of insomnia, perhaps due to the paucity of long-term efficacy studies. Therefore, pharmacotherapy has been the most commonly used approach to treat insomnia, including both acute and chronic types. Currently, hypnotics are approved for the short-term treatment of insomnia and are generally the treatment of choice for acute or transient types of insomnia—conditions that are largely caused by various psychosocial stressors. Hypnotics and other medications are also used to treat chronic insomnia, although relatively little data are available for this indication.

Initial improvement may occur more rapidly following treatment with hypnotic medications in comparison to behavioral treatments, such as relaxation and sleep hygiene education.6 Treatment effects over periods of 4–8 weeks are similar for both therapeutic modalities, as well as in combination.7 However, nonpharmacologic therapies appear to have longer-lasting efficacy after cessation of treatment and should therefore always be considered.6-8

 Behavioral Treatment

A variety of behavioral treatments have been developed for the treatment of insomnia (Table 1), and when used individually or in combination, can lead to significant improvement in sleep. Several meta-analyses of behavioral treatments for primary insomnia suggest that both individual procedures as well as multi-component approaches lead to improvements in various aspects of sleep. Effect sizes are also comparable to those obtained with pharmacotherapy.9-11


In 1999, The American Academy of Sleep Medicine published practice parameters for the nonpharmacologic treatment of insomnia.5 Treatment methods were graded according to the available empirical evidence and classified in one of three categories of recommendations: standard (evidence of randomized, well-designed trials with low-a and low-b errors or overwhelming evidence of randomized trials with high b errors), guideline (evidence of randomized trials with high b errors or consensus of evidence of nonrandomized controlled or concurrent cohort studies), and option (inconclusive or conflicting evidence or conflicting expert opinion).5 Stimulus control was recommended as a generally accepted patient-care strategy in the treatment of chronic insomnia (standard). Progressive muscle relaxation, paradoxical intention, and biofeedback were recommended as guideline strategies. Sleep restriction and multicomponent cognitive therapy were classified as options at that time. More recent reviews, however, advocate for the use of multicomponent cognitive therapy, or cognitive-behavioral therapy (CBT), in both primary and secondary/comorbid insomnias.12,13 In general, patients with chronic insomnia tend to exhibit multiple behaviors that perpetuate their sleep disturbance, including anxiety and hyperarousal,14 maladaptive attitudes about sleep, and disruption of circadian and homeostatic processes that govern sleep. Combination CBTs address all of these factors.

Several factors may affect the availability of behavioral treatments, including cost, the need for trained therapists, and difficulties with patient motivation and compliance in some cases. However, it has been estimated that about 70% to 80% of cases of primary insomnia could benefit from nonpharmacologic therapies,7 and as few as 2–4 sessions can lead to significant improvement.12,15

Sleep Hygiene

Regardless of the cause, treatment of insomnia should always include attention to sleep hygiene. Good sleep habits aim at reinforcing the circadian rhythm with regular bedtimes, waking-up times, and daily exercise. They also help to decrease arousal before bedtime by eliminating various factors (eg, environmental, chemical and cognitive) that may interfere with sleep. Maladaptive sleep-related behaviors are often present in patients with chronic insomnia and can contribute to or reinforce sleep difficulties. Changing sleep habits may improve sleep-onset insomnia or reduce sleep-maintenance problems; for example, instituting a regular sleep-wakefulness schedule was associated with decreased latency to sleep onset and increased sleep efficiency in a sample of college undergraduate students.16 Unfortunately, good sleep hygiene alone does not always lead to significant improvement in sleep. Nevertheless, it is an important starting point for other behavioral treatments, and poor sleep habits will likely decrease the efficacy of pharmacotherapy. Sleep hygiene recommendations are listed in Table 2.

 

Psychological and Behavioral Therapies

Psychological and behavioral therapies often produce reliable and long-lasting improvements in sleep in patients with chronic insomnia. Stimulus control therapy, relaxation training, sleep restriction, and cognitive therapy are different approaches used to eliminate the patient’s misconceptions about sleep, anxiety, and maladaptive conditioning to the sleep environment. Such misperceptions can cause or exacerbate the insomnia. Multifaceted CBT consists of combining behavioral (stimulus control, sleep restriction), cognitive (cognitive restructuring, paradoxical intention) and educational (sleep hygiene) interventions to treat insomnia.

The objective of stimulus control therapy is to reassociate bedtime and the bedroom with rapid onset of sleep. Patients are instructed to go to bed only when sleepy, to use the bed and bedroom only for sleep and sex, to get out of bed when unable to sleep, to arise from bed at a regular time each morning, and to avoid napping during the day. Meta-analyses of studies of nonpharmacologic treatment of insomnia have found that stimulus control reduced objective measures of sleep-onset latency and waking time after sleep onset in subjects with chronic insomnia.9,10

Relaxation training aims at reducing somatic arousal, with progressive muscle relaxation or biofeedback, or cognitive arousal, with imagery training or thought stopping, to promote sleep. Progressive muscle relaxation is the most studied type of relaxation therapy, and has shown to reduce sleep latency and time spent awake after sleep onset, leading to an increase of total sleep time in patients with chronic insomnia.9,10

Individuals with insomnia frequently increase their time in bed in an effort to obtain more sleep. With sleep restriction, the amount of time spent in bed is adjusted to the actual amount of sleep time, with the goal of lowering the chance of fragmented and poor-quality sleep. Sleep restriction also increases homeostatic pressure to sleep by producing partial sleep deprivation. It should therefore be used with caution in patients with bipolar disorder, who can have manic episodes triggered by sleep deprivation, or in those with epilepsy, since sleep deprivation lowers the seizure threshold. Reduction of objective measures of sleep latency and time awake after sleep onset can be achieved with this type of treatment.17

The objective of cognitive restructuring therapy is to replace sleep-related dysfunctional beliefs and unrealistic sleep expectations (eg, “if I do not get 8 hours of sleep, I will not be able to function at all”) with more adaptive concepts (eg, “I am usually able to manage pretty well as long as I get some sleep”). There is evidence of positive results when this approach is integrated as part of a multifaceted treatment strategy.18

Paradoxical intention is a cognitive strategy that involves instructing the patient to stay awake and give up trying to fall asleep. Despite reports of sleep latency reduction,19-21 some studies have failed to report significant post-treatment differences between paradoxical intention and placebo or wait-list control condition.22,23

 

Pharmacologic treatment

The ideal hypnotic medication should be effective at promoting sleep onset, maintaining sleep, improving sleep quality, and improving daytime performance without altering normal sleep architecture or leading to tolerance, withdrawal, or side effects. Although various classes of medications are used in treating insomnia because of their sedative-hypnotic effects (Table 3), the search for the ideal hypnotic has been hampered by our lack of knowledge of the function of sleep at a molecular level.

Current Food and Drug Administration-approved agents to treat primary insomnia are the benzodiazepines––flurazepam, triazolam, quazepam, estazolam, and temazepam––and the nonbenzodiazepine agents––zolpidem, zaleplon, and eszopiclone. Unfortunately, with the exception of eszopiclone, these agents are only indicated for the short-term treatment of insomnia, since most have not been evaluated for long-term use in randomized controlled studies.

Other medications with sedating properties are also commonly used to treat insomnia, including antidepressants, anticonvulsants, antipsychotics, and various over-the-counter medications. Despite their widespread use, little data on the efficacy of these agents in treating insomnia are available, and they are not approved by the FDA for such use at present.

Benzodiazepine Receptor Agonists

As allosteric modulators of the γ-aminobutyric acid (GABA)A receptor, benzodiazepine receptor agonists cause neuronal inhibition by facilitating the opening of chloride channels. Their effects on sleep depend on their half-life and, possibly, on receptor subtype selectivity.

Benzodiazepines

Benzodiazepines were the most commonly used hypnotic medications prior to the development of the nonbenzodiazepine agents. They reduce sleep latency, increase stage 2 sleep, decrease slow-wave sleep (SWS), prolong rapid eye movement (REM) latency, and may produce mild REM sleep suppression.24 Flurazepam, quazepam, and estazolam are longer acting and have been shown to decrease wake time after sleep onset and the number of awakenings in subjective and objective studies.25-29 However, their longer effect may also explain the association with next-day sedation and impaired cognitive and psychomotor functioning.30 Temazepam has been reported to reduce objective measures of sleep latency and may improve sleep maintenance.31-33 Temazepam has also been associated with next-day sedation and impairment of memory and cognition.34 Triazolam has a shorter half-life and, although effective in reducing latency to sleep onset, has not consistently been shown to improve sleep maintenance.31,33,35

Benzodiazepines can cause respiratory depression, due to their muscle relaxant effects. Flurazepam has been reported to increase the number and duration of apneic episodes, as well as increasing the degree of oxygen desaturation.36 Other concerns related to use of benzodiazepines include the risk of developing tolerance and withdrawal effects (including rebound insomnia). Despite the potential of physical dependence at therapeutic doses with long-term use, the risks of benzodiazepines for chronic treatment of insomnia may be overestimated.37

Other Benzodiazepine-Receptor Agonists

Recently, agonists of the benzodiazepine receptor that have chemical structures different from benzodiazepines have been developed. In contrast to the benzodiazepines that bind nonselectively to all GABAA α subtypes, these newer agents tend to show relative specificity for one or more of the GABAA α subtypes. They may cause less rebound insomnia, abuse potential, or respiratory depression than benzodiazepines when given at recommended therapeutic doses. This  is possibly related to their shorter half-lives and receptor binding specificities.24 Zolpidem, zaleplon, and eszopiclone are currently approved by the FDA for treatment of insomnia.

Zolpidem, a selective agonist of the type 1 GABAA α subunit (BZ1), is primarily effective for treating sleep-onset insomnia rather than for improving sleep maintenance later in the night, which is probably related to its relatively short half-life. It has been shown to improve subjective measures of sleep, as well as objective measures of sleep latency.38-41 The improvement in sleep efficiency appears to be related to the reduction in sleep latency. Unlike the benzodiazepines, therapeutic doses of zolpidem do not appear to alter normal sleep architecture. Specifically, the SWS and REM sleep suppression typically seen with benzodiazepines have not been reported with zolpidem use.

An advantage of zolpidem is that subjective residual next-day effects seem to be minimal.41-43 However, actual benefits on next-day cognitive, psychomotor, and subjective well-being have not been clearly demonstrated yet.44,45 Zolpidem also has fewer drug-drug interactions than benzodiazepines, possibly because the latter are metabolized by several cytochrome P450 (CYP) isozymes, whereas zolpidem is metabolized primarily by the CYP isoenzyme 3A4.

A general consideration in using hypnotics in the elderly is the risk of falls. A retrospective case-control study showed an association between the use of zolpidem in the elderly and a higher risk of hip fractures,46 although long-acting benzodiazepines are more likely associated with falls and hip fractures than shorter-acting agents.47 The clinician must also consider that untreated insomnia in the elderly may also represent a risk for falls, as sleep problems in this population are independently associated with an increased risk of falls.48

Zaleplon, another agent with specificity for the BZ1 receptor, has the shortest half-life of currently-available hypnotics and is primarily used for sleep induction.49,50 Its next-day side effects and residual sedation are minimal.51,52 In fact, its short half-life allows it to be used during the night for sleep initiation, if there are at least 4 hours of time in bed remaining. The recommended 10-mg dose taken at sleep onset has not shown to increase subjective total sleep time or decrease the number of awakenings, but doses of 20 mg have been reported to increase sleep duration and reduce the number of awakenings.49,50 However, side effects associated with the use of the 20-mg dose are not well known at this time. Like zolpidem, zaleplon does not appear to alter normal sleep architecture.43,53

Eszopiclone, with a half-life of five to six hours,54 binds GABAA receptor complexes at domains near the benzodiazepine receptor. It was recently approved by the FDA for treatment of sleep onset and sleep maintenance insomnia and is the first hypnotic agent for which a long-term, randomized, double-blind, placebo controlled study has been performed. As a result, it is the only currently available hypnotic without a short-term treatment indication. Patients with chronic primary insomnia treated with eszopiclone for 6 months showed a significant reduction of time to sleep onset, as well as reduction of wakefulness time after sleep onset and a decreased number of awakenings.55 Sleep quality and improvement of daytime alertness, sense of well-being, and daytime ability to function also improved. Its longer half-life likely accounts for its more consistent effects in improving sleep maintenance. No evidence of significant tolerance or residual next-day sedation was reported.55 A recent 6-week, placebo-controlled study showed that eszopiclone significantly improved sleep latency, sleep efficiency, and total sleep time in subjects with chronic insomnia. The most common side effect was unpleasant taste.56 As with benzodiazepines, zolpidem, zaleplon, and eszopiclone should be used with caution in patients taking other central nervous system depressants.

Antidepressants

Despite the paucity of research on their effectiveness in insomnia and the lack of FDA approval for this indication, antidepressants are commonly used to treat insomnia complaints.57 In contrast to benzodiazepine receptor agonists, antidepressants are non-scheduled drugs and clinicians are usually more familiar with their long-term prescription. Furthermore, given the strong association between depression and insomnia,58 the use of an antidepressant may be perceived as treating both the sleep condition, as well as the underlying problem. Doses of antidepressants generally used to treat insomnia are often lower than those found to be effective in treating depression. Mechanisms that may explain the sedating effect of antidepressants include histamine (H)1, serotonin type 2 (5-HT2) receptor antagonism, and possibly α1-adrenergic receptor antagonism.

Tricyclic antidepressants continue to be used for insomnia, despite their relatively unfavorable side-effect profile. A study of 40 patients with primary insomnia treated with 25–50 mg of doxepin showed short (1 night) and medium term (28 nights) improvement of objectively measured sleep efficiency, total sleep time, wake time after sleep onset, and stage 2 sleep percentages. A subjective improvement of sleep quality and next-day functioning was also reported by patients in this study.59 The use of tricyclic antidepressants should be monitored closely because of the potential for anticholinergic side effects (arrhythmias, orthostatic hypotension, constipation, urinary retention, cognitive deficits), and interactions with other drugs metabolized by the liver. Furthermore, abrupt withdrawal can cause rebound insomnia, including prominent REM sleep rebound, as many of these agents produce significant REM sleep suppression, making them problematic for use on an as-needed basis.

Trazodone, the most widely-prescribed antidepressant for insomnia, is another low-cost antidepressant with low abuse potential compared with benzodiazepine receptor agonists.60 Despite its frequent use, relatively little is known about its efficacy in primary insomnia because trazodone studies have usually been conducted in small samples of depressed patients for no longer than 8 weeks.61,62 There is evidence of improvement of sleep latency, sleep efficiency, total sleep time, and wakefulness during sleep associated with trazodone in older insomnia subjects63 and patients with depression.64 In terms of sleep architecture, trazodone has been associated with increase of SWS64 and minimal suppression of REM sleep.63

Trazodone is known to cause next-day sedation and it can possibly cause tolerance and rebound insomnia after discontinuation.42,63 Nevertheless, trazodone may be beneficial for treating insomnia associated with depression,24 or in patients with histories of substance abuse, who should not take benzodiazepine receptor agonists.

Paroxetine and mirtazapine are also used to treat insomnia, particularly in patients with depression. A small study (n=15) of paroxetine for treatment of primary insomnia showed a subjective improvement of sleep quality, but no increased sleep quantity.65 Effects of mirtazapine on sleep in patients with insomnia and depression include reduced sleep latency, increased sleep efficiency, and increased total sleep.66,67 Selective serotonin reuptake inhibitors (SSRIs), in general, tend to disrupt sleep,68 suggesting that their subjective efficacy may be related to improving depressive symptomatology.

Antipsychotics

Most antipsychotic drugs can produce sedation as a side effect, particularly the low-potency neuroleptics such as chlorpromazine. Some of the atypical antipsychotics, such as clozapine, risperidone, olanzapine, and quetiapine, are also known to promote sleep and have been useful for treatment of insomnia in psychiatric patients, including those with psychotic disorders, bipolar disorders or dementia. Olanzapine has been reported to prolong REM sleep latency, increase SWS, improve sleep continuity measures and subjective sleep quality, and decrease REM sleep in studies of healthy subjects.69 Reduction of sleep stage 1 with increases of sleep stage 2 and SWS was reported in a study of 20 schizophrenic patients.70

The use of atypical antipsychotics in primary insomnia is usually not recommended, due to the high prevalence of unwanted side effects, including daytime sedation, weight gain, extrapyramidal symptoms, and the risk of neuroleptic malignant syndrome. A possible association between the use of atypical antipsychotics and cerebrovascular adverse events has also been reported.71 The FDA recently ordered black-box warnings noting that treatment of behavioral disorders in elderly dementia patients with atypical (second generation) antipsychotics is associated with increased mortality.72

Anticonvulsants

Some anticonvulsant medications have sedating effects, presumably related to potentiation of GABA neurotransmission. These include gabapentin, tiagabine, and benzodiazepines.73 Although it has not been specifically studied for treatment of insomnia, gabapentin has been reported to decrease awakenings in stage 1 sleep, increase REM sleep, and SWS percentage in patients with epilepsy.74 A small (n=10) double-blind, placebo-controlled study, assessing the effect of a single 5-mg dose of tiagabine in elderly subjects showed that it significantly increased sleep efficiency, decreased wakefulness, and increased SWS activity.75 However, the FDA recently issued a warning regarding an increased risk of seizures in patients without epilepsy when treated with tiagabine, discouraging off-label use of this drug. Clonazepam, a benzodiazepine anticonvulsant, has a half-life longer than the benzodiazepines described above, and is commonly used to treat insomnia in patients with associated periodic limb movements, restless legs syndrome, or REM sleep behavior disorder. Tolerance has been reported as mild and infrequent with chronic use.37

Over-the-Counter Medications

The active ingredients in most over-the-counter sleeping pills are sedating antihistamines, usually diphenhydramine. These agents are antagonists of H1 receptors. Results of a placebo-controlled study showed that a 50-mg bedtime dose of diphenhydramine improved sleep latency.76 There are no controlled studies demonstrating objective efficacy of diphehydramine for longer than 3 weeks in the treatment of insomnia. A recent study suggested that tolerance to its sedating effects could occur within a few days.77 Antihistamines can cause next-day sedation,76 and impaired cognitive and psychomotor functioning.78

Melatonin is a hormone normally secreted at night and considered to regulate sleep. It binds to specific receptor subtypes MT1 and MT2, activating inhibitory G-protein pathways.79 Melatonin has been shown to reduce sleep latency,80,81 but has not consistently been found to increase total sleep time.82 Persistent improvement of sleep latency and efficiency over a 2-month period of administration of 1 mg of sustained release melatonin in elderly patients suggested lack of tolerance.80 Melatonin also has a chronobiotic effect and, is therefore, used to treat insomnia in patients with circadian rhythm problems.

Valerian is an herbal product that has been associated with subjective improvement of sleep latency, total sleep time, and sleep quality. Further research is needed to determine its mechanism of action, objective effects on sleep, and safety. Case reports have associated its use with the development of hepatotoxicity and next-day sedation.83

Newer Agents

New hypnotic agents will likely be released soon in the United States. Indiplon is a nonbenzodiazepine BZ1 receptor agonist with hypnotic properties, currently in clinical development. Its immediate-release form has been shown to improve objective and patient-reported measures of sleep onset over a 5-week period.84 The modified-release form improved subjective measures of time to sleep onset, total sleep time, and waking time after sleep onset in adult patients with insomnia in a 2-week study.85 Ramelteon is an MT1 melatonin receptor agonist currently under investigation for the treatment of insomnia. Its site of action (MT1 receptors are located in the suprachiasmatic nucleus) suggests it may have an effect on circadian regulation as well.

Pediatric Population

Insomnia is also a common problem in children and adolescents. Delayed sleep onset and disruptive nighttime awakenings have been reported in 25% to 50% of preschool-aged children.86,87 A community-based survey, showed that sleep onset delays and nighttime awakening were present in 11% of 5-year-old and 7% of 12-year-old children.88 Insomnia is also commonly comorbid with psychiatric problems in pediatric patients; for example 10% of a population sample of adolescents complained of difficulty falling asleep as well as symptoms of anxiety, depression, inattention, and conduct problems.89  

Behavioral Treatment

Like in adults, clinicians should determine if the difficulties with sleep onset, sleep maintenance, or non-restorative sleep represent primary or secondary insomnia. Behavioral factors commonly precipitate or complicate the course of insomnia in children and adolescents. Children who learn to self-soothe and fall asleep on their own are less likely to struggle initiating sleep or returning to sleep. Parental behavior often plays a role in the development of sleep problems in children as well. Insomnia is more likely to develop when parents become over-involved in the child’s sleep.90 Participation of the parents in the implementation of behavioral treatment interventions is therefore indicated.

A behavioral strategy that has been shown to be effective to treat sleep-onset insomnia and bedtime resistance in young children is gradual extinction,91 which involves parents putting the child to bed and ignoring the child’s protests, except for issues of safety. Parents should, for example, briefly check on the child without excessive negative or positive feedback to the child, after an initial delay of 3–5 minutes. This delay is then prolonged gradually to 15–20 minutes until the child falls asleep and the sequence is repeated for subsequent arousals.92 Allowing the child to go to bed later, at a time when rapid sleep onset is likely, and gradually moving bedtime earlier until the desired sleep onset time is achieved (fading), may also be effective.93 Adolescents can benefit from cognitive restructuring therapy and other behavioral interventions used in adults as listed in Table 2.

A particular problem in adolescents is sleep phase delay, in which they fall asleep much later than the desired bedtime and have difficulty awakening in the morning. Although this may present as a complaint of insomnia, it is a circadian rhythm disorder that tends to respond to aggressive behavioral treatments specifically designed to realign sleep with the desired schedule. Good sleep hygiene, rigid adherence to the schedule, and avoidance of exposure to bright light in the evening are essential.94 Hypnotic medications alone are generally not helpful in treating phase delay.95

 

Pharmacologic Treatment

Despite the lack of clinical studies investigating the efficacy and tolerability of medications to treat insomnia in children, several agents are commonly used, particularly in children with concomitant psychiatric disorders.92 Antihistamines, like diphenhydramine, at a dose of 1mg/kg can reduce sleep latency and number of awakenings,96 but can also lead to paradoxical activation in some children.97 Clonidine is an a-adrenergic agonist antihypertensive agent that has been found to cause sedation, and may be helpful in treating insomnia in children with attention-deficit/hyperactivity disorder.98 Melatonin is frequently used in children with developmental disorders and irregular sleep-wake patterns, despite limited evidence of efficacy; significant improvements, if present, are generally related to reduced latency of sleep onset.99 Melatonin has also been reported to be helpful in sleep-onset insomnia in non-neurologically impaired children.100

Partial arousals and enuresis are often treated with tricyclic antidepressants, particularly imipramine.101 Peripheral anticholinergic effects appear to be the mechanism implicated in the improvement of enuresis.102

Benzodiazepines decrease the frequency of arousals that occur during the night,92 but are generally not recommended in children due to their risk of inducing tolerance, rebound insomnia, and paradoxical activation. Clinicians need to carefully and individually assess risks and benefits of benzodiazepine use in young patients. For instance, low doses of clonazepam (0.25–0.5 mg at bedtime) may be helpful to treat parasomnias that put children at risk of hurting themselves, but side effects may be more harmful to children than the original condition in some cases.

 

Conclusion

In general, the treatment of patients with insomnia begins with careful determination of all possible factors affecting sleep initiation or sleep maintenance. In addition to treating comorbid medical and psychiatric conditions, multimodal treatment strategies (eg, sleep hygiene, behavioral therapies, medications) are often necessary for patients with secondary insomnia. The presence of psychiatric disorders or other associated sleep disorders may direct the choice of other medications such as antidepressants, antipsychotic, or anticonvulsant drugs that may also help promote sleep. PP  

References

1.    Buysse DJ, Reynolds CF 3rd, Hauri PJ, et al. Diagnostic concordance for DSM-IV sleep disorders: a report from the APA/NIMH DSM-IV field trial. Am J Psychiatry. 1994;151(9):1351-1360.

2.    Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry. 1999;60(10):668-676.

3.    Wehr TA. Sleep loss: a preventable cause of mania and other excited states. J Clin Psychiatry. 1989;50(Suppl):8-16;45-17.

4.    Foley DJ, Monjan A, Simonsick EM, Wallace RB, Blazer DG. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep. 1999;22(Suppl 2):S366-S372.

5.    Chesson AL, Jr., Anderson WM, Littner M, et al. Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22(8):1128-1133.

6.    McClusky HY, Milby JB, Switzer PK, Williams V, Wooten V. Efficacy of behavioral versus triazolam treatment in persistent sleep-onset insomnia. Am J Psychiatry. 1991;148(1):121-126.

7.    Hauri PJ. Can we mix behavioral therapy with hypnotics when treating insomniacs? Sleep. 1997;20(12):1111-1118.

8.    Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR. Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep. 1999;22(8):1134-1156.

9.    Morin C, Culbert J, Schwartz S. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry. 1994;151:1172-1180.

10.    Murtagh DR, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol. 1995;63(1):79-89.

11.    Smith MT, Perlis ML, Park A, et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry. 2002;159(1):5-11.

12.    Edinger JD, Means MK. Cognitive-behavioral therapy for primary insomnia. Clin Psychol Rev. 2005;25(5):539-558.

13.    Smith MT, Huang MI, Manber R. Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev.  2005;25(5):559-592.

14.    Bonnet MH, Arand DL. The consequences of a week of insomnia. Sleep. 1996;19(6):453-461.

15.    Edinger JD, Sampson WS. A primary care “friendly” cognitive behavioral insomnia therapy. Sleep. 2003;26(2):177-182.

16.    Manber R, Bootzin RR, Acebo C, Carskadon MA. The effects of regularizing sleep-wake schedules on daytime sleepiness. Sleep. 1996;19(5):432-441.

17.    Spielman AJ, Saskin P, Thorpy MJ. Treatment of chronic insomnia by restriction of time in bed. Sleep. 1987;10(1):45-56.

18.    Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999;281(11):991-999.

19.    Espie CA, Lindsay WR, Brooks DN, Hood EM, Turvey T. A controlled comparative investigation of psychological treatments for chronic sleep-onset insomnia. Behav Res Ther. 1989;27(1):79-88.

20.    Ladouceur R, Gros-Louis Y. Paradoxical intention vs stimulus control in the treatment of severe insomnia. J Behav Ther Exp Psychiatry. 1986;17(4):267-269.

21.    Turner RM, Ascher LM. Controlled comparison of progressive relaxation, stimulus control, and paradoxical intention therapies for insomnia. J Consult Clin Psychol. 1979;47(3):500-508.

22.    Turner RM, Ascher LM. Therapist factor in the treatment of insomnia. Behav Res Ther. 1982;20(1):33-40.

23.    Lacks P, Bertelson A, Gans L, Kunkel J. The effectiveness of three behavioral treatments for different degrees of sleep-onset insomnia. Behav Ther. 1983;14:593-605.

24.    Nishino S, Mishima K, Mignot E, Dement W. Sedative-Hypnotics. In: AF S, Nemeroff CB, eds. Textbook of Psychopharmacology. Arlington, VA: American Psychiatric Publishing, Inc.; 2004:651-670.

25.    Scharf MB, Roth PB, Dominguez RA, Ware JC. Estazolam and flurazepam: a multicenter, placebo-controlled comparative study in outpatients with insomnia. J Clin Pharmacol. 1990;30(5):461-467.

26.    Melo de Paula AJ. Comparative study of lormetazepam and flurazepam in the treatment of insomnia. Clin Ther. 1984;6(4):500-508.

27.    Hernandez Lara R, Del Rosal PL, Ponce MC. Short-term study of quazepam 15 milligrams in the treatment of insomnia. J Int Med Res. 1983;11(3):162-166.

28.    Cohn JB, Wilcox CS, Bremner J, Ettinger M. Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia. J Clin Pharmacol. 1991;31(8):747-750.

29.    Aden G, Thatcher C. Quazepam in the short-term treament of insomnia in outpatients. J Clin. Psychiatry. 1983;44(12):454-456.

30.    Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162(2):225-233.

31.    Kales A, Manfredi RL, Vgontzas AN, Bixler EO, Vela-Bueno A, Fee EC. Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther. 1991;49(4):468-476.

32.    Roehrs T, Vogel G, Vogel F, et al. Dose effects of temazepam tablets on sleep. Drugs Exp Clin Res. 1986;12(8):693-699.

33.    Mitler MM, Carskadon MA, Phillips RL, et al. Hypnotic efficacy of temazepam: A long-term sleep laboratory evaluation. Br J Clin Pharmacol. 1979;8:63S-68S.

34.    Ngen CC, Hassan R. A double-blind placebo-controlled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia. Int Clin Psychopharmacol. 1990;5(3):165-171.

35.    Mitler MM, Seidel WF, van den Hoed J, Greenblatt DJ, Dement WC. Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study. J Clin Psychopharmacol. 1984;4(1):2-13.

36.    Dolly FR, Block AJ. Effect of flurazepam on sleep-disordered breathing and nocturnal oxygen desaturation in asymptomatic subjects. Am J Med. 1982;73(2):239-243.

37.    Mahowald MW, Schenck CH. REM Sleep Parasomnias. In: Kryger MH, Roth T, Dement W, eds. Principles and Practice of Sleep Medicine. IV ed. Philadelphia, PA: Elsevier Saunders; 2005:897-916.

38.    Ware JC, Walsh JK, Scharf MB, Roehrs T, Roth T, Vogel GW. Minimal rebound insomnia after treatment with 10-mg zolpidem. Clin Neuropharmacol. 1997;20(2):116-125.

39.    Dockhorn RJ, Dockhorn DW. Zolpidem in the treatment of short-term insomnia: a randomized, double-blind, placebo-controlled clinical trial. Clin Neuropharmacol. 1996;19(4):333-340.

40.    Roth T, Roehrs T, Vogel G. Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. Sleep. 1995;18(4):246-251.

41.    Scharf MB, Roth T, Vogel GW, Walsh JK. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry. 1994;55(5):192-199.

42.    Walsh J, Erman M, Erwin C. Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Human Psychopharmacology. 1998;13:191-198.

43.    Walsh JK, Roth T, Randazzo A, et al. Eight weeks of non-nightly use of zolpidem for primary insomnia. Sleep. 2000;23(8):1087-1096.

44.    Saletu-Zyhlarz G, Anderer P, Brandstatter N, et al. Placebo-controlled sleep laboratory studies on the acute effects of zolpidem on objective and subjective sleep and awakening quality in nonorganic insomnia related to neurotic and stress-related disorder. Neuropsychobiol. 2000;41(3):139-148.

45.    Shaw SH, Curson H, Coquelin JP. A double-blind, comparative study of zolpidem and placebo in the treatment of insomnia in elderly psychiatric in-patients. J Int Med Res.  1992;20(2):150-161.

46.    Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J. Zolpidem use and hip fractures in older people. J Am Geriatr Soc. 2001;49(12):1685-1690.

47.    Mendelson WB. Clinical distinctions between long-acting and short-acting benzodiazepines. J Clin Psychiatry. 1992;53 Suppl:4-7;8-9.

48.    Brassington GS, King AC, Bliwise DL. Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64-99 years. J Am Geriatr Soc. 2000;48(10):1234-1240.

49.    Elie R, Ruther E, Farr I, Emilien G, Salinas E. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group. J Clin Psychiatry. 1999;60(8):536-544.

50.    Fry J, Scharf M, Mangano R, Fujimori M. Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Zaleplon Clinical Study Group. Int Clin Psychopharmacol. 2000;15(3):141-152.

51.    Verster JC, Volkerts ER, Schreuder AH, et al. Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol. 2002;22(6):576-583.

52.    Hedner J, Yaeche R, Emilien G, Farr I, Salinas E. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group. Int J Geriatr Psychiatry. 2000;15(8):704-712.

53.    Walsh JK, Vogel GW, Scharf M, et al. A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia. Sleep Med. 2000;1(1):41-49.

54.    Leese P, Maier G. Eszopiclone: pharmacokinetic and pharmacodynamic effects of a novel anti-insomnia agent after daytime administration in healthy patients. Sleep Abstract Suppl. 2002;25:A45.

55.    Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003;26(7):793-799.

56.    Zammit G, Gillin JC, McNabb L, Caron J, Roth T. Eszopiclone, a novel nonebenzodiazepine. Sleep Abstract Suppl. 2003;26:A297.

57.    Wilson S, Argyropoulos S. Antidepressants and sleep: a qualitative review of the literature. Drugs. 2005;65(7):927-947.

58.    Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract. 2002;51(3):229-235.

59.    Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62(6):453-463.

60.    Rush CR, Baker RW, Wright K. Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology (Berl). 1999;144(3):220-233.

61.    Parrino L, Spaggiari MC, Boselli M, Di Giovanni G, Terzano MG. Clinical and polysomnographic effects of trazodone CR in chronic insomnia associated with dysthymia. Psychopharmacology. 1994;116(4):389-395.

62.    Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. J Clin Psychiatry. 1990;51 Suppl:13-17.

63.    Montgomery I, Oswald I, Morgan K, Adam K. Trazodone enhances sleep in subjective quality but not in objective duration. Br J Clin Pharmacol. 1983;16(2):139-144.

64.    Saletu-Zyhlarz GM, Abu-Bakr MH, Anderer P, et al. Insomnia in depression: differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(2):249-260.

65.    Nowell PD, Reynolds CF, 3rd, Buysse DJ, Dew MA, Kupfer DJ. Paroxetine in the treatment of primary insomnia: preliminary clinical and electroencephalogram sleep data. J Clin Psychiatry. 1999;60(2):89-95.

66.    Winokur A, DeMartinis NA, 3rd, McNally DP, Gary EM, Cormier JL, Gary KA. Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. J Clin Psychiatry. 2003;64(10):1224-1229.

67.    Winokur A, Sateia MJ, Hayes JB, Bayles-Dazet W, MacDonald MM, Gary KA. Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study. Biol Psychiatry. 2000;48(1):75-78.

68.    Silvestri R, Pace-Schott EF, Gersh T, Stickgold R, Salzman C, Hobson JA. Effects of fluvoxamine and paroxetine on sleep structure in normal subjects: a home-based Nightcap evaluation during drug administration and withdrawal. J Clin Psychiatry. 2001;62(8):642-652.

69.    Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470.

70.    Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, Laurrabaquio MR. Olanzapine acute administration in schizophrenic patients increases delta sleep and sleep efficiency. Biol Psychiatry. 1999;46(1):141-143.

71.    Herrmann N, Lanctot KL. Do atypical antipsychotics cause stroke? CNS Drugs. 2005;19(2):91-103.

72.    Rosack J. FDA orders new warning on atypical antipsychotics. Psychiatric News. May  2005;40(9).

73.    Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(5 Suppl 2):S53-S67.

74.    Foldvary-Schaefer N. Sleep complaints and epilepsy: the role of seizures, antiepileptic drugs and sleep disorders. J Clin Neurophysiol. 2002;19(6):514-521.

75.    Mathias S, Wetter TC, Steiger A, Lancel M. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging. 2001;22(2):247-253.

76.    Rickels K, Morris RJ, Newman H, Rosenfeld H, Schiller H, Weinstock R. Diphenhydramine in insomniac family practice patients: a double-blind study. J Clin Pharmacol. 1983;23(5-6):234-242.

77.    Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol. 2002;22(5):511-515.

78.    Witek TJ, Jr., Canestrari DA, Miller RD, Yang JY, Riker DK. Characterization of daytime sleepiness and psychomotor performance following H1 receptor antagonists. Ann Allergy Asthma Immunol. 1995;74(5):419-426.

79.    Dubocovich ML. Melatonin receptors: are there multiple subtypes? Trends Pharmacol Sci. 1995;16(2):50-56.

80.    Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18(7):598-603.

81.    Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep- maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep. 1998;21(1):52-68.

82.    Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res. 1996;5(1):61-65.

83.    Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother. 1998;32(6):680-691.

84.    Walsh JK, Rosenberg R, Roth T. Treatment of primary insomnia for five weeks with Indiplon-IR. Sleep Abstract Suppl. 2004;27:A259.

85.    Jochelson P, Scharf M, Roth T. Efficacy of Indiplon in inducing and maintaining sleep in patients with chronic sleep maintenance insomnia. Sleep Abstract Suppl. 2004:A262.

86.    Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and sleep disturbance in elementary school-aged children. J Dev Behav Pediatr. 2000;21(1):27-36.

87.    Lozoff B, Wolf AW, Davis NS. Sleep problems seen in pediatric practice. Pediatrics. 1985;75(3):477-483.

88.    Blader JC, Koplewicz HS, Abikoff H, Foley C. Sleep problems of elementary school children. A community survey. Arch Pediatr Adolesc Med. 1997;151(5):473-480.

89.    Morrison DN, McGee R, Stanton WR. Sleep problems in adolescence. J Am Acad Child Adolesc Psychiatry. 1992;31(1):94-99.

90.    Ferber R. Sleeplessness in the child. In: Kryger MH, Roth T, Dement W, eds. Principles and Practice of Sleep Medicine. I ed. Philadelphia, PA: WB Saunders; 1989:633-639.

91.    Mindell JA. Empirically supported treatments in pediatric psychology: bedtime refusal and night wakings in young children. J Pediatr Psychol. 1999;24(6):465-481.

92.    Glaze DG. Childhood insomnia: why Chris can’t sleep. Pediatr Clin North Am. 2004;51(1):33-50.

93.    Owens JA, Palermo TM, CL R. Overview of current management of sleep disturbances in children. II: Behavioral interventions. Curr Ther Res Clin Exp. 2002;63(Suppl B):B38-B52.

94.    Reid KJ, Zee PC. Circadian disorders of the sleep-wake cycle. In: Kryger MH, Roth T, Dement W, eds. Principles and Practice of Sleep Medicine. IV ed. Philadelphia, PA: Elsevier Saunders; 2005:691-701.

95.    Pelayo R, Chen W, Monzon S, Guilleminault C. Pediatric sleep pharmacology: you want to give my kid sleeping pills? Pediatr Clin North Am. 2004;51(1):117-134.

96.    Reed M, Findling R. Overview of current management of sleep disturbances in children. I: Pharmacotherapy. Curr Ther Res Clin Exp. 2002;63(Suppl B):B18-B37.

97.    Thomas L, King R. Child and adolescent psychiatric emergencies. In: Lewis M, ed. Child and Adolescent Psychiatry A Comprehensive Textbook. Philadelphia, PA: Lippincott Williams & Wilkins; 2002:1104-1110.

98.    Greydanus DE, Sloane MA, Rappley MD. Psychopharmacology of ADHD in adolescents. Adolesc Med. 2002;13(3):599-624.

99.    Phillips L, Appleton RE. Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. Dev Med Child Neurol. 2004;46(11):771-775.

100. Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003;42(11):1286-1293.

101. Werry JS, Dowrick PW, Lampen EL, Vamos MJ. Imipramine in enuresis–psychological and physiological effects. J Child Psychol Psychiatry. 1975;16(4):289-299.

102. Rapoport JL, Mikkelsen EJ, Zavadil A, et al. Childhood enuresis. II. Psychopathology, tricyclic concentration in plasma, and antienuretic effect. Arch Gen Psychiatry. 1980;37(10):1146-1152.

 

 

 

 

Dr. Infante is assistant professor of psychiatry and Dr. Benca is professor of psychiatry at the University of Wisconsin Psychiatric Institute and Clinics in Madison.

Disclosure: Dr. Infante reports no affiliations with or financial interest in any organization that may pose a conflict of interest. Dr. Benca is a consultant to and/or on the speaker’s bureaus of King, Neurocrine/Pfizer, Sanofi-Aventis, Sepracor, Takeda, and Wyeth.

Please direct all correspondence to: Ruth M. Benca, MD, PhD, University of Wisconsin Psychiatric Institute and Clinics, 6001 Research Park Blvd, Madison, WI 53719; Tel: 608-263-6162; Fax: 608-265-2953; E-mail: rmbenca@facstaff.wisc.edu.

Column

Print Friendly 

James L. Levenson, MD

Primary Psychiatry. 2005;12(8):16-18

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the duloxetine advisory board for Eli Lilly.


 

 

Introduction

Psychosis profoundly impacts the medical care of patients with serious medical illness; patients with chronic psychosis are at increased risk for a number of general medical conditions. This article reviews psychosis, mania, and catatonia in the medically ill; both “primary” and “secondary” conditions, caused by a medical disease or drug, are discussed. For more detailed coverage of this topic, see Masand and colleagues.1

 

Because schizophrenia and other psychotic disorders occur in 1% to 2% of the general population, the possibility of a primary psychotic disorder should be considered in a medically ill patient manifesting psychotic symptoms before attributing it to medical illness or drugs. Primary psychotic disorders may adversely affect outcomes in the medically ill in a number of different ways. Schizophrenia carries increased risk for obesity and diabetes, and many antipsychotics add to these risks, causing weight gain, glucose intolerance, and hyperlipidemia. Patients with schizophrenia often have poor health habits, such as nonadherence with treatments, inadequate nutrition, physical inactivity, and high rates of smoking and substance abuse,2 as well as problems seeking and accessing health care. Psychosis may also adversely impact the patient’s relationship with healthcare providers.

When psychotic symptoms are observed in a patient who has a concurrent medical illness, the differential diagnosis should include a “primary” psychotic disorder (eg, schizophrenia, bipolar disorder), delirium or dementia, substance intoxication/withdrawal (including medications), or a psychotic disorder due to a general medical condition.

Clinical features differentiate primary from secondary psychotic disorders. In primary psychoses, cognitive function and level of consciousness are relatively normal, focal neurological signs are absent, hallucinations are most often auditory, delusions tend to be complex, thought disorder may be prominent, incontinence is usually absent, and vital  signs are usually normal. In secondary psychoses, cognitive function and level of consciousness are often abnormal, focal neurological signs may be present, hallucinations are most often visual, delusions if present are usually simple, thought disorder is not prominent, incontinence is common, and vital signs may be abnormal. A secondary psychosis is more likely if psychotic symptoms first appear at an older age and if there is no personal or family history of primary psychotic disorders. The temporal pattern of the symptoms may be the most important factor in making the diagnosis. If the course of the psychotic symptoms parallels the course of the medical disorder suspected as cause, a diagnosis of secondary psychosis is more likely.

Medical conditions commonly causing psychotic symptoms are shown in Table 1. Drugs most often causing psychotic symptoms include antidepressants, anticholinergics, antiarrhythmics, antihistamines, ciprofloxacin, antimalarials, antivirals, anticonvulsants, corticosteroids, dopamine agonists, opioids, and sympathomimetics. Delirium and dementia are perhaps the most common causes of psychotic symptoms in the medically ill. Delusions occur in approximately 20% of patients with delirium and 45% of those with dementia.2

When secondary psychosis is suspected, routine testing usually includes a complete blood count, complete metabolic panel, serum levels, thyroid stimulating hormone level, a test for syphilis, urinalysis, pulse oximetry, and a urine toxicology screen. Other commonly indicated tests include a chest radiograph, serum drug levels (eg, theophylline), arterial blood gases, vitamin B12 and folate levels, and testing for human immunodeficiency virus. If intracranial pathology is suspected, a computerized tomography or magnetic resonance imaging scan, and lumbar puncture may also be required. Additional tests may be indicated when particular diagnoses are suspected (eg porphyria).

Regardless of etiology, acutely psychotic medical inpatients may require constant observation, restraints, and/or involuntary treatment. Reassurance and education of the patient and the family about the symptoms and their cause(s), if known, are also helpful.

Unnecessary stimulation of the patient should be avoided (eg, repeated interviews by groups of trainees). All nonessential medications should be discontinued or reduced in dosage if they are possible contributors. To coordinate the patient’s medical care, close collaboration between psychiatric and medical staff is necessary and a joint determination should be made whether inpatients are best treated on a medical unit with psychiatric consultation, or a psychiatric unit with medical consultation.

If the cause cannot be eliminated in medically ill patients with primary or secondary psychosis, antipsychotics are selected, in part, based on potential side effects––some of which may be desired. For short-term use, haloperidol is usually preferred in medically ill patients because of extensive experience with its use, minimal side effects other than extrapyramidal ones, and since it can be administered by mouth, intramuscularly (IM), or intravenously (IV). Typical antipsychotics have the advantage of less extrapyramidal side effects. Some patients may require a particular method of drug administration, ie, as a liquid (eg, haloperidol, risperidone, or ziprasidone) or orally disintegrating tablet (risperidone) in patients who have difficulty swallowing pills.3 While several antipsychotics can be given IM, this route is not practicable if many parenteral doses are required and IV haloperidol should be considered. Most antipsychotics can be used in cardiac patients even after an acute myocardial infarction. While antipsychotics rarely cause adverse hepatic reactions, there is no evidence that liver disease increases their risk of hepatotoxicity. Since all antipsychotics are metabolized in the liver, they should be used more cautiously in patients with hepatic failure. While antipsychotics can lower seizure threshold, their use is not contraindicated in patients who are receiving anticonvulsants, though those with greater liability in this regard (eg, clozapine), should be avoided. In patients with diabetes mellitus or those who at high risk for the condition, antipsychotics are less likely to induce glucose intolerance and are therefore preferred.4

 

Mania in the Medically Ill

In medical settings, most manic patients have primary bipolar disorder, but secondary causes of mania should often be considered. In Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,5 secondary mania is termed as a mood disorder secondary to a general medical condition. Mania can sometimes be difficult to distinguish from delirium. Both can present abruptly with inattention, agitation, poor sleep, and psychosis. Delirium differs in its waxing and waning course, clouding of consciousness, and visual hallucinations/illusions, whereas mania is characterized by elation, hypersexuality, and pressured speech. A prior history of chronic recurrent mood disturbance points to a diagnosis of primary bipolar illness, whereas patients with secondary mania usually have no prior personal or family history of bipolar disorder. In secondary mania the episode may begin within hours or days of the organic insult, and cognitive dysfunction or focal neurologic signs may be present. The differentiation between primary and secondary mania is based mainly on a temporal correlation between an organic factor and the onset of mania. Age of onset is also a clue, since initial bipolar episodes are uncommon after age 50. One should also consider the possibility that mania is secondary, rather than primary, when it fails to respond to usual treatments. In some cases, there may not be a clear demarcation between primary and secondary mania, since a personal or family history of the former may increase risk of the latter.

Selected causes of secondary mania are listed in Table 2. In most cases of secondary mania, caused by medications or metabolic disturbance, manic symptoms are totally reversible; however, symptoms may persist in patients with mania secondary to diseases in which there is damage to the central nervous system. Patients with suspected secondary mania should have a complete evaluation, which includes a careful history, physical examination,appropriate laboratory tests, and imaging studies selected depending on the likelihood of particular etiologies.

Treatment for secondary manic syndromes has been guided by case reports and clinical experience.6 Ideally, one would first treat the underlying disorder or eliminate the offending agent. This is not always possible (eg, steroid induced mania in a patient with vasculitis), in which case symptomatic treatment is indicated using the same drugs used for primary bipolar disorder; for example, mood stabilizers and antipsychotics can also be used prophylactically to prevent drug-induced mania. For patients with acute secondary mania, particularly when it is expected to be temporary, antipsychotics may be more helpful than lithium or anticonvulsants due to their quicker onset of benefit. Lithium may be contraindicated by the underlying medical disorder (eg, unstable fluid/electrolyte status or renal function). More recently developed anticonvulsants (eg, lamotrigine) may also prove helpful in patients who do not respond to or cannot tolerate first-line drugs.

 

Catatonia in the Medically Ill

Catatonia may be acute or chronic and is relatively rare––usually thought of as occurring in patients with schizophrenia or severe affective illness. This section focuses primarily on secondary catatonia caused by medical illness or drugs, and the medical complications encountered in chronic catatonia of any cause. The core features of catatonia are stupor, motoric immobility, mutism, negativism, excitement, catalepsy, and posturing.7 Most catatonic patients cannot provide a history or cooperate for a full physical examination, so information must be obtained from collateral sources.

Catatonia has been associated with a number of medical conditions and substances, as listed in Table 3. Neuroleptic malignant syndrome (NMS) may be particularly difficult to distinguish from severe agitated primary catatonia, known as “lethal catatonia.”6 If a patient with catatonia of any cause is treated with a neuroleptic, it can be difficult, if not impossible, to discriminate the original catatonia from neuroleptic-induced catatonia and from NMS. Other disease states may share some signs of catatonia and should be considered in the differential diagnosis when appropriate, including serotonin syndrome, stiff-person syndrome, strychnine poisoning, locked-in syndrome, elective mutism, and hyperkinetic (eg, Tourette’s syndrome) and hypokinetic states (eg, Parkinson’s disease).

Patients with chronic catatonia are often bedridden and undernourished, leading to frequent long-term medical complications, including deep venous thrombosis, pulmonary embolism, cardiovascular deconditioning (especially orthostatic intolerance), aspiration and other complications of enteral feeding, pressure ulcers (decubiti), skeletal muscle deconditioning, flexion contractures, rhabdomyolysis, urinary tract infection, urosepsis, cachexia, and dehydration/hypernatremia.8

If a medical condition or substance is determined to be the cause of catatonia, the underlying condition should be treated or the substance should be discontinued. When this is not possible or the catatonia persists, more direct treatments include benzodiazepines and electroconvulsive therapy (ECT). Benzodiazepines may provide immediate relief of the motor and speech signs of catatonia. ECT is the most effective treatment for catatonia,7 and can be used safely in almost all medically ill patients.9   PP

 

References

1. Masand PS, Christopher E, Clary GL, et al. Mania, catatonia, and psychosis in the medically ill. In: Levenson JL, ed. The American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing, Inc; 2005:235-250.

2. Dixon L. Health, medical comorbidities and diabetes in schizophrenia. Drug Benefit Trends. 2003;4(suppl):6-11.

3. Kelleher JP, Centorrino F, Albert MJ, et al. Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents. CNS Drugs. 2002;16:249-261.

4. Robinson MJ, Owen JA. Psychopharmacology in the medically ill. In: Levenson JL, ed. The American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing, Inc; 2005:979-1008.

5.    Diagnostic and Statistics Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

6. Evans DL, Byerly MJ, Greer RA. Secondary mania: diagnosis and treatment. J Clin Psychiatry. 1995;56:31-37.

7. Caroff SN, Mann SC, Francis A, Fricchione GL, eds. Catatonia: From Psychopathology to Neurobiology. American Psychiatric Publishing, Washington, DC; 2005.

8.    Levenson JL, Pandurangi AK. Catatonia: long-term prognosis, outcome, and medical complications. In: Caroff SN, Mann SC, Francis A, Fricchione GL, eds. Catatonia: From Psychopathology to Neurobiology. American Psychiatric Publishing, Washington, DC; 2005:161-172.

9. Rasmussen KG, Rummans TA, Tsang TSM, Barnes RD. Electroconvulsive therapy. In: Levenson JL, ed. The American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing, Inc; 2005:957-978.

Column

Print Friendly 

Complementary and Alternative Medicine

Anita H. Clayton, MD

Primary Psychiatry. 2005;12(8):37-44

 

Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.

Disclosure: Dr. Clayton is a consultant to and on the advisory boards of Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pfizer, Vela, and Wyeth; is on the speaker’s bureaus of and receives honorarium from Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and receives grants and/or research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Neuronetics, Pfizer, and Wyeth.


 

 

Prevalence of Complementary and Alternative Medicine Use

Complementary and alternative medicine refers to pharmacologic and biological treatments, such as herbal therapies; dietary supplements; natural hormones; health and healing practices, such as hypnosis, meditation, yoga, biofeedback, exercise, chiropractic or massage therapy; and nontraditional medical systems, such as acupuncture (Table). These modalities are utilized by many women in the United States. In 1993, Eisenberg and colleagues1 reported that one in three people used complementary and alternative medical treatment in the previous year. Women are even more likely than men to use complementary and alternative medicine,2  particularly among those with a chronic illness.

Demographics of use include women who are non-Hispanic white, 35–64 years of age, with higher education level and financial resources, use alcohol, live in the South or West, and have chronic conditions with functional limitations.3 In a study specific to urban Hispanics, 63% reported use of some alternative medicine.4 Most were women (75%) who used herbs (57%), prayer (43%), and dietary supplements (21%). Reasons for use included pain (61%), lack of energy (39%), and being overweight (23%). Still, only 5% believed that herbs were more effective than prescription medications, and only 7% believed complementary and alternative medical options were safer than prescribed medication. In addition, among women over 65 years of age, annual prevalence of dietary supplement use doubled in 2002.5 In women with gynecologic or breast malignancies, nearly half reported complementary and alternative medicine use in a survey, while only about half told their physicians about their use of alternative therapies.6 In this population, complementary and alternative medicine use was related to higher educational status, with 62% with a postgraduate degree using complementary and alternative medicine versus 33% of women with a high school education or less, and was associated with a desire for personal control.7 Even pregnant women used vitamins, minerals, and herbals in significant numbers (62%).8

Unfortunately, healthcare providers (physicians and nurses) have limited information about complementary and alternative medicine, with two-thirds reporting little or no knowledge of botanical dietary supplements, due to inadequate formal training.9 Most providers want additional information and are open to using these therapies in their perimenopausal and postmenopausal patients, either alone or in combination with conventional treatments. Providers who have been in practice for a longer period of time are more likely to have independently studied complementary and alternative medicine, to believe that botanicals were part of evidence-based medicine, to be knowledgeable about dietary supplements, and to have spoken to their patients about use of these therapies.

 

Efficacy of Alternative Treatments

In general, meta-analyses have not demonstrated significant efficacy of various complementary and alternative medicine therapies. Folic acid alone or in combination with vitamin B12 did not demonstrate significant efficacy over placebo in adults with cognitive impairment or dementia, despite a significant lowering of serum homocysteine concentrations with active treatment.10 A similar review of short-term use of vitamin B6 in healthy older adults failed to demonstrate an effect on cognition.11 Similarly, dehydroepiandrosterone (DHEA) failed to improve memory or other aspects of cognitive function in healthy older people.12

Herbal therapies demonstrated mixed results: ginkgo biloba slows the progression of dementia, but is associated with an increased risk of bleeding; ginseng improves well-being in women in the menopausal transition, but has significant side effects and drug interactions; garlic slightly lowers blood pressure and lipid levels; echinacea decreases the duration of upper respiratory infections, but does not prevent them; valerian aids insomnia; and black cohosh improves perimenopausal symptoms while chasteberry reduces premenstrual symptoms.13 Soy protein has not been demonstrated to have a significant positive effect on bone mineral density or serum lipid profiles in early postmenopausal women,14 but might be of benefit in older postmenopausal women, women with lower body weight, or women with poor dietary calcium intake.15

Purported treatments for depression with support from placebo-controlled trials include omega-3 fatty acids, St. John’s Wort, S-adenosyl-methionine (SAMe), folate, 5-hydroxytryptophan, acupuncture, exercise, and light therapy, particularly in women.16 Kava-Kava use in the menopausal transition was associated with a decrease in anxiety within the first month of treatment, with depressive symptoms reduced after 3 months, along with climacteric symptoms.17 Premenstrual symptoms were reduced over placebo with an odds ratio (OR) of 2.32 for vitamin B6 up to 100 mg/day, and an OR of 1.69 for improvement in depressive symptoms.18

Review of complementary and alternative medicine therapies for perimenopausal symptoms support the use of soy and black cohosh (phytoestrogens) for hot flashes, although long-term pro-estrogen effects have not been studied.19 Dong quai, evening primrose oil, vitamin E, red clover, and acupuncture have not convincingly demonstrated an effect on hot flashes. DHEA may be an option for androgen replacement in postmenopausal women with androgen deficiency.20

Yet, patients report significant efficacy with clinical use of botanical dietary supplements, without complaints of side effects (68%).21 This may represent a placebo effect, but may also mean that sufficiently powered, well-designed, placebo-controlled studies still need to be performed.

 

Clinical Implications and Management

Whenever I see a new patient, I ask about concomitant medications, vitamins, herbals, and all other treatments. At every subsequent visit, I confirm any change in medications or dosing, and the use of vitamins and other supplements/herbals. In clinical practice, my first recommendations are for lifestyle modifications such as dietary adaptations (a balanced diet, avoidance of alcohol and caffeine), exercise, stress reduction, and a scheduled sleep-wake cycle. Use of yoga, meditation, acupuncture, phototherapy, and hypnosis also appear to have greater potential benefit than risk. Other possible interventions include massage therapy, reflexology, chiropractic and biofeedback.

Despite the studies cited above, standard doses of vitamins appear to have positive results, particularly if used in combination. In my experience, daily dosing for 2–3 months may be necessary for full effect, although some individuals experience a benefit within the first week. For example, vitamin B100 complex plus folate (500 mcg) may benefit patients with depressive symptoms, those on hormonal contraceptives, and women with migraines. Vitamin B and vitamin E (400–800 IU/day) may reduce symptoms of tardive dyskinesia. Calcium and vitamin D are important for all women, and may help with migraine headaches. Magnesium may also have a beneficial effect on premenstrual symptoms, but often has poorly tolerated gastrointestinal side effects. Amino acids such as SAMe may improve mood, but can be very expensive. Omega-3 fatty acids may also improve mood, if the patient can tolerate the aftertaste.

Supplements such as phytoestrogens may improve mood, sexual arousal problems, and climacteric symptoms, such as hot flashes and problems with memory. DHEA ≥25 mg/day may improve libido. All hormonal supplements should be considered in the context of hormone levels, potential increase in cancer risk, and secondary effects on lipids.

Lowest on my list for use in combination with standard medications are the botanicals or herbals. Most have some negative side effects or drug interactions. In particular, I do not recommend the use of St. John’s Wort or ginkgo biloba, especially in combination with traditional antidepressant medications. Few of my patients have reported to me that they have taken kava-kava, echinacea, or valerian, so an absence of observable adverse effects is not surprising.

Although many patients are using complementary and alternative medicine in addition to traditional medical therapies, there remains a dearth of systematic, randomized, placebo-controlled trials, due to the the lack of regulation of biological or botanical supplements. Remaining open to the use of complementary and alternative medicine in our patients may provide them with a better outcome than with the use of prescription medications alone.  PP

 

References

1. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States: prevalence, costs, and patterns of use. N Engl J Med. 1993;328(4):246-252.

2. Fennell D. Determinants of supplement usage. Prev Med. 2004;39(5):932-939.

3. Yu SM, Ghandour RM, Huang ZJ. Herbal supplement use among US women, 2000. J Am Med Womens Assoc. 2004;59(1):17-24.

4. Mikhail N, Wali S, Ziment I. Use of alternative medicine among Hispanics. J Altern Complement Med. 2004;10(5):851-859.

5. Kelly JP, Kaufman DW, Kelley K, Rosenberg L, Anderson TE, Mitchell AA. Recent trends in use of herbal and other natural products. Arch Intern Med. 2005;165(3):281-286.

6. Navo MA, Phan J, Vaughan C, et al. An assessment of the utilization of complementary and alternative medication in women with gynecologic or breast malignancies. J Clin Onco. 2004;22(4):671-677.

7. Hedderson MM, Patterson RE, Neuhouser ML, et al. Sex differences in motives for use of complementary and alternative medicine among cancer patients. Altern Ther Health Med. 2004;10(5):58-64.

8. Maats FH, Crowther CA. Patterns of vitamin, mineral and herbal supplement use prior to and during pregnancy. Aust N Z J Obstet Gynaecol. 2002;42(5):494-496.

9. Geller SE, Studee L, Chandra G. Knowledge, attitudes, and behaviors of healthcare providers for botanical and dietary supplement use for postmenopausal health. Menopause. 2005;12(1):49-55.

10. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003;(4):CD004514.

11. Malouf R, Grimley EJ. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev. 2003;(4):CD004393.

12. Huppert FA, Van Niekerk JK. Dehydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev. 2001;(2):CD000304.

13. Tesch BJ. Herbs commonly used by women: an evidence-based review. Am J Obstet Gynecol. 2003;188(Suppl 5):S44-S55.

14. Gallagher JC, Satpathy R, Rafferty K, Haynatzka V. The effect of soy protein isolate on bone metabolism. Menopause. 2004;11(3):290-298.

15. Chen YM, Ho SC, Lam SS, Ho SS, Woo JL. Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: a double-blind, randomized, controlled trial. Menopause. 2004;11(3):246-254.

16. Freeman MP, Helgason C, Hill RA. Selected integrative medicine treatments for depression: considerations for women. J Am Med Womens Assoc. 2004;59(3):216-224.

17. Cagnacci A, Arangino S, Renzi A, Zanni AL, Malmusi S, Volpe A. Kava-Kava administration reduces anxiety in perimenopausal women. Maturitas. 2003;44(2):103-109.

18. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318(7195):1375-1381.

19. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002;137(10):805-813.

20. Arlt W. Dehydroepiandrosterone replacement therapy. Semin Reprod Med. 2004;22(4):379-388.

21. Mahady GB, Parrot J, Lee C, Yun GS, Dan A. Botanical dietary supplement use in peri- and postmenopausal women. Menopause. 2003;10(1):65-72.

Articles

Print Friendly 

John W. Winkelman, MD, PhD

Primary Psychiatry. 2005;12(8):31-34

Dr. Winkelman is assistant professor of Psychiatry at Harvard Medical School and medical director of the Sleep Health Center at Brigham and Women’s Hospital in Boston, Massachusetts. His research has largely focused on clinical sleep disorders, including insomnia, hypersomnia, parasomnias, and circadian rhythm disorders. He has directed and developed multiple courses in sleep disorders and biological psychiatry, and has also done clinical work in psychopharmacology and psychotherapy.

 

Have studies been conducted to indicate whether there are different types of insomnia linked to different psychiatric disorders?

All psychiatric illnesses can, and frequently do, produce insomnia. In fact, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, lists insomnia as a diagnostic criterion for a number of psychiatric disorders, while for other disorders insomnia is considered a common feature. However, the characteristics of insomnia are not distinct between the different psychiatric illnesses. There have certainly been polysomnographic studies of sleep in individuals with different psychiatric illnesses, although they are difficult to interpret.

Not only do psychiatric disorders produce insomnia, but insomnia is associated with an increased incidence, or new onset of, psychiatric illness. In particular, this has been observed in long-and short-term studies, which have shown an increased risk for the development of new-onset or recurrent depression in people with persistent insomnia. A study by Chang evaluated Johns Hopkins Medical School graduates over 40 years (Chang PP, Ford DE, Mead LA, et al. Am J Epidemiol. 1997;146:105-114). Medical school seniors who reported insomnia had a higher risk of depression 15 years later, and this excess risk continued to increase up to 40 years after graduation.

Is there a cause-and-effect relationship between insomnia and depression, or is it merely an association?

It is unclear whether insomnia is a marker of early depression, or itself predisposes people to depression. Hypercortisolemia, particularly in late afternoon/early evening, has been seen in individuals with chronic primary insomnia. Increased cortisol may indicate a vulnerability to depression, or could be causally related to insomnia.

Since insomnia can be linked to other diseases, should treatment be administered quickly?

Even though we do not have a cause-and-effect relationship established, insomnia should be aggressively treated for a variety of potential reasons, including protection against future psychiatric illnesses. A doctor would not deprive a chronic pain patient of medication just because 5% of the people who take analgesics develop a dependence and tolerance to it. Similarly, insomnia should be treated aggressively, as the majority of those who take hypnotics do not develop dependence or tolerance.

Should we be concerned that patients who rely on medication to sleep over a long period of time will become dependent and abuse the drugs?

Overall, abuse of sleep drugs by insomniacs is rare. Most patients with insomnia are not seeking a high; rather they are seeking adequate treatment for their insomnia. Those with a prior history of substance or alcohol abuse may abuse or develop rapid tolerance to these medications. For patients with addictive tendencies, there are other effective approaches to the treatment of chronic insomnia. For example, cognitive-behavioral therapies have been shown in numerous studies to be as effective as hypnotics in reducing time awake during the night and the amount of time it takes to fall asleep. They work predominantly by restricting time in bed and by reducing dysfunctional sleep-related cognitions.

What differences exist between the benzodiazepines, the sedating antidepressants, and atypical antipsychotics in the treatment of insomnia?

There are very few controlled trials of sedating antidepressants for insomnia and none for atypical antipsychotics or anticonvulsants, which are both being used to treat insomnia. I believe that tolerance can develop to any medication that is sedating. My experience is that people develop a tolerance to alternative agents as often as they do to the benzodiazepine and benzodiazepine receptor agonists.

The short-acting benzodiazepine receptor agonists are generally free of next day carry-over effects. However, because they have a longer half-life (eg, trazodone=5–9 hours; gabapentin=7 hours), sedation is reported more commonly with these agents than with the short-acting benzodiazepines and benzodiazepine receptor agonists.

Should treatment of insomnia be adjusted depending on what the primary disorder is?

Always try to treat the underlying disorder first, whether it is depression, psychosis, thyroid disease, or restless legs syndrome. For patients with substantial insomnia, who have consequences for daytime functioning and quality of life, I start treatment with a benzodiazepine or benzodiazepine receptor agonist, because I believe they work the best. Patients with less substantial adverse consequences can use one of the less reliably sedating agents, such as antidepressants, antipsychotics, or anticonvulsants. In patients with a history of alcohol or substance abuse, I am more likely not to use an agent that works at the benzodiazepine receptor.

I am hesitant to give patients with bipolar disorder antidepressants for sedation. Even though they are taking low doses, there is the risk of inducing a switch to mania. For patients with mood instability or bipolar spectrum disorders, it is important to be aggressive in treating insomnia.

For people who have depression and severe insomnia, it is important to treat both disorders. A sedating agent should be used during the first couple of weeks to provide immediate insomnia relief.

A new drug, eszopiclone, is indicated for long-term use in the treatment of insomnia. Is it safer and more effective than current agents, such as zaleplon, zolpidem, and the benzodiazepines?

No head-to-head studies have been performed comparing eszopiclone to the these other approved medications for sleep. However, a 6-month placebo-controlled study of eszopiclone in the treatment of primary insomnia demonstrated that advantages of this agent over placebo in promoting sleep onset and reductions in time awake during the night were maintained over 6 months of nightly use. Long-term data for the other agents are pretty much absent, except for long-term data on intermittent dosing with zolpidem.

Zaleplon and zolpidem predominantly bind to the α1 subtype of the γ-aminobutyric acid (GABA)A receptor, which carries amnestic, psychomotor, and anticonvulsant properties.  They do not bind to α2, which carries anxiolytic properties. Zolpidem and zaleplon may lack anxiolytic properties, because of this receptor selectivity.

Some patients who take zolpidem actually develop psychiatric symptoms the next day. Can you explain this behavioral toxicity?

I think that can happen with all benzodiazepines and non-benzodiazepines. Many patients develop disinhibition in the hospital when they are given lorazepam or triazolam for sleep or anxiolysis. In hospitalized medical or psychiatric patients this can occur with the non-benzodiazepines as well. It is rare, but there have been reports of disinhibition, amnesia, and occasionally hallucinations, as potential side effects of any agent in this class.

Is modafinil an effective medication for sleep disorders?

Modafinil is generally effective for sleepiness and fatigue, regardless of etiology. The label has been expanded from daytime sleepiness in narcolepsy to include daytime sleepiness associated with shift work and incompletely treated obstructive sleep apnea. I think that it is effective for fatigue and sleepiness regardless of the cause––narcolepsy, depression, sleep apnea, or even inadequate sleep. However, the modafinil data on mood-elevating properties have not demonstrated improvement in total Hamilton Rating Scale for Depression scores or any components other than energy and fatigue.

As for the negative effects, modafinil can occasionally cause the patient to be jittery and anxious the way a sympathomimetic stimulant can. It can also reduce the efficacy of steroidal contraceptives. The most common side effect is headache, but that is usually transient. Also, at this point in time it is a very expensive medication, but it will become available in a generic form within approximately 18 months.

How often is sleep apnea a cause of psychiatric symptoms?

These disorders coincide more often than would be seen by chance. However, it is not clear to me whether sleep apnea produces a vulnerability for depression. My experience has been that rarely does the treatment of sleep apnea obviate the need for independent treatment of the depression.

Are there any instances when psychiatric symptoms caused by a sleep disorder are resolved when the primary sleep disorder is treated?

People with an acute, severe insomnia can  meet criteria for depression: they are agitated, they are not sleeping, they have lost interest in things, they feel hopeless and at times suicidal, their appetite is poor, and they have no energy. However, if you treat their insomnia with an appropriate medication, their “depression” resolves. At times, restless legs syndrome or obstructive sleep apnea have been misdiagnosed as psychiatric disorders, and treatment of these makes the symptoms improve.

Do insomnia patients tend to exaggerate their symptoms, such as how long it takes them to fall asleep?

Insomnia is a diagnosis that is made by self report. When a patient over-estimates sleep difficulties, we call it sleep state misperception, but these people have insomnia. Just because we can record that they have slept in the sleep laboratory, does not necessarily mean that their sleep is refreshing or restorative. Sleep has two components; it has the objective component, measured by an electroencephalogram (EEG), and the subjective component. EEG results, recorded when the patient is asleep do show a difference between insomniacs and people who do not have insomnia.

People with insomnia are not excessively sleepy. Insomnia is a state of hyperarousal in a variety of contexts. The endocrine context has to do with cortisol levels. The cognitive context is characterized in terms of the patient’s ideas about their insomnia, beliefs regarding the consequences of their insomnia, and exaggeration of how much or how little they have slept. The physiological context  refers to the whole body metabolic rate, EEG activity, and hypermetabolism by functional imaging. People with insomnia are hyperaroused, but whether that is a marker of their insomnia or a cause of their insomnia is not clear.

Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression, but reportedly produce many side effects, including sleep disturbances, daytime somnolence, and fatigue. Do you think that these effects are clinically significant?

When given to normal volunteers, SSRIs increase the time to fall asleep; they increase the amount of light sleep; and they have profound effects on REM sleep, which contributes to subjective and behavioral toxicity for sleep. SSRIs fragment REM sleep so that there are more awake periods mixed in between the REM periods. They can also disinhibit motor activity, both during REM sleep and non-REM sleep. However, because these agents are so effective in the treatment of depression, and the insomnia of depression is so severe, their net effect on sleep for people with depression is usually beneficial.  

In non-REM sleep, effects of SSRIs are seen as an increase in the number of periodic leg movements of sleep, which may end up disturbing sleep. “Twitchiness,” or myoclonic events, as well as longer motor events during REM sleep are observed. SSRIs can actually produce REM sleep behavior disorder, which is a more severe case of disinhibition of REM motor activity.

SSRIs partially reverse the paralysis/atonia that usually occurs during REM sleep. This fragmentation of REM and motor activity in REM may be responsible for patient’s experiences of vivid dreams. Therefore, patients can end up acting out their dreams by thrashing, kicking, or propelling themselves out of bed. I have seen this with the use of several SSRIs, clomipramine, as well as monoamine oxidase inhibitors. Also, SSRIs produce marked excess of eye movements during non-REM sleep, REM sleep, and while awake.

For a patient who is on an antidepressant and has sleep disruption, I recommend lowering the SSRI dose to reduce or eliminate the side effect, and hopefully maintaining the beneficial effect. If that is not possible, one can either consider switching to a nonserotonergic antidepressant or adding a sedative at bedtime to improve sleep quality.

Is REM sleep behavior disorder an early manifestation of Parkinson’s disease?

In approximately 50% of people with REM sleep disorder, the condition seems to be associated with synucleinopathies, which is a class of neurologic disorders that includes Parkinson’s disease. The most common cause of REM sleep behavior disorder is probably antidepressant related. I recommend using shorter benzodiazepines, such as  lorazepam or oxazepam, which have less potential daytime consequences than the longer acting ones. This is important because many people with Parkinson’s or other neurologic disease are older and have problems with motor activity and cognitive function.

Are there any other psychotropic drugs with sleep effects that are unique or noteworthy?

In people with restless legs syndrome, an exacerbation may occur with SSRIs, so nonserotonergic agents like bupropion or desipramine may be a better option for these individuals. In addition, any dopaminergic antagonist, such as quetiapine and other atypicals, can produce restless leg syndrome or periodic legs movements of sleep.

Some psychiatric medicines, such as tiagabine and olanzapine, can increase slow-wave sleep. However, it is not clear what the clinical consequences of this increase in slow-wave sleep are; the data for tiagabine and insomnia were negative. I think that these slow-wave sleep findings are very interesting, but need to be supported by clinical consequences.

Are there any common mistakes that general practioners or general psychiatrists make in approaching diagnosis of sleep-related problems or insomnia?

The most common mistake is that the physician does not ask questions about the patient’s sleep. Many physicians have limited time and do not ask questions about sleep because they are concerned that they will not have enough time to make an adequate diagnosis or treatment plan. Also, some of the physicians have never been educated about the appropriate differential diagnoses. The amount of education about sleep in medical school and residency is minimal; possibly only one or two lectures. Thus, physicians tend to avoid the issue because they feel they do not have enough time or knowledge to appropriately address it. The most common mistake is ignoring the issue.

Obstructive sleep apnea is frequently missed by psychiatrists. Many psychiatric medications produce weight gain, which causes vulnerability to sleep apnea. The fatigue and sleepiness are commonly attributed to side effects of medications or to an underlying psychiatric illness, such as apathy, depression, or negative symptoms of schizophrenia. The diagnosis of sleep apnea can be made easily by asking about snoring and looking at the patient’s neck size to see if they have a short, squat neck. Patients who have a neck size of >16.5–17 inches have a 50% chance of having sleep apnea. Sleep study is then recommended.

The diagnosis of restless legs syndrome is commonly missed as well, and the sleep complaints are attributed to primary insomnia or an anxiety or mood disorder.

Similarly, acute insomnia can be misdiagnosed as depression. One can determine if it is insomnia by giving the patient a hypnotic for 3 days and observing whether the symptoms resolve. On the other hand, antidepressant trials may take 1 month, and can worsen insomnia.

Are there some patients who need large doses of benzodiazepines in order for these drugs to be effective?

Patients who require large doses are often those who have taken benzodiazepines in the past and have developed some tolerance to them. When I initiate treatment with a benzodiazepine agent, I tell the patient what the maximum dose is that I feel comfortable prescribing. If the patient develops tolerance and needs an increase in dosage beyond that level, I taper the patient off the medication and use one of the other classes of agents to help them sleep.

Another instance where patients require massive doses of medication is with sleep state misperception. For example, a patient can be taking quetiapine 600 mg, clonazepam 2 mg, zolpidem 20 mg, gabapentin 1,200 mg, and trazodone 150 mg, and still claim they are not sleeping. However, they seem to sleep fine in a sleep laboratory. In this case, there is something wrong with the patient’s subjective appreciation of sleep. I tell these patients that their body is getting enough sleep and that because of the adverse consequences of daytime sedation, that I would like to taper the medication. Many times these patients will have anxiety about the consequences of sleeplessness. This is an instance where bringing them into the sleep laboratory and confirming sleep state misperception can be helpful and reassuring to the patient.

Is there a standard sleep questionnaire that is available?

While there is no standard screening questionnaire for sleep disorders,  a helpful sleep assessment is the Pittsburgh Sleep Quality Index (Buysse DJ, Reynolds CF, Monk TH, et al. Psychiatry Res. 1989;28:193-213). PP

 

 

 

 

This interview took place on March 15, 2005, and was conducted by Norman Sussman, MD.