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 depression advisory board for Eli Lilly.

 


 

 

Psychiatric issues are common in sickle cell disease (SCD)1 but have not received sufficient attention in the clinical or research literature. These issues are further complicated by the social, economic, and healthcare disparities experienced by many African Americans. This column reviews the following psychiatric issues in SCD, with particular focus on recent research: first, depression and anxiety resulting from living with a chronic stigmatizing disease associated with chronic pain, unpredictable painful crises, multiple serious complications, poor health-related quality of life (HRQOL), and high mortality; second, problems of pain management, frequent undertreatment, and potential for substance abuse and addiction; third, coping styles; fourth, alcohol abuse; and last, central nervous system (CNS) injury and resulting cognitive dysfunction from strokes, primarily during childhood.

 

Overview of Sickle Cell Disease

SCD is an autosomal recessive genetic disorder of hemoglobin (Hb) structure and the most common of the hemoglobinopathies. While it usually results in anemia, the primary symptomatic manifestation of SCD is pain. The most severe form of SCD, homozygous sickle cell anemia (Hb SS), occurs when Hb S is inherited from both parents. In the United States, this happens in approximately one in 375 African-American births. Other genetic variants producing SCD include two forms of sickle cell-beta thalassemia (Sβ° and Sβ+ ) and sickle cell-hemoglobin C (SC). Individuals with sickle cell trait, ie, heterozygotes for Hb S, do not experience any adverse clinical consequences (except under acute hypoxic conditions, eg, exposure to high altitude without time to accommodate) and have had a selective advantage against malaria. Those with the homozygous disease face a chronic disease, with onset in childhood leading to devastating consequences.

SCD occurs primarily in those of African descent, but it also afflicts people of Mediterranean, Middle Eastern, and Asian origins. Approximately one in 300 African-Americans have SCD (>70,000 people) and 8% have sickle cell trait. The consequences of SCD are aggravated by social, economic, and healthcare disparities. African Americans are on average poorer, have more limited access to healthcare services, and die sooner than Caucasians.2 Medical advances, such as prophylactic penicillin for children, have transformed the disease from a pediatric illness with few surviving beyond adolescence into one chronically extending into adulthood. Life expectancy has increased from a mean of 14 years of age in the 1970s to close to 50 years of age at present.3 By the 1980s, the federally funded Cooperative Study of Sickle Cell Disease (CSSCD)4 found median survival was into the fourth decade for homozygous patients. Patients with doubly heterozygous forms of SCD, such as Hb SC, fared even better, and the presence of a higher percentage of persistent fetal hemoglobin (Hb F) was associated with less severe disease and greater longevity.

This improved survival has created the relatively new phenomenon of adults with chronic SCD. Consequently, much less is known about psychosocial factors in adults with SCD than in many other chronic medical disorders, with most studies to date addressing prevalence of depression (see below). The increase in longevity has also resulted in physicians for adults treating pain resulting from a disease for which they have limited training and experience. In one inpatient study, one-third of patients reported inadequate pain relief and nearly 50% reported long delays in being treated for pain.5 The evidence base used to guide treatment for the growing population of adults with SCD has been very limited, with even less data regarding psychosomatic interactions, though both are now an active focus of investigators.

Most familiar to clinicians are the acute painful episodes known as “sickle cell crises,” thought to be due to acute vaso-occlusion by sickled red blood cells. Recurrent crises represent the most common reason patients seek acute medical care. Dehydration, temperature extremes, infection, changes in altitude, stress, and physical exertion may precipitate crises, but most crises occur without an identifiable cause. Vaso-occlusion causes acute pain in the short run and chronic pain and end-organ damage in the long run, potentially affecting all organ systems with particular harm to bones, kidneys, lungs, eyes, and brain. Complications include acute chest syndrome, avascular necrosis, priapism, ischemic leg ulcers, transient ischemic attacks and stroke, osteomyelitis, gallstones and cholecystitis, and renal insufficiency.

Clinicians and investigators have tended to focus on acute crisis pain and to equate crisis with acute healthcare utilization, ie, emergency room visits or hospitalization. However, the recent Pain in Sickle Cell Epidemiology Study (PiSCES)6-13 has demonstrated that pain in adults with SCD is far more prevalent and severe than previous studies have portrayed, and it is mostly managed at home.6 Therefore, it has been vastly underestimated when measured by using only healthcare utilization. In this prospective study, >50% of adults with SCD experienced pain, crises, or healthcare utilization on >50% of the days. Almost 33% experienced pain nearly every day, with the mean intensity in the middle range. In contrast, only approximately 15% rarely experienced pain. Crises and healthcare utilization were far less common than reported pain days; pain days that were not associated with a crisis occurred 10 times more often as pain days associated with healthcare utilization. Thus, contrary to commonly held belief, pain in adults with SCD is the rule rather than the exception. Since SCD adults infrequently utilize health care even in response to severe pain, there is a vast, mostly submerged iceberg of sickle cell pain that is managed outside of medical facilities and not seen by most professionals.

Smaller longitudinal studies measuring daily pain in children have also found that pain was most often managed at home rather than within healthcare facilities.7 How might this be explained? Behavioral theories suggest that many factors, besides pain itself, influence the response to pain.7 Adults with SCD carefully weigh the decision to come to a busy emergency department for treatment of even severe pain, where they may face long waits, stigmatization, and labeling as “drug-seeking.” Some manage their pain at home because of barriers in accessing health care, especially finding clinicians with SCD expertise, competing life priorities (eg, no child care), and lack of transportation. Evidence of each of these may be found in behavioral studies of SCD.7

HRQOL in adults with SCD is significantly worse than national norms.8 Adults with SCD have quality of life (QOL) that is similar to dialysis patients and poorer than adults with cystic fibrosis (except for mental health). Not surpisingly, QOL in adults with SCD significantly decreases as pain levels increase.

 

Depression and Anxiety

As with most chronic diseases, depression and other psychiatric disorders are common in SCD.13-15 Rates of depression are similar to those found in other serious chronic medical disorders, ranging from 18% to 44%,16-18 and are increased over rates in the general population even when one controls for illness-related physical symptoms.19 In a Nigerian study, subjects with SCD had a prevalence rate of depression greater than those with cancer or malaria (but less than those with HIV/AIDS).20 While studies of depression in children with SCD have shown mixed results, children experience high rates of fatigue and other somatic complaints, impaired self-esteem, feelings of hopelessness in the context of frequent hospitalizations, absences from school, and the inability to experience a normal childhood.1

There are many potential contributing causes to symptoms of depression and anxiety in SCD. These include the chronicity of the illness; unpredictability of crises; chronic pain; overwhelming nature of medical complications, including anemia, fatigue, growth retardation, physical deformities, leg ulcers, renal failure, strokes, and substantially reduced life expectancy; and racial prejudice and stereotyping. SCD may result in social derision, disability, and financial stress21 as well as stigmatization for pseudoaddiction to opioid analgesics.22 One study found that adults with SCD had lower self-esteem than those with HIV/AIDS or cancer.20 Chronically prescribed opioids may contribute a component of substance-induced mood disorder.15

Children with SCD are often underweight, shorter than normal children, and have delayed puberty. With their small stature, adolescents with SCD encounter problems with self esteem, dissatisfaction with body image, and social isolation, with participation in athletics also limited due to fear of initiating a vaso-occlusive crisis.1 School performance suffers when hospitalizations lead to missing multiple school days. Accordingly, adolescents often experience hopelessness and social withdrawal.23

PiSCES found that 27.6% of adults with SCD were depressed and 6.5% had ananxiety disorder.13 Depressed subjects had pain on significantly more days than nondepressed subjects (mean pain days=71.1% versus 49.6%, P<.001). On non-crisis days, depressed subjects had higher mean pain, distress from pain, and interference from pain than those without depression. Both depressed and anxious subjects had poorer functioning on all dimensions of HRQOL, even after controlling for demographics, hemoglobin type, and pain. The anxious subjects had more pain, distress from pain, and interference from pain, both on non-crisis days and on crisis days, and used opioids more often. Anxious patients were also more likely to be emergency room “frequent flyers.”

 

Chronic and Acute Pain and Opioid Use

As noted above, recurrent painful crises represent the most common reason patients with SCD seek acute medical care. Painful crises most frequently involve the abdomen, chest, back, and extremities. The average adult patient experiences <1 vaso-occlusive crisis per year for which he or she seeks medical care, but a very small fraction (approximately 1%) do so several times per year.24 However, the PiSCES found that most self-defined painful crises do not result in acute healthcare visits.6 Both the unpredictability and the severity of crisis pain contribute to its psychological morbidity and debilitation. It is interesting that higher hematocrit is associated with more pain. Contrary to many studies of acute and chronic pain of other causes, men and women with SCD report generally similar pain experiences, both in terms of acute crisis pain and chronic pain, as well as HRQOL.8,9

Opioid analgesics are the mainstay of therapy for acute pain crises in SCD. Therefore, by adulthood, most patients have had many years of intermittent exposure to opioids. Opioids help control pain, improve functional capacity, and decrease hospitalizations in patients with SCD.25 Chronic opioid use often results in tolerance and physiologic dependence, but much less often abuse and addiction. Opioid abuse and addiction behaviors can be difficult to define when prescribed for chronic pain. While there is little evidence in the medical literature that suggests addiction is frequent in SCD, physicians and other healthcare providers routinely overestimate its risk and prevalence.26 Over 60% of nurses believe addiction is prevalent in SCD,27 and >50% of emergency department physicians and 25% of hematologists thought that >20% of SCD patients are addicted.28 Some of this distorted perception results from failure to distinguish between physiologic tolerance and dependence versus addictive behaviors.22

Because of their fear of causing or exacerbating addiction, physicians may under-treat pain in patients with SCD.29 This may result in pseudoaddiction, where addiction-like behaviors occur as a result of inadequate pain management.30 An example mislabeled as “drug-seeking behavior” occurs when a patient with acute crisis pain asks for a higher dose of opioid than he has been given because the physician has failed to increase normal dosage in recognition of tolerance developed through chronic opioid therapy.22 Opioid abuse and addiction can occur in adults with SCD; some patients may inappropriately use opioids for non-pain symptoms such as insomnia, depression, and anxiety. It should be noted, however, that opioids do not have any specific adverse effects on SCD. In contrast, cocaine is very harmful since in causing small vessel spasm it may precipitate or escalate sickling, and it increases the already elevated risk of stroke and other ischemic events.31 One form of opioid misuse in SCD to be aware of is the barter exchange of prescribed opioids for cocaine. This possibility should always be considered whenever a urine toxicology screen is negative for opioids in a SCD patient who says he has been taking his analgesic as prescribed.

 

Coping Style

Numerous studies have examined the influence of coping style in SCD, specifically how negative thinking and passive adherence contribute to increases in pain perception, opioid use, and healthcare utilization.11 “Negative thinking” is a cognitive set composed of catastrophizing and self-statements of fear and anger, in which catastrophizing has seemed the most important component in pain research. “Catastrophizing” refers to an exaggerated negative orientation or “mental set” toward pain stimuli and pain experience. Individuals who catastrophize may develop beliefs with a high degree of aversion to pain-eliciting situations, pay more attention to their pain sensations, and consume more opioids.32 Catastrophizing can be understood as a set that includes rumination, magnification, and helplessness to deal with pain. Although it has been identified as an important factor affecting outcomes in several painful conditions, it appears that the role of catastrophizing in other conditions cannot be generalized to SCD. While adults with SCD have higher mean catastrophizing scores than found in studies of other chronic pain conditions that are not lifelong and life-threatening, no differences were found between higher and lower catastrophizers in intensity of pain, distress, interference, opioid use, or healthcare utilization.11

 

Alcohol Abuse

Alcohol abuse is common in patients with chronic pain and painful medical disorders, but until recently it had not been studied in SCD. In the prospective PiSCES cohort, almost one-third of SCD adults were abusing alcohol.10 There were no significant differences between alcohol abusers and nonabusers on demographics, biologic variables, depression, anxiety, or measures of pain and crisis. Alcohol abusers did not use opioids any more often, but they reported more pain relief from opioids than did nonabusers. Alcohol abusers had fewer unscheduled clinic visits, emergency room visits, hospital days, and any healthcare utilization for SCD; however, this was only statistically significant for emergency room visits. Surprisingly, QOL was similar between both groups, except that alcohol abusers unexpectedly had better overall physical QOL. Alcohol abusers were more likely to report coping by ignoring pain, diverting attention, and using particular self statements.

 

Psychosocial Interventions

There have only been a few small short-term biobehavioral intervention trials that have attempted to alter pain and healthcare utilization in SCD. A multidimensional, intense intervention to improve pain management of SCD patients through counseling and carefully monitored opioid prescribing reduced emergency department visits and hospital admissions.33

In another trial,34 a pain-coping skills intervention in adults with SCD lowered pain perceptions from a laboratory-induced pain stimulus and significantly increased coping attempts. On pain days when subjects used coping strategies, they had fewer healthcare contacts than on pain days when they did not use coping strategies. Other interventions have met with limited success. A brief training in cognitive coping skills resulted in increased coping attempts, decreased negative thinking, and lower tendency to report pain during laboratory-induced noxious stimulation.35 A family intervention in children met with some success.36 Self hypnosis as an adjunct to traditional treatment improved sleep, reduced pain days, and reduced. the use of pain medications.37 There are no published randomized controlled trials of antidepressants in patients with SCD.

 

Central Nervous System Injury

Brain disease from SCD complications may begin early in life. Children with SCD may experience a wide variety of neurologic syndromes, including ischemic and hemorrhagic stroke, transient ischemic attacks, “soft neurologic signs,” seizures, headache, coma, visual loss, altered mental status, cognitive difficulties, and covert or “silent” infarction. Approximately 25% to 33% of affected children have CNS consequences of SCD.38 Seizures occur in 12% to 14%.39,40  Once very common in children with SCD, the incidence of stroke has been reduced through chronic transfusion and other interventions.41 Intellectual deficits, including borderline-to-moderate mental retardation and reduced language function, have been reported.42 Not surprisingly, cognitive deficits in children with SCD lead to educational and social problems, and even dementia later in life.43 Acquired neurologic impairments in children with SCD are associated with difficulties in the decoding of emotions of other children and adults.44 A small, nonrandomized study45 suggests that hydroxyurea therapy may improve cognitive functioning in SCD. PP

 

References

1. Becker M, Axelrod DJ, Oyesanmi O, Markov DD, Kunkel EJ. Hematologic problems in psychosomatic medicine.Psychiatr Clin North Am. 2007;30(4):739-759.
2. Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. 1st ed. Washington, DC: National Academies Press; 2002.
3. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-1644.
4. Lee A, Thomas P, Cupidore L, Serjeant B, Serjeant G. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ. 1995;311(7020):1600-1602.
5. Gaston MH, Rosse W. The cooperative study of sickle cell disease: review of study design and objectives. Am J Pediatr Hematol Oncol. 1982;4(2):197-200.
6. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily pain in sickle cell disease. Ann Intern Med. 2008;148(2):94-101.
7. Smith WR, Bovbjerg VE, Penberthy LT, et al. Understanding pain and improving management of sickle cell disease: the PiSCES study. J Natl Med Assoc. 2005;97(2):183-193.
8. McClish DK, Penberthy LT, Bovbjerg VE, et al. Health related quality of life in sickle cell patients: the PiSCES project. Health Qual Life Outcomes. 2005;3:50.
9. McClish DK, Levenson JL, Penberthy LT, et al. Gender differences in pain and health care utilization for adult sickle cell patients: the PiSCES Project. J Womens Health (Larchmt). 2006;15(2):146-154.
10. Levenson JL, McClish DK, Dahman BA, et al. Alcohol abuse in sickle cell disease: the PiSCES project. Am J Addict. 2007;16(5):383-388.
11. Citero VA, Levenson JL, McClish DK, et al. The role of catastrophizing in sickle cell disease–the PiSCES project. Pain. 2007;133(1-3):39-46.
12. Aisiku IP, Penberthy LT, Smith WR, et al. Patient satisfaction in specialized versus nonspecialized adult sickle cell care centers: the PiSCES study. J Natl Med Assoc. 2007;99(8):886-890.
13. Levenson JL, McClish DK, Dahman BA, et al. Depression and anxiety in adults with sickle cell disease: the PiSCES project. Psychosom Med. 2008;70(2):192-196.
14. Alao AO, Cooley E. Depression and sickle cell disease. Harv Rev Psychiatry. 2001;9(4):169-177.
15. Alao AO, Dewan MJ, Jindal S, Effron M. Psychopathology in sickle cell disease. West Afr J Med. 2003;22(4):334-337.
16. Wison Schaeffer JJ, Gil KM, Burchinal M, et al. Depression, disease severity, and sickle cell disease. J Behav Med. 1999;22(2):115-126.
17. Hasan SP, Hashmi S, Alhassen M, Lawson W, Castro O. Depression in sickle cell disease. J Natl Med Assoc. 2003;95(7):533-537.
18. Laurence B, George D, Woods D. Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease. J Natl Med Assoc. 2006;98(3):365-369.
19. Molock SD, Belgrave FZ. Depression and anxiety in patients with sickle cell disease: conceptual and methodological considerations. J Health Soc Policy. 1994;5(3-4):39-53.
20. Ehigie BO. Comparative analysis of the psychological consequences of the traumatic experiences of cancer, HIV/AIDS, and sickle cell anemia patients. IFE Psychologia. 2003;11(3):34-54.
21. Scott KD, Scott AA. Cultural therapeutic awareness of sickle cell anemia. J Black Psychol. 1999;25(3):316-335.
22. Elander J, Lusher J, Bevan D, Telfer P, Burton B. Understanding the causes of problematic pain management in sickle cell disease: evidence that pseudoaddiction plays a more important role than genuine analgesic dependence. J Pain Symptom Manage. 2004;27(2):156-169.
23. Hurtig AL, Park KB. Adjustment and coping in adolescents with sickle cell disease. Ann N Y Acad Sci. 1989;565:172-182.
24. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325(1):11-16.
25. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116(5):364-368.
26. Labbe E, Herbert D, Haynes J. Physicians’ attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21(4):246-251.
27. Pack-Mabien A, Labbe E, Herbert D, Haynes J Jr. Nurses’ attitudes and practices in sickle cell pain management. Appl Nurs Res. 2001;14(4):187-192.
28. Shapiro BS, Benjamin LJ, Payne R, Heidrich G. Sickle cell-related pain: perceptions of medical practitioners. J Pain Symptom Manage. 1997;14(3):168-174.
29. Labbe E, Herbert D, Haynes J. Physicians’ attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21(4):246-251.
30. Weissman DE, Haddox JD. Opioid pseudoaddiction–an iatrogenic syndrome. Pain. 1989;36(3):363-366.
31. Strauss A, LaCandia S. Sickle cell disease and cocaine abuse–a deadly mixture? South Med J. 1989;82(11):1455-1456.
32. Elander J, Lusher J, Bevan D, Telfer P. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci Med. 2003;57(9):1683-1696.
33. Grant MM, Gil KM, Floyd MY, Abrams M. Depression and functioning in relation to health care use in sickle cell disease. Ann Behav Med. 2000;22(2):149-157.
34. Gil KM, Carson JW, Porter LS, et al. Daily stress and mood and their association with pain, healthcare use, and school activity in adolescents with sickle cell disease. J Pediatr Psychol. 2003;28(5):363-373.
35. Gil KM, Carson JW, Porter LS, Scipio C, Bediako SM, Orringer E. Daily mood and stress predict pain, health care use and work activity in African-American adults with sickle cell disease. Health Psychol. 2004;23(3):267-274.
36. Vichinsky EP, Johnson R, Lubin BH. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol. 1982;4(3):328-333.
37. Gil KM, Carson JW, Sedway JA, Porter LS, Schaeffer JJ, Orringer E. Follow-up of coping skills training in adults with sickle cell disease: analysis of daily pain and coping practice diaries. Health Psychol. 2000;19(1):85-90.
38. Schatz J, McClellan CB. Sickle cell disease as a neurodevelopmental disorder. Ment Retard Dev Disabil Res Rev. 2006;12(3):200-207.
39.Prengler M, Pavlakis SG, Boyd S, Connelly A, Calamante F, Chong WK, Saunders D, Cox T, Bynevelt M, Lane R, Laverty A, Kirkham FJ. Sickle cell disease: ischemia and seizures. Ann Neurol. 2005;58(2):290-302.
40. Liu JE, Gzesh DJ, Ballas SK. The spectrum of epilepsy in sickle cell anemia. J Neurol Sci. 1994;123(1-2):6-10.
41. Wang WC. The pathophysiology, prevention, and treatment of stroke in sickle cell disease. Curr Opin Hematol. 2007;14(3):191-197.
42. Hariman LM, Griffith ER, Hurtig AL, Keehn MT. Functional outcomes of children with sickle-cell disease affected by stroke. Arch Phys Med Rehabil. 1991;72(7):498-502.
43. Anie KA. Psychological complications in sickle cell disease. Br J Haematol. 2005;129(6):723-729.
44. Boni LC, Brown RT, Davis PC, Hsu L, Hopkins K. Social information processing and magnetic resonance imaging in children with sickle cell disease. J Pediatr Psychol. 2001;26(5):309-319.
45. Puffer E, Schatz J, Roberts CW. The association of oral hydroxyurea therapy with improved cognitive functioning in sickle cell disease. Child Neuropsychol. 2007;13(2):142-154.

 

 

 

Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.

 

 
 

A growing body of evidence supports the efficacy and cost effectiveness of psychotherapy and disease management for mental illness provided over the telephone. However, telephone behavioral health care is not reimbursable under present Center for Medicare and Medicaid Services standards. Nonetheless, elements of telephone-based behavioral health care are being incorporated into Veterans Administration health programs and by a limited number of major insurers. A review of the evidence suggests this trend will continue.

 

Are Telephone-based Interventions Needed?

Cohen and colleagues1 recently wrote:

In the face of increasingly constrained resources, there is a realistic way of achieving better health results: conduct careful analysis to identify evidence-based opportunities for more efficient delivery of health care—whether prevention or treatment—and then restructure the system to create incentives that encourage the appropriate delivery of efficient interventions.1

What follows argues that telephone screening and interventions for common behavioral health problems may be both effective and efficient.

There is considerable evidence indicating that screening and interventions for both depression and at-risk or unhealthy drinking are effective by telephone. In addition, a variety of interventions for dementia caregivers conducted by “dementia managers” via telephone lead to better outcomes for both dementia patients and caregivers.2-6 Nonetheless, telephone screening and interventions for behavioral health are best characterized as emerging, rather than established, evidenced-based practices.7

 

Depression

In studies of depression care,8 uniformly superior outcomes result from the integration of mental health specialists into primary care sites. Nonetheless, the integration of mental health specialists is not considered economically viable, leaving the primary care practices ill-prepared to reduce the disability of depression.9 In contrast to an “integrated model” where mental health specialists are co-located with primary care physicians (PCPs), a collaborative disease management model utilizing behavioral health managers supervised by psychiatrists has demonstrated benefits. Large-scale, multisite studies10-12 have shown greater rates of response and remission as well as reduced levels of suicidality and costs associated with the disease management for depression. Even when routine care is enhanced by improved access to specialist consultation, the collaborative disease management model proves superior. The critical element that distinguishes disease management from routine care is a third party (eg, a master’s level social worker, psychologist, or nurse) who collaborates with the primary care provider, patient, and family to achieve superior outcomes. Telephone management of depression by behavioral health managers not located in the primary care sites also appears to be an effective alternative to integrated care.13,14 Studies of depression care15-17 incorporating telephone psychotherapy as part of the disease management package show benefits as well. However, the economic benefits of behavioral health management are uncertain. In contrast, disease management in managed care practices controls costs by reducing hospital admissions related to diabetes and congestive heart failure without shifting the expense from the hospital to the primary care provider or sacrificing patient satisfaction.18,19

Perhaps the most fully developed telephone disease management (TDM) is described by Oslin and colleagues14 and Zanjani and colleagues.20 TDM was originally developed for Veterans Administration outpatient programs to reduce depression and at-risk drinking as a Behavioral Health Laboratory (BHL). TDM has been adopted by AETNA and Blue Cross/Blue Shield of South Carolina to reduce costs among primary care populations by offering a more aggressive care plan to patients prescribed to antidepressants. Although cost offset data have not been made available, the explicit expectation is that the carriers’ investment in depression care will reduce the volume of claims for primary care and hospital services (DW Oslin, MD, personal communication, March 2008).

The BHL is a screening and assessment service designed to help manage the behavioral health needs of patients seen in primary care. The Core Assessment of the BHL is a briefly scripted interview that provides PCPs with an assessment of patients’ substance abuse and behavioral health symptoms. In addition, the BHL both offers structured treatment response and outcomes assessments and serves as a base for the disease management approach to specific mental illnesses. The BHL is capable of focused decision support, including triage to specialty behavioral health or substance abuse care. For older adults, the BHL quantifies the level of impairment and comorbid psychiatric disorders such as depression, at-risk drinking, and anxiety. The University of Pennsylvania and Philadelphia Veterans Affairs Medical Center are the development and founding sites of the BHL. The BHL has been recognized as a “Best Practice” for identification and early intervention in behavioral health problems of primary care patients within the Department of Veterans Affairs.

In the BHL, the telephone interaction is “facilitation” rather than psychotherapy. Facilitated care by telephone limits scope, but it does not necessarily limit the number of interactions with the patient.21 These interactions between patient and the behavioral health manager include solving problems with barriers such as reluctance to either initiate prescribed antidepressant therapy or communicate difficulties with side effects to the PCP; providing positive reinforcement and praise once barriers are overcome; monitoring progress, assessing response to treatment, and countering premature discontinuation of medication; purposefully scheduling physical activity and pleasant events for behavioral activation; and teaching self-management techniques. Periodic case reviews with a supervising psychiatrist and reports to the PCP are used to both coordinate care and facilitate referrals when psychotherapy or direct psychiatric consultations are indicated.

The BHL uses the Patient Health Questionnaire9 (PHQ) for screening (2 items), initiating treatment (9 items), and assessing outcome as non-response, response, or remission. At each juncture, the PHQ score is used to indicate the need for assessment, treatment or referral, or adequacy of antidepressant therapy. The BHL is fully manualized with sections specific for implementation, documentation, assessment, interventions, and oversight. The structured assessments and scripted interventions for depression, anxiety, and at-risk drinking are fully adapted to telephone administration.

 

At-risk Drinking

Hospitalizations related to alcohol among older adults are nearly as frequent as those related to heart attack.22 At-risk alcohol use among older adults increases both medical complexity and costs to patients as well as their families and communities.23 However, existing services are not prepared to meet the needs of the projected 2-fold increase in alcohol- and substance-abusing older adults in the next 15 years.24 Using a nationally representative sample of 12,413 people from the Current Medicare Beneficiary Survey, Merrick and colleagues25 found unhealthy drinking patterns in 16% of men and 4% of women. Unhealthy drinking was defined either by >30 drinks in any month or >4 drinks in any single day during the last year. As operationalized by Merrick and colleagues25 in their Medicare Beneficiary Survey, respondents were considered to be at-risk or unhealthy if they either consumed as much as one drink daily for 30 days in any month during the last year or exceeded four drinks in any given day during the last year. This level of intake is slightly above what was recommended for screening in the Substance Abuse and Mental Health Services Administration’s (SAMHSA) Treatment Improvement Protocol26 for substance abuse among people ≥65 years of age; however, the level of intake is well below a score of ≥3 on the  Short Michigan Alcohol Screening Test-Geriatric Version employed by Oslin and colleagues’ Telephone Disease Management study of ambulatory care Veterans Administration patients.14,20

Numerous studies suggest that at-risk or unhealthy drinking can be reliably detected through telephone interviews and that interventions conducted by telephone can reduce the number of “risky drinking” days among people not seeking treatment for problem drinking.14,20,27-29 These data are further supported by the literature on brief interventions among primary care patients that reduce risky/harmful drinking without requiring lengthy or multiple counseling sessions to be effective.29 Approaching select patients during “teachable moment” following admission to the emergency department or discharge from hospital may heighten the probability of an alliance for change.17,30

 

Dementia Caregiver Burden

It is widely acknowledged that primary care settings are poorly designed and under-resourced to provide comprehensive care for dementia patients and their family caregivers.2,3,31 Even when routine primary care is augmented with improved access to dementia specialists, patients and families fare better from a collaborative care, disease management model similar to that used for chronic illnesses such as congestive heart failure or diabetes.2,3 In addition, disease management services provided to dementia care givers allow for cost savings.1 Given the increasing number of people with dementia, the need to find more efficient models of care is pressing. Estimates of the prevalence of memory problems or confusion in the National Health Interview representative survey32 of older community residents 65–85 years of age range from 7% to 20%, respectively. However these data are based on self-report or proxy respondents. In the Aging, Demographics, and Memory Study,33 in-home comprehensive assessments with diagnoses determined by expert consensus found dementia among 13.9% people ≥71 years of age.

Deficits in the cognitive domains of memory and executive function threaten the older adults’ capacity to adhere to medical therapy, avoid institutionalization, and survive in the community.34,35 However, screening for memory impairment to detect dementia in primary care settings remains controversial due to the confounding influence of physical illness, education, race and language on the screening test’s reliability.36,37 Moreover, evidence-based practices combining patient and caregiver interventions from mild cognitive impairment to end-of-life dementia care exceed the resources of most primary care practices.2,3,30 The critical period to screen for cognitive impairment may be immediately after hospital discharge when unrecognized persistent delirium or dementia places the patient at heightened risk for re-admission.

Brief screening measures for memory impairment and executive dysfunction have been validated for telephone administration by the Einstein Aging Study.38 More recent data suggest these measures, when used as part of a two-step screening procedure may represent an advance over the more commonly used Mini-Mental Status Examination in both distinguishing Alzheimer’s from vascular dementia and reducing the test’s sensitivity to education and race.37 Two separate studies listed in SAMHSA’s National Registry of Evidence-based Programs and Practices39 reduced depression among dementia caregivers of various racial and ethnic backgrounds.20,40,41 In addition, the Resources for Enhancing Alzheimer’s Caregiver Health II improved caregiver quality of life.41 The New York University Caregiver Intervention demonstrated superior health and perceived social support for caregivers as well as substantial delay in nursing home admissions for spouses with dementia.18,41 Although face-to-face counseling and peer support groups formed the bulk of the intervention, contact by telephone was included as well.

In contrast, two studies2,3 conducted in primary care sites used a disease management model with the care manager integrated into the primary care site or modified to include care mangers recruited from community based agencies. In the latter, caregiver interventions were conducted mainly by social workers via telephone following an in-home assessment. Outcomes for both patients and caregivers in the intervention groups were generally superior to enhanced routine care. Four of the studies cited suggest that some, if not all, of the caregiver intervention may be conducted by telephone. The potential of caregiver interventions to reduce costs1 and the detection of cognitive impairment to delay re-hospitalization warrant consideration.

 

Cultural Considerations and Issues with Access

Rather than presume that the communications between the patient and primary care provider are adequate, the Behavioral Health Manager can follow up by telephone to ensure that self-management and treatment adherence are optimized. Limited health literacy can be overcome with additional information regarding etiology, diagnosis, and treatment. Telephone-based depression care programs offer hope of reducing disparities in both access to and receipt of antidepressant treatment.42-45 Finally, although telephone interventions are limited to people without substantial hearing impairment, the capacity to provide behavioral health services by telephone is a marked advantage for individuals whose physical disability or geographic distance poses as barriers to more frequent office visits.

 

Conclusion

Depression, at-risk drinking, and caregiver burden are prevalent, and each is the subject of an emerging evidence-based practice incorporating interventions administered by telephone. Although the effectiveness and economic value of the interventions are yet to be established, their accessibility offers the hope of reducing behavioral health disparities among ethnic, minority, and physically disabled groups. If behavioral health interventions delivered by telephone reduce the costs of primary care or the risk of hospitalization, the Center for Medicare and Medicaid Services may be compelled to approve reimbursement. PP

 

References

1. Cohen JT, Neumann PJ, Weinstein MC. Does preventive care save money? Health economics and the presidential candidates. N Eng J Med. 2008;358(7):661-663.
2. Callahan CM, Boustani MA, Unverzagt FW, et al. Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized controlled trial. JAMA. 2006;295(18):2148-2157.
3. Vickrey BG, Mittman BS, Connor KI, et al. The effect of a disease management intervention on quality and outcomes of dementia care: a randomized controlled trial. Ann Intern Med. 2006;145(10):713-726.
4. Gaugler JE, Roth DL, Haley WE, Mittelman MS. Can counseling and support reduce burden and depressive symptoms in caregivers of people with Alzheimer’s disease during the transition to institutionalization? Results from the New York University caregiver intervention study. J Am Geriatr Soc. 2008;56(3):421-428.
5. Nichols LO, Chang C, Lummus A, et al. The cost-effectiveness of a behavior intervention with caregivers of patients with Alzheimer’s disease. J Am Geriatr Soc. 2008;56(3):413-420.
6. Austrom MG, Damush TM, Hartwell CW, et al. Development and implementation of nonpharmacologic protocols for the management of patients with Alzheimer’s disease and their families in a multiracial primary care setting. Gerontologist. 2004;44(4):548–553.
7. Areán PA, Gum A. Selecting evidence-based practice. In: Levkoff SE, Chen H, McIntyre J, eds. Evidence-Based Behavioral Health Practices for Older Adults: A Guide to Implementation. 1st ed. New York, NY: Springer Publishing Company; 2006:1-13.
8. Badamgarav E, Weingarten SR, Henning JM, et al. Effectiveness of disease management programs in depression: a systematic review. Am J Psychiatry. 2003;160(12):2080-2090.
9. Oxman TE. Re-Engineering Systems for Primary Care Treatment of Depression; The Respect Depression Care Process Supervising Psychiatrist Manual. Hanover, New Hampshire: Trustees of Dartmouth College; 2003.
10. Bruce ML, Ten Have TR, Reynolds CF 3rd, et al. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291(9):1081-1091.
11. Unützer J, Tang L, Oishi S, et al. Reducing suicidal ideation in depressed older primary care patients. J Am Geriatr Soc. 2006;54(10):1550-1556.
12. Gilbody S, Bower P, Whitty P. Costs and consequences of enhanced care for depression: systematic review of randomized economic evaluations. Br J Psychiatry. 2006;189:297-308.
13. Datto CJ, Thompspn R, Horowitz D, Disbot M, Oslin DW. The pilot study of a telephone disease management program for depression. Gen Hosp Psychiatry. 2003;25(3):169-177.
14. Oslin DW, Sayers S, Ross J, et al. Disease management for depression and at-risk drinking via telephone in an older population of veterans. Psychosom Med. 2003;65(6):931-937.
15. Ludman EJ, Simon GE, Tutty S, Von Korff M. A randomized trial of telephone psychotherapy and pharmacotherapy for depression: continuation and durability of effects. J Consult Clin Psychol. 2007;75(2):257-266.
16. Ludman EJ, Simon GE, Grothaus LC, Luce C, Markley DK, Schaefer J. A pilot study of telephone care management and structured disease self-management groups for chronic depression. Psychiatric Serv. 2007;58(8):1065-1072.
17. Beckner V, Vella L, Howard I, Mohr DC. Alliance in two telephone-administered treatments: relationship with depression and health outcomes. J Consult Clin Psychol. 2007;75(3):508-512.
18. Katon W, Von Korff M, Lini E, et al. Improving primary care treatment of depression among patients with diabetes mellitus: the design of the pathways study. Gen Hosp Psychiatry. 2003;25(3):158-168.
19. Riegel B, Carlson B, Kpoo Z, LePetri B, Unger A. Effect of a standardized nurse case-management telephone intervention on resources use in patients with chronic heart failure. Arch Intern Med. 2002;162(6):705-712.
20. Zanjani F, Mavandadi S, TenHave T, et al. Longitudinal course of substance treatment benefits in older male veteran at-risk drinkers. J Gerontol A Biol Sci Med Sci. 2008;63(1):98-106.
21. Kennedy GJ. Telephone-facilitated treatment of depression in primary care using the PHQ-9. Primary Psychiatry. 2004;11(6):18-21.
22. Adams WI, Yuan Z, Barboriak J, et al. Alcohol-related hospitalizations of elderly people. JAMA. 1993;270(10):1222-1225.
23. Dyson J. Alcohol misuse and older people. Nurs Older People. 2006;18(7):32-35.
24. Gfroerer J, Penne M, Pemberton M, Folsom R. Substance abuse treatment need among older adults in 2020: the impact of the aging baby-boom cohort. Drug Alcohol Depend. 2003;69(2):127-135.
25. Merrick EL, Horgan CM, Hodgkin D, et al. Unhealthy drinking patterns in older adults: prevalence and associated characteristics. J Am Geriatr Soc. 2008;56(2):214-223.
26. Blow FC. Substance Abuse Among Older Adults Treatment Improvement Protocol (TIP) Series. Washington, DC: U.S. Department of Health and Human Services; 2004.
27. Brown RL, Saunders LA, Bobula JA, Mundt MP, Koch PE. Randomized-controlled trial of a telephone and mail intervention for alcohol use disorders: three-month drinking outcomes. Alcohol Clin Exp Res. 2007;31(8):1372-1379.
28. Bischof G, Grothues JM, Reinhardt S, Meyer C, John U, Rumpf HJ. Evaluation of a telephone-based stepped care intervention for alcohol-related disorders: a randomized controlled trial. Drug Alcohol Depend. 2008;93(3):244-251.
29. Whitlock EP, Polen MR, Green CA, et al. Behavioral counseling interventions in primary care to reduce risk/harmful alcohol use by adults: a summary of evidence for the U.S. Preventative Services Task Force. Ann Int Med. 2004;140(7):557-568.
30. Academic ED SBIRT Research Collaborative. The impact of screening, brief intervention, and referral for treatment on emergency department patients’ alcohol use. Ann Emerg Med. 2007;50(6):699-710.
31. Brayne C, Fox C, Boustani M. Dementai screening in primary care: is it time? JAMA. 2007;298(2):2409-2411.
32. Bernstein AB, Remsburg RE. Estimated prevalence of people with cognitive impairment: results from nationally representative community and institutional surveys. Gerontologist. 2007;47(3):350–354.
33. Plassman BL, Lnaga KM, Fisher GG, et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1-2):125-132.
34. Cooney LM, Kennedy GJ, Hawkins KA, Hurme SB. Who can stay at home? Assessing the capacity to choose to live in the community. Arch Intern Med. 2004;164(4):357-360.
35. Kelman HR, Thomas C, Kennedy GJ, Cheng J. Cognitive impairment and mortality among older community residents. Am J Public Health. 1994;84(8):1255-1260.
36. Grober E, Hall C, Lipton RB, Teresi JA. Primary care screen for early dementia. J Am Geriatr Soc. 2008;56(2):199-205.
37. Grober E, Hall C, McGinn M, et al. Neuropsychological strategies for detecting early dementia. J Int Neuropsychol Soc. 2008;14(1):1-13.
38. Lipton RB, Katz MJ, Kuslansky G, et al. Screening for dementia by telephone using the memory impairment screen. J Am Geriatr Soc. 2003;51(10):1382–1390.
39. U.S. Department of Health and Human Services: Substance Abuse and Mental Health Services Administration (SAMSHA). Alcohol Use in Past Month by State Treatment Planning Area and Age Group. Available at: www.oas.samhsa.gov/subState2k6/ageAlc.htm. Accessed April 2, 2008.
40. Belle SH, Burgio L, Burns R, et al. Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial. Ann Intern Med. 2006;145(10):727-738.
41. Mittelman MS, Roth DL, Clay OJ, Haley WE. Preserving health of Alzheimer caregivers: impact of a spouse caregiver intervention. Am J Geriatr Psychiatry. 2007;15(9):780-789.
42. Rivas A, Kennedy GJ, Woolis W, et al. Recruitment of disadvantaged minority groups for mental health services research is no greater a challenge than recruitment of their physicians. Poster presented at: The Annual Meeting of the American Association for Geriatric Psychiatry; March 1-4, 2007; New Orleans, LA.
43. Colemon YR, Kennedy GJ, Mudge R, Martinez-Kekenak M. Depression treatment of African American’s within a primary care setting. Poster presentation at: the Annual Meeting of the American Association for Geriatric Psychiatry; March 14-17, 2008; Orlando, FL.
44. Areán PA, Unützer J. Inequities in depression management in low-income, minority, and old-old adults: a matter of access to preferred treatments? J Am Geriatr Soc. 2003;51(12):1808-1809.
45. Fischer LR, Wei F, Solberg LI, Rush WA, Heinrich RL. Treatment of elderly and other adult patients for depression in primary care. J Am Geriatr Soc. 2003;51(11):1554-1562.

To the Editor:                     February 16, 2008

Milton K. Erman, MD’s, critique of the popularity of trazodone and other non-benzodiazepine analogs for off-label use as soporifics1 fails to acknowledge some stark realities, namely, that trazodone is the most widely prescribed soporific because it works well and is very safe. Grasping for examples of the National Institutes of Health-cited “potentially significant adverse events” associated with trazodone, Erman is only able to come up with priapism, of which the risk is 1 in 6,000.2 Regarding cardiac arrhythmia, this risk is low when trazodone is prescribed at low, soporific doses rather than higher, antidepressant-range doses; the risk is further reduced with electrocardiogram monitoring for individuals with a history of arrhythmia or who are prescribed other arrhythmogenic medications.

The reason that there are no long-term studies on the use of trazodone for the treatment of insomnia, as Erman states,1 is that trazodone is a generic drug for which there is no financial incentive to fund the double-blind, placebo-controlled study needed to demonstrate what front-line prescribers already know. I did not wait for Food and Drug Administration on-label approval to offer divalproex to my patients for mood stabilization or quietapine for bipolar-spectrum depression. Likewise, I will not deny my patients the benefit of trazdodone which, when used appropriately, is a safe, effective, and non-addictive soporific with the potential to augment antidepressants in the treatment of depressive and anxiety disorders that are associated with insomnia.3

I know that I am not alone among my colleagues in being able to count on one hand the combined instances of trazodone-induced arrhythmia or priapism in my entire history of practice, whereas I have already a great deal of experience with the array of interesting side effects associated with the newer agents. Zolpidem, for example, has manifested as a robust inducer of parasomnias, including sleepwalking4 and amnestic nocturnal eating.5 There have additionally been reports of visual hallucinations6 and abuse.7 Regarding the latter, the World Health Organization Expert Committee on Drug Dependence in 2000 described “rates of actual abuse and dependence on zolpidem appear(ing) to be similar to those of other hypnotic benzodiazepines currently listed in Schedule IV…”8

I am in agreement with all that Erman says regarding ramelteon, another drug produced by one of his underwriters, including its remarkable safety profile and lack of abuse potential. Erman might concede another factor regarding ramelteon, that it is generally ineffective for insomnia.

Sincerely,

Michael S. Hanau, MD, FAPA

Dr. Hanau is medical director of Community Counseling Services at Lawrence Memorial Hospital in Medford, Massachusetts.

Disclosure: Dr. Hanau reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

 

References

1. Erman MK. Is it a sleeping pill? Primary Psychiatry. 2008;15(1)34-36.
2. Janicak PG, Davis JM, Preskorn SH, Ayd Jr FJ. Treatment with Antidepressants. Janicak PG, Davis JM, Preskorn SH, Ayd Jr FJ. Principles and Practice of Psychopharmacotherapy. 3rd ed, Chapt. 7, Philadelphia, PA: Lippincott Williams and Wilkins; 2001:295.
3. Fabre LF. Trazodone dosing regimen: experience with single daily administration. J Clin Psychiatry. 1990;51(suppl):23-26.
4. Sansone RA, Sansone LA. Zolpidem, somnambulism, and nocturnal eating. Gen Hosp Psychiatry. 2008;30(1):90-91.
5. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med. 2007;3(6):637-638.
6. Tsai MJ, Huang YB, Wu PC. A novel clinical pattern of visual hallucination after zolpidem use. J Toxicol Clin Toxicol. 2003;41(6):869-872.
7. Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol. 2007;64(2):198-209.
8. WHO. World Health Organization Expert Committee on Drug Dependence. Thirty-second Report. Geneva: World Health Organization; 2001 (as cited in: The National Institute for Health and Clinical Excellence Assessment report: The clinical and cost-effectiveness of zaleplon, zolpidem and zopiclone for the management of insomnia (10/20/2003).

 

Response

I thank Michael S. Hanau, MD, FAPA, for his observations. He notes that use of trazodone is very widespread; this was commented on (and supported by citations) in the opening paragraphs of my column.1-3

To paraphrase his argument, “Everybody is doing it, so it must be safe and effective.” The history of treatment in psychiatry is replete with examples of widespread prescribing practices (eg, rapid neurolepticization for acute psychosis, use of neuroleptics for management of dementia) later proven to be ineffective, risky, or both.

In support of use of trazodone for insomnia, Hanau cites Fabre’s 1990 review.4 This article reviewed the use of single daily dosing. The basic thrust of the article is that HS dosing is good for depressed patients, including depressed insomniacs. To support use for insomniacs without depression, Fabre cites a study by Montgomery and colleagues5 of “nine volunteers who were poor sleepers,” noting that it improved sleep quality. Interestingly, the title of the article is, “Trazodone enhances sleep in subjective quality but not in objective duration”; objective measures are the hallmark by which the Food and Drug Administration determines that drugs are worthy of approval.

With regard to published data on the efficacy of trazodone in treatment of insomnia, I would refer Hanau to the largest published data-set on the subject (of which I was a co-author), which involved a double-blind, placebo-controlled comparison of zolpidem 10 mg, trazodone 50 mg, and placebo in >300 adults diagnosed with primary insomnia.6 The study utilized subjective measures only; by the end of the second week of assessment, the trazodone group did not differ significantly from the placebo group with regard to reported sleep latency, sleep duration, sleep quality, wake after sleep onset, or number of awakenings demonstrated.

I did not need to “grasp” for examples of why trazodone is not a recommended treatment for insomnia; the National Institutes of Health (NIH) State of the Science Conference,7 a “blue ribbon” panel reviewing the published scientific literature with regard to treatment recommendations, stated quite directly (as I cited in the column) that “all antidepressants have potentially significant adverse events, raising concern about the risk-benefit ratio.”

Hanau states that, with regard to priapism, “the risk is 1 in 6,000.” This is a widely cited statistic, although in one series of 74 patients receiving trazodone in treatment of posttraumatic stress disorder, the reported incidence rate was 12%.8 Even accepting the rate of 1 in 6,000, this is not a trivial issue; usage rates suggest that the millions of patients currently receiving this medication in treatment of insomnia in this country are placed at risk. Other safety issues, including sedation and cardiac safety (eg, hypotension, orthostasis, ventricular arrhythmias) are explored by Mendelson.9

Regarding the safety of other agents (eg, zolpidem), I cited the NIH panel’s observation about the general safety of benzodiazepine receptor agonists. Case reports and case series have been published demonstrating amnestic behaviors of various types seen in association with several benzodiazepines and benzodiazepine-receptor agonists. Physicians should clearly consider issues of risk and benefit before prescribing any medication. With regard to the frequency of these problems occurring with zolpidem, sanofi-aventis noted in a press release in 2006 that zolpidem had a history of >14 billion nights of use worldwide.10 The number of amnestic events seen and reported worldwide should be considered using this number as the denominator in any fractional assessment of risk.

Sincerely,

Milton K. Erman, MD

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, chief medical officer of Avastra USA, and author of the Primary Psychiatry bi-monthly column “Clinical Updates in Sleep Medicine.”

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.

 

References

1. Erman MK. Is it a sleeping pill? Primary Psychiatry. 2008;15(1)34-36.
2. Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia. Sleep. 1999;22(3):371-375.
3. Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep. 2004;27(8):1441-1442.
4. Fabre LF. Trazodone dosing regimen: experience with single daily administration. J Clin Psychiatry. 1990;51(suppl):23-26.
5. 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.
6. Walsh J, Erman M, Erwin M, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol. 1998;13(3):191-198.
7. NIH State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults. J Clin Sleep Med. 2005;1(4):412-421.
8. Warner M, Dorn M, Peabody C. Survey on the usefulness of trazodone in patients with PTSD with insomnia or nightmares. Pharmacopsychiatry. 2001;34(4):128-131.
9. Mendelson W. A review of the evidence for the safety and efficacy of trazodone in insomnia. J Clin Psychiatry. 2005;66(4):469-476.
10. Statement Responding to Recent Media Reports Regarding Appropriate Use of AMBIEN(R) (zolpidem tartrate) CIV in the US. Bridgewater, NJ. March 20, 2006. Available at: http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/03-20-2006/0004323684&EDATE. Accessed March 24, 2008.


Please send letters to the editor to Primary Psychiatry, c/o Norman Sussman, MD, 333 Hudson St., 7th Floor, New York, NY 10013; E-mail: ns@mblcommunications.com.

 

 

Dr. Zammit is president and CEO of Clinilabs, director of the Sleep Disorders Institute, and clinical associate professor at the Columbia University College of Physicians and Surgeons in New York City.

Disclosure: Dr. Zammit is a consultant to Boehringer-Ingelheim, sanofi-aventis, Sepracor, and Takeda; receives research support from Forest, GlaxoSmithKline, Pfizer, sanofi-aventis, Sepracor, Takeda Pharmaceuticals North America, Transcept, and Wyeth; and receives honoraria from Takeda.

Acknowledgments: The author would like to thank Ms. Bridget Banas for her assistance in the preparation of this manuscript.

Please direct all correspondence to: Gary Zammit, PhD, Clinilabs, Inc, 423 W.  55th St, 4th Floor, New York, NY 10019; Tel: 212-994-4560; Fax: 212-523-1704; E-mail: gzammit@clinilabs.com; Website: www.clinilabs.com.

 


 

Abstract

Mood disorders and insomnia are often comorbid conditions, sharing a complex and bi-directional relationship. Complicating the situation, mood stabilizers can disrupt sleep in a variety of different ways depending on a drug’s mechanism of action, dosage level, and timing of administration. The treatment of comorbid depression and insomnia can be achieved through the use of a sedating antidepressant, a combination of two antidepressants, or a combination of an antidepressant in conjunction with a hypnotic. Common practices typically include the concomitant use of an alerting and a sedating antidepressant. However, the empirical evidence supporting this approach is limited, and there are few indicators that sedating antidepressants are efficacious in the treatment of primary insomnia. This article examines the evidence supporting the efficacy and safety of mood stabilizers in the treatment of comorbid and primary insomnia.

 

Introduction

Psychiatric disorders and chronic insomnia are often comorbid with each other. The presence of insomnia symptoms in individuals with a current episode of major depressve disprder (MDD) has been shown to approach 80% to 90%.1-4 The incidence of comorbid insomnia is higher when anxiety complicates the clinical presentation, affecting approximately 90% with a concurrent anxiety disorder.1 Furthermore, mood disorder symptoms are typically more pronounced in people with insomnia symptoms.5-10

Insomnia is often a precursor to depression. Several longitudinal studies have examined the incidence of psychiatric disorders over periods ranging from 1–40 years following the initial diagnosis of insomnia.11-17 In every study completed to date, insomnia has been found to be a significant risk factor for the subsequent onset of depression, with a greater incidence of affective disorder found in people with insomnia. These findings do not suggest that insomnia is merely part of a prodrome that occurs in close temporal association with affective disorders, as depression may first appear several years after the initial diagnosis of insomnia. In addition to these findings, it has been shown that insomnia is a precursor to the recurrence of depression in patients in remission,18,19 and that persistent sleep disturbance is associated with non-response to antidepressant therapy.20

While insomnia often precedes the onset of affective illness, symptoms of depression and insomnia may be concurrent. Complicating this picture is the fact that many antidepressants used to treat depression disturb sleep, potentially exacerbating the relationship between the two disorders. The type of sleep disturbance produced by depression pharmacotherapy varies based on the compound’s mechanism of action and the dosage employed. Effects may include decrements in rapid eye movement (REM) sleep, a lengthening of the time to sleep onset, and an increase in nocturnal arousals (Table 1).24,86-88 This article reviews the effectiveness and safety of several treatment options for comorbid depression and insomnia.

 

 

Prescribing Patterns

Between 1987 and 1996, the pharmacologic treatment of insomnia decreased markedly. A recent review21 covering this period found that drug mentions (ie, patient contact that resulted in drug therapy or a mention of drug therapy) fell by >50% for hypnotics, and were down approximately 25% for all forms of insomnia pharmacotherapy combined. Antidepressants used for the treatment of insomnia were the only drug category showing signs of growth—tripling in drug mentions over this period.

In 1996, the two drugs mentioned most frequently for the treatment of insomnia were trazodone, a sedating tricyclic antidepressant (TCA), and zolpidem, a non-benzodiazepine hypnotic. Trazodone is indicated for the treatment of depression, but not specifically labeled for use as a hypnotic. Over the 10-year period examined, the total number of trazodone mentions was steady.21 However, mentions associated with antidepressant action fell from >70% of all occurrences in 1987 to only 31% in 1996. In contrast, the number of mentions associated with insomnia rose from only 6.5% to almost 42% over the same period.

The conclusion that the use of sedating antidepressants for the treatment of insomnia rose between 1987 and 1996 was based on reported medication doses. The therapeutic daily dosage of trazodone for depression therapy is 150–600 mg/day. Doses below this level may provide sedative effects but are not expected to combat the symptoms of depression. By 1996, two-thirds of all trazodone mentions were associated with a daily dose of ≤100 mg—strongly suggesting that antidepressant effects were not the intended results. Furthermore, almost 40% of treatment mentions in 1996 were concomitant with the mention of another antidepressant. This analysis is consistent with a more recent survey of psychiatrists’ prescribing practices.22 The survey was conducted at a psychopharmacology review course to investigate the management of antidepressant-induced side effects. Almost 80% of the survey respondents indicated that they would prescribe trazodone to address selective serotonin reuptake inhibitor (SSRI)-induced insomnia.

 

Treatment Options

In light of the common use of trazodone as adjunctive insomnia therapy in depressed patients, it is important to remember that several treatment approaches are available. Insomnia comorbid with depression may be treated using a single hypnotic, a single antidepressant, a combination of two antidepressants, and a combination of one antidepressant and one hypnotic.23

 

Option 1: A Single Hypnotic

There is no evidence to support the treatment of patients with MDD and comorbid insomnia with a hypnotic medication alone. Even though these medications are highly efficacious in ameliorating sleep disturbances in a wide range of patient populations, neither the older benzodiazepine nor the newer non-benzodiazepine hypnotics have been shown to be effective therapy for MDD.

 

Option 2: A Single Antidepressant

A single, sedating antidepressant can be employed as a treatment for both insomnia and depression. Candidates for this therapeutic approach include the TCAs and several atypical antidepressants.23 Most of these TCAs inhibit the reuptake of noradrenaline and serotonin and block histamine (H)1 receptors and α1-adrenoceptors.24 Amitriptyline and trimipramine, both particularly associated with sedation, also block serotonin (5-HT)2 action.24 Trazodone is an antagonist at the α1-adrenoceptors, 5-HT1A, and 5-HT2 receptors.24 Nefazodone has strong 5-HT2 antagonist properties and mild serotonin reuptake-blocking effects.24 Finally, mirtazapine blocks 5-HT2 receptors, H1 receptors, and α2-adrenoceptors.24

Some practitioners use a single, sedating antidepressant to treat comorbid depression and insomnia. When administered at therapeutic doses for depression, these medications are known to produce sedative side-effects that may be exploited in an effort to treat insomnia and to provide relief from depression. This approach has intuitive appeal, as the use of one medication to treat multiple disorders has the advantage of minimizing the risks associated with drug-drug interactions and may make patient compliance easier. However, the utility of this approach may be limited by current treatment guidelines and safety concerns.

 

Option 3: A Combination of Two Antidepressants

This approach typically involves employing a therapeutic dose of a non-sedating antidepressant (eg, SSRIs, monoamine oxidase inhibitors [MAOIs]) to treat depression, and a lower, non-therapeutic dose of a sedating antidepressant to treat insomnia. While this strategy has been used with some popularity, there are relatively few data demonstrating the safety and efficacy of this approach.23,25,26

 

Option 4: A Combination of One Antidepressant and One Hypnotic

This treatment approach enables clinicians to decouple the treatment for depression from the treatment of insomnia. This approach represents an important treatment option because it is often necessary to experiment with different antidepressants, titrate dosage levels, and modify dose timing to find the most appropriate therapy for an individual with MDD. Employing a hypnotic as an adjunctive treatment enables the clinician to directly and immediately address a patient’s insomnia symptoms while still making necessary adjustments to the pharmacotherapeutic used to treat depression. When present, antidepressant-induced insomnia typically occurs during the first 3–4 weeks of treatment.27 Therefore, addressing sleep complaints early may provide rapid relief to the patient and may also contribute to compliance with depression therapy.

 

Evidence Supporting the Use of a Single Antidepressant

Efficacy

The SSRIs and MAOIs are generally alerting; these drugs tend to exacerbate existing insomnia symptoms or produce treatment-related insomnia (Table 1). As such, they are not considered appropriate for addressing insomnia symptoms in depressed patients as monotherapy.

In contrast, the TCAs commonly produce sedation as a side effect, even though they also tend to suppress REM sleep like the SSRIs and MAOIs. Three TCAs appear to offer the greatest potential for combining both antidepressant and hypnotic effects,24 namely, amitriptyline,28,29 doxepin,28 and trimipramine. Improvements were seen in depressed patients treated with amitriptyline in measures of early morning awakenings,20 nocturnal waking,20 and sleep latency30 as compared to the results produced by imipramine or fluoxetine. Doxepin has been shown to significantly improve Hamilton Rating Scale for Depression (HAM-D) sleep scores as compared to placebo31 and bupropion.32 Trimipramine has been reported to improve sleep efficiency, increase sleep time, and reduce nocturnal awakenings as compared to both fluoxetine33 and imipramine.34

The atypical antidepressants most often used to treat depression and comorbid insomnia are mirtazapine, nefazodone, and trazodone.24 Mirtazapine has been shown to produce a range of effects on sleep in depressed patients. Rapid improvements on quality of sleep and other subjective sleep assessments have been seen with mirtazapine as compared to citalopram,35 while improvements in sleep efficiency and nocturnal distress have been seen relative to both fluoxetine36 or paroxetine treatment.37 It is of interest that HAM-D sleep item scores have been shown to improve more when patients are treated with mirtazapine than with either venlafaxine38 or paroxetine.39 Nefazodone has also been shown to improve HAM-D sleep item scores relative to treatment with placebo.40 It also produces less nocturnal disturbance than either fluoxetine41 or paroxetine.42

Trazodone’s effects on sleep in depressed patients are perhaps better characterized than that of any other sedating antidepressant. Two studies have found that, relative to placebo, trazodone objectively increases total sleep time, sleep efficiency, and slow wave sleep (SWS) with limited next-day sedative effects.43,44 It has also been shown that trazodone 75 mg results in increases in SWS and improvements in HAM-D scores and subjective assessments of daytime alertness.45 Higher doses of trazodone also appear to have effects on depression and sleep. Trazodone (150–400 mg) produces significant improvement in symptoms of depression and changes in objective measures of sleep architecture.46 Specifically, sleep latency declined, and total sleep time, SWS, and sleep efficiency increased following active treatment. Doses of 400–600 mg produce significant improvements in Montgomery-Asberg Depression Rating Scale (MADRS) scores (>60% reduction), reduce sleep latency, and increase total sleep time and SWS.47

 

Safety

Employing a sedating antidepressant to treat both depression and comorbid insomnia is appealing because of the reduced opportunity for drug-drug interactions and the potential increase in patient compliance due to a less complex treatment regimen. However, the available literature suggests caution should be exercised when considering this approach. A recent conference that reviewed the evidence supporting the use of both TCAs and SSRIs resulted in a published statement suggesting that TCAs are no longer justified as first-line antidepressant therapy in most situations.48 This position reflects concerns about the differential efficacy and safety profiles of the TCAs relative to newer therapies.

Two of the three sedating atypical antidepressants reviewed here are also of questionable value as first-line treatment. First, mirtazapine is indicated for the treatment of depression but often is used as an alternative or augmentation therapy for depression rather than a first-line monotherapy.49 Second, sales of nefazodone have been discontinued in several countries including the United States (branded version) due to concerns of liver toxicity.

The process of elimination leaves trazodone as the most likely candidate for monotherapy in depression with comorbid insomnia. However, while trazodone is considered to be safer than the TCAs, it remains associated with a series of significant side effects. The most common adverse events seen with trazodone at doses of ≥75 mg/day are drowsiness, dizziness, dry mouth, nausea, vomiting, constipation, headache, hypotension, and blurred vision.50 A review of published data from controlled trials in depressed patients found that 25% to 30% of patients experienced some treatment-emergent adverse event attributed to trazodone.51 Reported discontinuation rates from clinical trials were relatively high (25% to 60%), with 25% to 50% specifically attributable to adverse events.50 Most importantly, a recent literature review identified a sizable number of reports of treatment-emergent cardiac events.52 Adverse events noted in clinical studies and case reports include hypotension, ventricular arrhythmias, cardiac conduction disturbances, and exacerbation of ischemic attacks. Torsades de pointes, a prolongation of the QTc interval, and other cardiac arrhythmias, have been observed in patients treated with trazodone.53-57 Finally, a review of psychotropics and priapism found that almost 80% of cases reviewed were associated with trazodone, while the balance was associated with antipsychotics.58

 

Evidence Supporting the Use of a Combination of Two Antidepressants

Efficacy

Trazodone
Trazodone is the most widely used sedating antidepressant used as adjunctive therapy to other antidepressants. Given the frequency with which this treatment course is pursued, it is remarkable that the combination of trazodone and other antidepressants has not been ardently investigated. Of the studies that have been conducted, almost all have employed small samples and, therefore, may be of limited applicability to the general population of patients with depression.

In one study,59 trazodone 100 mg or placebo was given to patients (N=12) stable on different SSRIs for a period of 7 days. At the end of this period, trazodone co-therapy significantly increased total sleep time and  SWS, and reduced the number of awakenings seen on polysomnography. Another study60 examined the impact of prescribing trazodone for patients (N=17) with an incomplete response to fluoxetine or bupropion. In this evaluation, trazodone produced significantly more improvement than placebo in several subjective measures of sleep.

Trazodone has been added to fluoxetine in one study of a group of depressed patients (N=8) for the purposes of either improving sleep or as a possible antidepressant potentiator.61 Three of the eight patients experienced improvements in both sleep and depression symptoms. A second group of patients on fluoxetine (N=16) was given adjunctive trazodone for complaints of insomnia.62 All patients had a positive hypnotic response, but five discontinued trazodone due to excessive sedation.

Trazodone was compared to placebo in depressed patients (N=7) who developed insomnia while treated with the MAOI brofaromine.63 Trazodone increased SWS and was associated with subjective reports of better and deeper sleep. A review of MAOI-induced insomnia treated with trazodone found 13 case-studies.64 Twelve reported an initial positive response to co-therapy while only nine were able to continue treatment without intolerable side effects.

Depressed patients (N=50) participated in a 4-week study of the atypical antidepressant venlafaxine with adjunctive trazodone, as needed, for the development of comorbid insomnia.65 The timing and dosage of trazodone was left to the discretion of the clinicians to simulate a naturalistic setting. Patients who received adjunctive trazodone had a lower response to venlafaxine monotherapy on MADRS measures of insomnia and inner tension. Once trazodone was introduced, these patients showed improvements in insomnia symptoms but not in other measures of depression.

Other Antidepressants
Aside from trazodone, very little information is available about the impact on sleep parameters of sedating antidepressants used as adjunctive therapy to any of the alerting SSRIs or MAOIs.

 

Safety

Trazodone
In one study of trazodone as adjunctive therapy for fluoxetine, five of eight patients were unaffected by the addition of trazodone to fluoxetine or had intolerable adverse drug reactions.61 In a second study62 of trazodone-fluoxetine co-therapy, all patients reported marked daytime sedation with five of 16 discontinuing trazodone as a consequence. The implications of these case reports suggest that the utility of the combination of fluoxetine and trazodone may be limited by adverse effects.

Co-administration of trazodone and brofaromine produced few adverse events and was well tolerated by study participants.63 A review of several case studies of trazodone-MAOI co-therapy found that one of 13 patients was unable to tolerate the combination initially and another three discontinued this course of treatment due to side effects over a longer period of time.64

Serotonin syndrome has been described when trazodone was prescribed in combination with nefazodone.66 Serotonin syndrome has also been reported following the use of venlafaxine and fluoxetine.67

Other Sedating Antidepressants
Co-administration of the atypical antidepressant venlafaxine and the TCAs clomipramine or imipramine has been well tolerated.68 Venlafaxine has been used as adjunctive therapy when patients have realized only partial response to the TCA. However, no effects on sleep parameters were reviewed.

Adjunctive paroxetine has been employed to increase the effectiveness of TCAs (amitriptyline and imipramine) in patients who had not sufficiently responded after 3 weeks of monotherapy.69 This combination increased TCA serum levels as intended and was well tolerated. Effects on sleep were not reviewed.

When used in combination, the SSRI fluoxetine was shown to increase TCA plasma levels for several members of this class of antidepressants.70 This increase was highest with clomipramine and imipramine and less notable with amitriptyline. These pharmacokinetic changes did not induce side effects in the patients evaluated. The effects on sleep were not reviewed.

 

Evidence Supporting the Use of a Combination of One Antidepressant and One Hypnotic

Efficacy

Although numerous drug-drug interaction studies have been conducted to evaluate the interaction between hypnotics and antidepressants, efforts to evaluate the effectiveness of co-administration of these treatments on comorbid depression and insomnia are still in the early stages.

The use of zolpidem was examined in SSRI-treated patients with persistent comorbid insomnia.71 Patients who participated in this study were diagnosed with depression, treated stably with the SSRIs fluoxetine, sertaline, or paroxetine, and complained of sleep onset difficulty or too-short sleep time at least 3 nights a week and associated with daytime impairment. Over a 4-week period, treatment with zolpidem 10 mg lengthened sleep time, improved sleep quality, reduced the number of awakenings, and improved multiple measures of daytime functioning as compared to placebo.

A recent study evaluated the co-administration of eszopiclone 3 mg with the SSRI fluoxetine in patients with MDD over an 8-week period.72 Compared to fluoxetine alone, the fluoxetine-eszopiclone group demonstrated statistically significant improvements in all sleep parameters evaluated at all time points. Measures included sleep latency, wake time after sleep onset, total sleep time, sleep quality, and depth of sleep. Importantly, eszopiclone also resulted in a greater treatment response to fluoxetine as measured by improvements on the 17-item HAM-D, Clinical Global Impression (CGI) Improvement scale, and CGI Severity scale. Furthermore, a significantly greater percentage of individuals in the co-therapy group were classified as responders (59% versus 48%) and remitters (42% versus 33%) at the end of the study.

 

Safety

In the zolpidem-SSRI-induced insomnia study, adverse events were similar between the placebo and zolpidem groups.71 There was no evidence of dependence or withdrawal from zolpidem during the placebo substitution period at the conclusion of the study.

Zolpidem drug-drug interaction studies have been conducted with two TCAs and two SSRIs.73 Co-administration of zolpidem and imipramine produced a 20% decrease in peak levels of imipramine and an additive effect of decreased alertness. Chlorpromazine in combination with zolpidem produced no pharmacokinetic interactions; however, decreases in alertness and psychomotor performance were potentiated. Both of these studies evaluated single-dose interactions in healthy volunteers. Thus, the results may not be predictive for chronic administration in depressed patients.

Zolpidem-fluoxetine interactions were examined in both single-dose and multiple-dose studies. A single-dose study in male volunteers with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels did not find any clinically significant pharmacokinetic or pharmacodynamic interactions.73,74 Healthy females participated in a multiple-dose study of zolpidem and fluoxetine at steady-state concentrations.73 The only significant change in this evaluation was a 17% increase in the half-life of zolpidem. No changes in psychomotor performance were seen.

Healthy female volunteers were dosed with sertraline 50 mg for 17 days. Once steady-state levels were reached, subjects were dosed for 5 consecutive nights with zolpidem 10 mg. The pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem, but zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%).

Adverse events and dropout rates were similar between the placebo and eszopiclone groups in the 8-week eszopiclone-fluoxetine MDD study.72 The frequency of adverse events continued to be similar between both groups during the placebo washout period at the conclusion of study.75 No evidence of withdrawal effects, rebound insomnia, or rebound depression was observed. A single-dose study of co-administration of eszopiclone 3 mg with paroxetine 20 mg (7 days) found no pharmacokinetic or pharmacodynamic interactions.73

Zaleplon was evaluated in three single-dose antidepressant drug interaction studies.73 Zaleplon 20 mg co-administered with the TCA imipramine 75 mg potentiated decrements in next-day alertness and psychomotor performance as compared to either compound administered alone. There was no alteration of the pharmacokinetics of either drug. In two separate studies, neither co-administration of zaleplon with the SSRI paroxetine 20 mg (7 days) or with the atypical antidepressant venlafaxine 150 mg resulted in any pharmacokinetic or pharmacodynamic changes to either zaleplon or the antidepressant.

Ramelteon is the newest hypnotic approved for the treatment of insomnia in the US. It has been evaluated for use in conjunction with two SSRIs. A single-dose of ramelteon 16 mg was co-administered with fluvoxamine 100 mg (3 days).73 This combination increased the area under the curve (AUC)0-inf of ramelteon by approximately 190-fold, and the Cmax by approximately 70-fold. This effect appeared to be specific to fluvoxamine and cytochrome P450 1A2 inhibitors rather than being a class effect which could be expected to occur with other SSRIs.

A multiple dose study of co-administration of ramelteon and sertraline was conducted.76 Ramelteon had no effect on the systemic availability of sertraline. Decreases in ramelteon AUC and Cmax (23% and 43%, respectively) were deemed clinically irrelevant due to ramelteon’s highly variable inter-subject pharmacokinetic profile.

 

 

Antidepressants and Non-Depressed Patients

A small number of studies have evaluated the efficacy of antidepressants in non-depressed, primary insomnia patients. The extremely limited nature of this evidence and the small scale of most of these studies strongly argues against the use of antidepressants as hypnotics in non-depressed patients.

The largest study (N=306) reported to date has been the only placebo-controlled study of trazodone in insomnia patients.77 Over a 2-week period, trazodone improved sleep latency and total sleep time relative to placebo during the first week of treatment only. The loss of efficacy during the second week suggests that trazodone is not an appropriate insomnia treatment choice for non-depressed patients. No other trazodone studies have been reported in primary insomnia patients.

A low-dose formulation of doxepin is currently in development as a hypnotic. Three published studies have examined doxepin’s effects in primary insomnia patients. A placebo-controlled, 4-week study of doxepin 25–50 mg (N=47) found that active treatment improved sleep efficiency and sleep quality over the entire treatment period.78 Notably, more rebound insomnia was observed in the doxepin treatment group during the placebo run-out period. Adverse effects were comparable between the two groups, but two doxepin patients discontinued due to adverse effects. In the second study, patients (N=10) were treated with placebo for 1 night and doxepin 25 mg for 3 weeks.79 Relative to placebo, sleep was improved after one dose of doxepin during the double-blind phase of the trial. At the end of 3 weeks of open-label treatment, doxepin also improved sleep relative to baseline values. Adverse events and rebound insomnia remained a concern in some patients. Finally, a 2-night cross-over study80 (N=67) was employed to evaluate doxepin 1–6 mg. All three doses improved wake time during sleep, total sleep time, and sleep efficiency relative to placebo. The safety profile of doxepin was similar to that of placebo with no evidence of anticholinergic effects, memory impairment, or significant hangover/next-day residual effects.

Two studies evaluated paroxetine in primary insomnia patients. Fifteen insomnia patients were treated for 6 weeks with a flexible dose of paroxetine (median dose=20 mg).81 At the end of the treatment period, 11 patients had improved and seven no longer met the diagnostic criteria for insomnia. Subjective measures of sleep quality and daytime function were significantly improved, but neither objective nor subjective measures of sleep quantity were consistently changed with treatment. One participant dropped out due to adverse side effects. A double-blind comparison82 of paroxetine and placebo in older adults (N=27) found improvements in subjective sleep quality and several measures of daytime function. Sleep efficiency, sleep latency, and wake time appeared to be unaffected by active treatment. Both evaluations suggest that paroxetine is ineffective for treating primary insomnia.

Trimipramine was studied in two groups of primary insomnia patients.83 It was shown to produce significant improvements in sleep efficiency, total sleep time, wake time after sleep onset, sleep quality, and next-day well-being in 19 primary insomnia patients (mean dose=166 mg ). Side effects included dry mouth and the anticholinergic properties of the drug. No rebound insomnia was observed at either 4 or 14 days following drug discontinuation. A 4-week study84 of trimipramine (mean dose=100 mg) in 55 insomnia patients found significant improvements in sleep efficiency but no impact on total sleep time. Adverse effects were deemed minimal and no rebound insomnia was observed.

One open label study85 of nefazodone in primary insomnia has been reported. Patients (N=32) were treated with 100 mg nefazodone at bedtime. Over the 4-week period evaluated, this dose could be titrated up to 400 mg depending on treatment response. At the end of the treatment period sleep latency was prolonged and there was less SWS relative to baseline values. The duration of REM sleep was greater and improvements were seen in subjective Pittsburgh Sleep Quality Index scores, but overall sleep effects were decidedly mixed. Furthermore, 12 of 32 participants dropped out of the study citing either lack of efficacy or intolerable side effects.

 

Conclusion

Mood disorders are frequently comorbid with insomnia. Treatment options to address both conditions simultaneously include the use of a sedating antidepressant, two antidepressants (one sedating), or an antidepressant in conjunction with a hypnotic. Although the simultaneous use of two antidepressants is perhaps the most common course of action, it has not been well studied and is associated with significant safety concerns. Recent studies suggest that combining an antidepressant with a hypnotic may be a more promising, efficacious, and safe strategy for the treatment of comorbid mood disorders and insomnia. PP

 

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66.    Margolese HC, Chouinard G. Serotonin syndrome from addition of low-dose trazodone to nefazodone. Am J Psychiatry. 2000;157(6):1022.
67.    Bhatara VS, Magnus RD, Paul KL, Preskorn SH. Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms. Ann Pharmacother. 1998;32(4):432-436.
68.    Gomez Gomez JM, Teixido Perramon C. Combined treatment with venlafaxine and tricyclic antidepressants in depressed patients who had partial response to clomipramine or imipramine: initial findings. J Clin Psychiatry. 2000;61(4):285-289.
69.    Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R. Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology (Berl). 2000;147(4):378-383.
70.    Vandel S, Bertschy G, Bonin B, et al. Tricyclic antidepressant plasma levels after fluoxetine addition. Neuropsychobiology. 1992;25(4):202-207.
71.    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.
72.    Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060.
73.    Physicians’ Desk Reference. 60th ed. Montvale, NJ: Thomson Healthcare; 2006.
74.    Piergies AA, Sweet J, Johnson M, Roth-Schechter BF, Allard S. The effect of co-administration of zolpidem with fluoxetine: pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther. 1996;34(4):178-183.
75.    Krystal A, Fava M, Rubens R, et al. Evaluation of eszopiclone discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med. 2007;3(1):48-55.
76.    Karim A. Effect of Multiple Oral Doses of Sertraline on the Systemic Availability of Ramelteon, an MT1/MT2-Receptor Agonist [abstract]. Paper presented at: 35th Annual Meeting of the American College of Clinical Pharmacology; September 17-19, 2006; Cambridge, MA.
77.    Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII-R primary insomnia. Hum Psychopharmacol. 1998;13(3):191-198.
78.    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.
79.    Rodenbeck A, Cohrs S, Jordan W, Huether G, Ruther E, Hajak G. The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed by an open treatment over 3 weeks. Psychopharmacology (Berl). 2003;170(4):423-428.
80.    Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561.
81.    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.
82.    Reynolds CF 3rd. Paroxetine treatment of depression in late life. Psychopharmacol Bull. 2003;37(suppl 1):123-134.
83.    Hohagen F, Montero RF, Weiss E, et al. Treatment of primary insomnia with trimipramine: an alternative to benzodiazepine hypnotics? Eur Arch Psychiatry Clin Neurosci. 1994;244(2):65-72.
84.    Riemann D, Voderholzer U, Cohrs S, et al. Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study. Pharmacopsychiatry. 2002;35(5):165-174.
85.    Wiegand MH, Galanakis P, Schreiner R. Nefazodone in primary insomnia: an open pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(7):1071-1078.
86.    Sharpley AL, Cowen PJ. Effect of pharmacologic treatments on the sleep of depressed patients. Biol Psychiatry. 1995;37(2):85-98.
87.    Antai-Otong D. Antidepressant-induced insomnia: treatment options. Perspect Psychiatr Care. 2004;40(1):29-33.
88.    Clark NA, Alexander B. Increased rate of trazodone prescribing with bupropion and selective serotonin-reuptake inhibitors versus tricyclic antidepressants. Ann Pharmacother. 2000;34(9):1007-1012.

 

Mr. Pandi-Perumal is a research scientist and Dr. Trakht is an assistant professor in the Division of Clinical Pharmacology and Experimental Therapeutics in the Department of Medicine at the College of Physicians and Surgeons of Columbia University in New York City. Dr. Brown is professor emeritus in the Department of Psychiatry at the University of Toronto in Canada. Dr. Cardinali is professor in the Department of Physiology and director of the Institute of Applied Neuroscience at the University of Buenos Aires in Argentina.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: S.R. Pandi-Perumal, MSc, Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 W 168th St, Rm #BB813, New York, NY 10032; Tel: 212-305-6861; Fax: 212-342-2969; E-mail: sleepresearch@gmail.com.

 


 

Abstract

Sleep is a behavioral process that is governed by both homeostatic and circadian processes. While the intensity and duration of sleep is governed mainly by the homeostatic process (sleep debt), the timing of sleep is orchestrated by the anterior hypothalamic suprachiasmatic nuclei (SCN). Disturbances in the organization of the sleep/wake cycle as well as circadian (approximately 24-hour periodicity) dysregulation are often noted in mental illness. The circadian rhythm of pineal melatonin secretion, which is controlled by the SCN, is reflective of mechanisms that are involved in the control of the sleep/wake cycle. Melatonin influences sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of melatonin (MT)1 and MT2 receptors, highly concentrated in the SCN. In healthy humans, melatonin induces sleep by a process influenced by the circadian phase. The hypnotic and rhythm-regulating properties of melatonin and its agonists (ramelteon, agomelatine) make them an important addition to the armamentarium of drugs for treating sleep disturbances and circadian rhythm sleep disorders associated with mental illness.

 

Introduction

Most physiologic processes in a wide range of organisms show daily cyclical changes. In mammals, including humans, a central circadian pacemaker, or biological clock, is the site of generation and entrainment of circadian rhythms. It is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus (Image). This clock generates a genetically programmed endogenous rhythmicity, which is slightly different from 24 hours and needs to be synchronized (entrained) to the 24-hour day cycle by external timekeeping cues (mainly the light/dark cycle, and secondarily the timing of meals or social contacts). In the absence of these “Zeitgebers,” circadian rhythms persist and express their own period that is “circa” but not exactly 24 hours. In humans, the endogenous period of the circadian clock has a mean value of 24.2 hours; that is, every day our biological clock is delayed by approximately 12 minutes as compared with the environmental light/dark cycle.

 

 

 

The SCN receive direct light information through the retino-hypothalamic tract, which is a visual tract not linked to behavioral visual processes, and indirect light information through the thalamus, using the retino-geniculo-hypothalamic tract. The photic entrainment of the pacemaker is achieved by a specialized subset of intrinsically photosensitive ganglion cells that are spread throughout the retina rather than concentrated in the fovea. These specialized, melanopsin-containing ganglion cells also receive input from rods and cones, acting as a redundant input pathway for synchronizing the circadian system, but can still function even if the rods and cones are so severely damaged that the individual is behaviorally blind.1

The central circadian oscillator adjusts its functioning via the integration of various parameters of the light signal (eg, time of presentation, duration, intensity, wavelength). Light presented in the evening and early night (before the core body temperature [cBT] minimum) affects the human circadian pacemaker to phase-delay its rhythms, while a light stimulus given in late night and early morning (after cBT minimum) produces a phase advance (phase response curve).

During the past decade, enormous progress has been made in determining the molecular components of the biological clock.2 The molecular mechanisms that underlie the function of the clock are universally present in all cells and consist of gene-protein-gene feedback loops in which proteins can down-regulate their own transcription and stimulate the transcription of other clock proteins. At the start of circadian day, core clock genes “period” (PER) and “cryptochrome” (CRY) are activated by protein “circadian locomotor output cycles kaput/brain and muscle aryl hydrocarbon receptor nuclear translocator-like” (CLOCK/BMAL) heterodimers via E-box sequences. Following a delay, protein PER/CRY complexes accumulate in the nucleus late in the day and turn off their own expression, establishing the primary feedback loop of the oscillation. Clearance of PER/CRY complexes during the circadian night allows for reactivation of the loop on the following day. In addition, over the course of the day, REV-ERBα accumulation, which is also driven by CLOCK/BMAL, suppresses Bmal expression. The clearance during early circadian night of REV-ERBα derepresses Bmal, thereby cueing the next circadian cycle of gene expression. Clock-controlled gene products transduce the core oscillation to downstream output systems.2 Via neural pathways (the autonomic nervous system) and humoral pathways (melatonin, cortisol) the SCN impose their rhythmicity on the peripheral oscillators.

Disruption in circadian organization occurs in numerous affective disorders, such as major depressive disorder (MDD), bipolar depressive disorder, seasonal affective disorder (SAD), and premenstrual dysphoric disorder (PMDD). Whether altered rhythmicity is a cause or effect of altered affective states remains a matter of debate. However, it is agreed that the large prevalence of circadian dysfunction in affective states certainly supports a major role of the circadian system in the etiology and the treatment of affective disorders.

As a major circadian rhythm, the abnormality of the sleep/wake rhythm constitutes one of the most prevalent symptoms of mental illness and forms part of the diagnostic criteria for most mood disorders as well as for several anxiety disorders.3 CLOCK gene polymorphisms have been associated with an increased rate of recurrence in patients with bipolar disorder and relapse in recurrent MDD.4-6 Similar polymorphisms could affect the occurrence of insomnia in depressed patients and its response during antidepressant treatment. Other polymorphisms were found to be significantly associated with susceptibility to SAD.7,8

 

Two Processes of Sleep Regulation

Two different processes participate in sleep regulation, namely, a homeostatic mechanism depending on sleep debt (referred to as process “S,” for sleep) and the circadian system that regulates sleep induction and wakefulness (process “C,” for circadian).9 Non-rapid eye movement (NREM) sleep and, in particular, slow wave sleep (SWS), are controlled by the homeostatic process. Periods of NREM sleep constitute nearly 80% of the total sleep time while REM sleep accounts for 20% of the sleep time. During each night, individuals experience approximately five ultradian cycles of NREM sleep and REM sleep that last 70–90 minutes each. REM sleep grows longer with each successive ultradian cycle.10 The S component controls NREM sleep and the C component controls both REM sleep and the ratio of NREM/REM sleep. The SCN interacts with both sleep regulatory mechanisms, S and C, and it has been proposed that functional disruption of the master clock plays a major role in disorders of sleep and wakefulness.11

The function of the SCN in the control of sleep has been studied in various species including non-human primates. Squirrel monkeys with SCN lesions suffer from the absence of a consolidated sleep/wake cycle.12 The circadian signal produced by the SCN promotes wakefulness during the subjective day and consolidation of sleep at night.12 Neurons present in the hypothalamic ventral subparaventricular zone (SPZ) are needed for the circadian sleep/wake rhythm and project to the dorsomedial hypothalamus (DMH). Hence, the sleep/wake rhythms are controlled by two relays, one from the SCN to the ventral SPZ and a second one from the ventral SPZ to the DMH.10 Although rhythmic SCN neurons express Per-1 and Per-2 during photophase, independently of diurnal or nocturnal activity nature of the individual,13 their output neurons in the ventrolateral preoptic area are active during night; orexin-containing neurons of DMH, however, are predominantly active during daytime.10

 

Melatonin’s Role in the Regulation of Sleep

That the nocturnal increase of melatonin secretion starts approximately 2 hours prior to the individual’s habitual bedtime and that this correlates well with the onset of evening sleepiness have prompted many investigators to suggest that melatonin is involved in the physiologic regulation of sleep.14 The period of wakefulness immediately prior to the increase of sleep propensity (“opening of sleep gate”) is known as the “forbidden zone” for sleep.15 During this time, the sleep propensity is lowest and SCN neuronal activity is high.16,17 The transition from wakefulness/arousal to high sleep propensity coincides with the nocturnal rise of endogenous melatonin secretion.18

Melatonin exerts its physiologic actions on sleep by acting through Gi protein linked to specific melatonin (MT)1 and MT2 receptors which are present on cell membranes in the SCN and elsewhere.19 While the MT1 receptor decreases neuronal firing rate, the MT2 receptor regulates phase shifts. The G protein-coupled receptor 50 (GPR50), although lacking the ability to bind melatonin itself, can dimerize with the MT1 receptor and inhibit it.21,22 A study by Thomson and colleagues23 reported a sex-specific association between bipolar affective disorder in women in Southeastern Scotland and a polymorphism in the gene for GPR50. Nuclear receptors for melatonin have also been described.24 In addition, melatonin exerts direct effects on intracellular proteins such as calmodulin25 and has strong free radical scavenger properties26 which are non-receptor mediated. The possibility that melatonin, a major hormone involved in the regulation of sleep, could be one of the triggering factors underlying the pathogenesis of MDD, bipolar depressive disorder, SAD or PMDD has been considered.27

The first evidence that melatonin affects sleep came from Lerner and colleagues,28 who discovered melatonin in 1958. When they started to treat patients suffering from vitiligo, a human pigmentation disease, the patients fell asleep. After this initial observation, several clinical trials have examined the role of melatonin in sleep and have pointed out the value of melatonin as a hypnotic agent.29 In human studies, administration of either physiologic or pharmacologic doses of melatonin promotes both sleep onset and sleep maintenance.30-32

Brain imaging studies have revealed that melatonin modulates brain activity pattern in wake subjects in a manner resembling actual sleep.33 Melatonin administration attenuated activation in the rostromedial aspect of the occipital cortex during a visual-search task and in the auditory cortex during a music task.33 However, phase-resetting actions of melatonin have also been advocated as the major mechanism by which exogenous melatonin affects sleep regulation.34 Melatonin administration is useful to effectively synchronize sleep/wake cycles in blind individuals as well as in people suffering from jet lag, delayed sleep phase syndrome, or advanced sleep phase syndrome.35

Phase resetting effects of endogenous as opposed to administered melatonin are evidenced by studies of polymorphisms of the gene for the enzyme arylalkylamine N-acetyltransferase (AA-NAT), which is a key factor in triggering synthesis of melatonin in the pineal gland. Polymorphisms of this gene are reported to be associated with advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS), conditions in which individuals have extreme difficulty in falling asleep and in arising at desired times. In DSPS, there is a delay in sleep onset and wakening together with a delay in onset of the nocturnal melatonin rise.36,37 A single nucleotide polymorphism (SNP) of the AA-NAT gene has been associated with the DSPS.38 In familial ASPS,39,40 affected family members on average have sleep onset and wakening 3–3.5 hours earlier than unaffected members, and the nocturnal melatonin onset is also 3.5 hours earlier. SNP of the promoter region of AA-NAT was found to be associated with ASPS.41

Exogenous melatonin administration can induce sleepiness at night even at very low doses.29 Unlike some other hypnotic drugs, melatonin does not cause hangover effects the next morning.29 A meta-analysis of 17 studies involving 284 subjects42 concluded that melatonin is effective in reducing sleep onset latency and in increasing sleep efficiency. However, another survey,43 which included all age groups, failed to confirm whether exogenously administered melatonin had any clinically meaningful effects on sleep. It is important to stress that in this report an increase in sleep efficiency in people with secondary sleep disorders (approximately 2%) was statistically significant with melatonin, but the authors considered this effect to be clinically unimportant due to its small magnitude. Nevertheless, the authors’ conclusions may merit reconsideration inasmuch as the noted reductions in sleep onset latency were of the same magnitude as those observed with some marketed hypnotics. In any event, it seems possible that a prerequisite for exogenous melatonin effects is the existence of low endogenous melatonin secretion.44 There is a very large interindividual variation in nocturnal melatonin levels.45-47 It is, therefore, possible that those with a higher endogenous output of melatonin could need a larger dose for effective treatment.

In view of this factual evidence, the use of a melatonin analog with a longer half life and increased potency than melatonin, which might have a greater effect on melatonergic receptors in the SCN and other regions of the brain, have been advocated.48 Ramelteon is a novel melatonin receptor agonist for MT1 and MT2 receptors approved for its clinical use by the United States Food and Drug Administration and it is being tried clinically to treat sleep problems of the elderly. Ramelteon is effective in increasing total sleep time in the elderly.49-51

 

The Link Between Sleep and Mood Disorders

Considerable controversy exists concerning the question of whether sleep disturbances in depression are a “trait-like” feature.52 Patients with MDD have nightmares at least twice a week and, compared to normal, have significantly higher suicide scale scores.53 Some studies54 of patients with depression have shown changes in sleep architecture that persist even during the remission phase. Changes in sleep architecture often precede changes in patients’ ongoing clinical state or can signal relapse.

Depressed patients experience difficulty falling asleep, difficulty staying asleep, and early morning awakenings.55 Analysis of SWS in NREM sleep has shown that delta wave counts in patients with MDD are decreased when compared to controls. Fast frequency beta and elevated alpha activities have been recorded during sleep in depressed patients, indicating that hyperarousal and increased sleep fragmentation are major characteristics of sleep in depression.56 These changes are present in non-medicated patients or in clinical remission, suggesting that they are trait-like features of depressive illness.56

Disturbances in the organization of the sleep/wake cycle in MDD patients are thought to be due to abnormalities in the timing of the REM/NREM sleep cycle.57 The temporal distribution of REM sleep is altered during overnight sleep in depressives. Decreased REM latency has been shown to be common in severe or endogenous depression. It has been suggested that reductions in REM latency in depression are due to reduction of NREM sleep, particularly SWS.58 Patients with least amounts of SWS also showed the greatest psychomotor retardation.56 These findings support the conclusion that disruptions to sleep homeostasis are a major form of sleep disturbance in depression. Additionally, increases in REM sleep density have also been found to be specific to affective disorders59 and are now thought to be a reliable sleep marker for depression.60 Consistent with this view are findings that suggest that many of the antidepressants produce REM sleep suppression as well as increases in REM latency.

 

Antidepressants and the Role of Melatonin

Many antidepressants increase melatonin levels,61-67 and the central nervous system distribution of melatonin receptor messenger ribonucleic acid (mRNA) is modified by prolonged treatment with antidepressants such as desipramine, clomipramine, or fluoxetine. With the exception of fluoxetine, those drugs were found to increase the amount of mRNA for MT1 receptors and to decrease that for MT2 receptors in the hippocampus.68,69 Based on these findings, it was hypothesized that endogenous levels of melatonin could contribute to antidepressant effects depending upon the expression pattern of melatonin receptors in the brain.

It has been suggested that diminished melatonin secretion is at least partially responsible for the deterioration of sleep maintenance that is seen in insomniacs. In a study70 undertaken in 382 postmenopausal women with a family history of depression, a delay in urinary 6-sufatoxymelatonin excretion was found. Other studies in aging women have documented that reductions in circulating melatonin levels accompany menopause, and programs of melatonin-replacement therapy have been proposed.71,72 In a study conducted on 10 patients with MDD, slow release melatonin tablets in the doses of 5 mg/day (which was raised to 10 mg/day at the end of 2 weeks) were administered for 4 weeks along with fluoxetine 20 mg/day.73 Melatonin treatment promoted a significant improvement in sleep quality, as evidenced from scores on the Pittsburgh Sleep Quality Index. As reported earlier,74 despite the melatonin-induced enhancements of sleep quality, no improvements were found in the clinical status of the depressed patients.73 In another study75 of patients suffering from both delayed sleep phase syndrome and depression, melatonin treatment not only significantly improved the total sleep time but also significantly reduced psychometric scores for depression. In two studies73,76 of combination therapy in patients with MDD or treatment-resistant depression, the combination of melatonin (slow-release formulation) plus fluoxetine or other antidepressants was found to improve the sleep quality of the patients, but there was no additive effect of melatonin on the depressive symptoms.

 

Conclusion

Evidence that antidepressant treatment can promote favorable melatonin receptor expression has led to the suggestion that combination therapy using an antidepressant plus a melatonergic agent may be an effective strategy for treating sleep disorders in the context of depression.68,69 One such antidepressant combining both properties in a single molecule is the newly developed agent agomelatine (Valdoxan, Servier). Agomelatine is an MT1 and MT2 receptor agonist with serotonin-2C antagonist properties that has been found to be beneficial in treating patients with MDD.77-84 Agomelatine is a naphthalenic compound with an overall selectivity (>100 fold) for MT1 and MT2 receptors but has no significant affinities to muscarinic, histaminergic, adrenergic, or dopaminergic receptor subtypes.82 The proven chronobiotic action of agomelatine is due to its agonist activity on MT1 and MT2 receptors in the suprachiasmatic nucleus.83-86 Inasmuch as disruptions in circadian rhythms are linked to depressive states, agomelatine’s effectiveness in treating these symptoms support the conclusion that it has a broader range of effect than other antidepressants and may address the complexities of depressive illness more effectively. PP

 

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47. Travis RC, Allen NE, Peeters PH, van Noord PA, Key TJ. Reproducibility over 5 years of measurements of 6-sulphatoxymelatonin in urine samples from postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2003;12(8):806-808.
48. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004;5(6):523-532.
49. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005;28(3):303-307.
50. Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006;7(4):312-318.
51. Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med. 2006;7(1):17-24
52.     Berger M, Riemann D. Symposium: Normal and abnormal REM sleep regulation: REM sleep in depression-an overview. J Sleep Res. 1993;2(4):211-223.
53. Agargun MY, Cilli AS, Kara H, Tarhan N, Kincir F, Oz H. Repetitive and frightening dreams and suicidal behavior in patients with major depression. Compr Psychiatry. 1998;39(4):198-202.
54. Kupfer DJ, Spiker DG, Coble PA, Neil JF, Ulrich R, Shaw DH. Sleep and treatment prediction in endogenous depression. Am J Psychiatry. 1981;138(4):429-434.
55. Cajochen C, Brunner DP, Krauchi K, Graw P, Wirz-Justice A. EEG and subjective sleepiness during extended wakefulness in seasonal affective disorder: circadian and homeostatic influences. Biol Psychiatry. 2000;47(7):610-617.
56. Armitage R. Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl. 2007;(433):104-115.
57. Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin Psychopharmacol. 2006; 21 Suppl 1:S11-S15.
58. Lustberg L, Reynolds CF. Depression and insomnia: questions of cause and effect. Sleep Med Rev. 2000;4(3):253-262.
59. Wichniak A, Riemann D, Kiemen A, Voderholzer U, Jernajczyk W. Comparison between eye movement latency and REM sleep parameters in major depression. Eur Arch Psychiatry Clin Neurosci. 2000;250(1):48-52.
60. Lam RW. Sleep disturbances and depression: a challenge for antidepressants. Int Clin Psychopharmacol. 2006;21(suppl 1):25-29.
61. Venkoba Rao A, Parvathi Devi S, Srinivasan V. Urinary melatonin in depression. Indian J Psychiatry. 1983;25:167-172.
62. Thompson C, Mezey G, Corn T, et al. The effect of desipramine upon melatonin and cortisol secretion in depressed and normal subjects. Br J Psychiatry. 1985;147:389-393.
63. Sack RL, Lewy AJ. Desmethylimipramine treatment increases melatonin production in humans. Biol Psychiatry. 1986;21(4):406-410.
64. Golden RN, Markey SP, Risby ED, Rudorfer MV, Cowdry RW, Potter WZ. Antidepressants reduce whole-body norepinephrine turnover while enhancing 6-hydroxymelatonin output. Arch Gen Psychiatry. 1988;45(2):150-154.
65. Srinivasan V. Psychoactive drugs, pineal gland and affective disorders. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13(5):653-664.
66. Borjigin J, Li X, Snyder SH. The pineal gland and melatonin: molecular and pharmacologic regulation. Annu Rev Pharmacol Toxicol. 1999;39:53-65.
67. Szymanska A, Rabe-Jablonska J, Karasek M. Diurnal profile of melatonin concentrations in patients with major depression: relationship to the clinical manifestation and antidepressant treatment. Neuro Endocrinol Lett. 2001;22(3):192-198.
68. Larson J, Jessen RE, Uz T, et al. Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice. Neurosci Lett. 2006;393(1):23-26.
69. Hirsch-Rodriguez E, Imbesi M, Manev R, Uz T, Manev H. The pattern of melatonin receptor expression in the brain may influence antidepressant treatment. Med Hypotheses. 2007;69(1):120-124.
70. Tuunainen A, Kripke DF, Elliott JA, et al. Depression and endogenous melatonin in postmenopausal women. J Affect Disord. 2002;69(1-3):149-158.
71. Bellipanni G, DI Marzo F, Blasi F, Di Marzo A. Effects of melatonin in perimenopausal and menopausal women: our personal experience. Ann N Y Acad Sci. 2005;1057:393-402.
71. Bellipanni G, Bianchi P, Pierpaoli W, Bulian D, Ilyia E. Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study. Exp Gerontol. 2001;36(2):297-310.
73. Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry. 1998;155(8):1119-1121.
74. Fainstein I, Bonetto A, Brusco LI, Cardinali DP. Effects of melatonin in elderly patients with sleep disturbance. A pilot study. Curr Ther Res. 1997;58:990-1000.
75. Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med. 2001;63(1):40-48.
76. Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci. 2000;25(1):48-52.
77. Loo H, Hale A, D’haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17(5):239-247.
78. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16(2):93-100.
79. Montgomery SA. Major depressive disorders: clinical efficacy and tolerability of agomelatine, a new melatonergic agonist. Eur Neuropsychopharmacol. 2006;16(suppl 5):633-638.
80. Pandi-Perumal SR, Srinivasan V, Cardinali DP, Monti JM. Could agomelatine be the ideal antidepressant? Expert Rev Neurother. 2006;6(11):1595-1608.
81. Kupfer DJ. Depression and associated sleep disturbances: patient benefits with agomelatine. Eur Neuropsychopharmacol. 2006;16(suppl 5):639-643.
82. Rouillon F. Efficacy and tolerance profile of agomelatine and practical use in depressed patients. Int Clin Psychopharmacol. 2006;21(suppl 1):31-35.
83. Redman JR, Francis AJ. Entrainment of rat circadian rhythms by the melatonin agonist S-20098 requires intact suprachiasmatic nuclei but not the pineal. J Biol Rhythms. 1998;13(1):39-51.
84. Weibel L, Turek FW, Mocaer E, Van Reeth O. A melatonin agonist facilitates circadian resynchronization in old hamsters after abrupt shifts in the light-dark cycle. Brain Res. 2000;880(1-2):207-211.
85. Van Reeth O, Weibel L, Olivares E, Maccari S, Mocaer E, Turek FW. Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus. Am J Physiol Regul Integr Comp Physiol. 2001;280(5):R1582-R1591.
86. Tuma J, Strubbe JH, Mocaer E, Koolhaas JM. S20098 affects the free-running rhythms of body temperature and activity and decreases light-induced phase delays of circadian rhythms of the rat. Chronobiol Int. 2001;18(5):781-799.

 

Dr. Pavletic is senior staff clinician in the Office of the Clinical Director, Mr. Luckenbaugh is medical statistician in the Mood and Anxiety Program, Dr. Pao is deputy clinical director in the Intramural Research Program, and Dr. Pine is chief of developmental studies in the Mood and Anxiety Program, all at the National Institute of Mental Health in Bethesda, Maryland.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Disclaimer: The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, the National Institutes of Health, the United States Department of Health and Human Services, or the United States Government.

Please direct all correspondence to: Adriana J. Pavletic, MD, MS, 10 CRC, Room 6-5340, 10 Center Drive, MSC 1276, Bethesda, MD 20892-1276; Tel: 301-594-7386; Fax: 301-402-2588; E-mail: pavletia@mail.nih.gov.

 


 

Focus Points

• Assessments based on research volunteer-provided history are not sufficient in determining eligibility for protocols.
• Physical examination may discover psychiatric and/or medical disorder.
• Toxicology screen is often positive in research volunteers.
• Medical evaluation is equally important in healthy controls and anxiety patients.

 


 

Abstract

Introduction: The importance of psychiatric screening of volunteers participating in research on mental illness is well established. Although psychiatric research frequently relies on subjects presumed to be free of medical conditions that affect nervous system function or safety of participants, little information exists on the value of medical screening in this population. This study describes findings on medical evaluations that potentially impact psychiatric research.
Methods: The authors conducted a retrospective analysis of medical evaluations in 476 consecutively referred healthy controls and 64 anxiety patients to determine the prevalence of conditions that resulted in exclusion from studies. All subjects had history and physical examination by a board-certified family physician and 37% of participants completed laboratory assessment.
Results: One-hundred ten (20%) volunteers were excluded. Exclusion rates were similar for controls and patients. The most common reasons for exclusion were psychiatric conditions (6.3%), positive toxicology screen (5.4%), abnormal liver function tests (4.5%), cardiovascular abnormalities (3.9%), positive viral markers including hepatitis C, hepatitis B, and human immunodeficiency virus (3.5%), anemia (2.5%), neurologic disorders (1.6%), and electrolyte abnormalities (1.0%).
Discussion: Medical screening identifies a relatively high rate of conditions in both healthy controls and anxiety patients that could impact on psychiatric research. A significant proportion of exclusions was found on physical exam, laboratory assessment, and toxicology screen.
Conclusion: These findings demonstrate the complementary nature of medical and psychiatric evaluations and underscore the need to develop further standards in medical screening procedures of volunteers in psychiatric research.

 

Introduction

Previous reports demonstrate the importance of psychiatric evaluation1-5 and toxicology screening6-7 in individuals volunteering for mental health research. Research on mental illness typically attempts to recruit volunteers without medical conditions that might affect the functioning of the nervous system or safety of participants. However, in contrast to considerable work on mental health evaluation, few studies consider the value of comprehensive medical evaluation in this population.

Particular debate exists among mental health researchers regarding the need to perform physical exam and laboratory testing in volunteers participating in noninvasive studies such as functional magnetic resonance imaging (fMRI). Consequently, assessment of physical health often relies on a self report of medical history by potential volunteers. However, histories often fail to detect exclusionary conditions in volunteers participating in both psychiatric and medical research, possibly due to financial incentive.6-10 The aim of this article is to describe findings on medical evaluation that resulted in exclusions of volunteers from studies.

 

Methods

Subjects

Five-hundred forty consecutive research volunteers, between 18–55 years of age (476 healthy controls and 64 anxiety patients) were medically evaluated from May 2003 through April 2005 to determine eligibility for one of nine protocols from four principal investigators. Volunteers were financially compensated for their participation. All protocols were approved by the National Institute of Mental Health (NIMH)-Intramural Research Program (IRP) Institutional Review Board. Two studies involved fMRI, four studies involved fear conditioning with electric nerve stimulation, and three studies involved fear conditioning and/or one-time medication administration.

These subjects were recruited when they contacted the NIMH-IRP. Recruitment methods for NIMH-IRP studies are modeled after those used throughout the various National Institutes of Health (NIH) IRPs, which, in turn, are modeled after those used throughout the medical community. Data on recruitment methods were not collected in this study. All subjects requesting participation were required to undergo an initial phone screen to determine potential eligibility. This initial screen typically led to exclusions among a relatively high proportion of potential subjects. Rates and reasons for these exclusions were not examined since the focus of the current report concerns rates of exclusion among subjects deemed to be eligible based on this initial screen.

 

Medical and Psychiatric Eligibility Criteria

All protocols required the absence of medical conditions and/or use of psychoactive medications that may affect the functioning of the nervous system or safety of participants. For healthy volunteers, inclusion criterion required the absence of a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,11 Axis I mental disorder as determined either by the Structured Clinical Interview for DSM-IV Disorders (SCID), Non-Patient Edition,12 in seven studies or history and physical examination (H&P) in two studies. For anxiety disorder patients, inclusion criteria comprised current diagnosis of generalized anxiety disorder, social anxiety disorder, panic disorder, or specific phobia as determined by the SCID, Patient Edition,13 and study psychiatrist (D.S. Pine, MD).

 

Medical and Psychiatric Screening

Volunteers who passed initial standardized phone screens conducted by college level research assistants for healthy controls and mental health professionals for patients were subsequently evaluated in person. Clinical screening was completed by licensed mental health professionals (psychologists, mental health nurses, social workers) for the SCID and by a board-certified family physician (A.J. Pavletic, MD, MS) for the H&P and laboratory assessment. The order of in-person evaluation was determined by the availability of clinicians. Identification of exclusion criteria on an initial H&P or SCID precluded further evaluation. Thus, for example, volunteers initially receiving the SCID who met exclusion criteria were not medically evaluated and are not included in this report.

For healthy volunteers, screening procedures varied by protocol, including H&P in two studies, H&P and SCID in two studies, and comprehensive evaluations (H&P, laboratory assessment, electrocardiogram, and SCID) in five studies. For anxiety patients, all subjects received the comprehensive evaluation. Laboratory workup included complete blood count with differential, acute care panel (electrolytes, glucose, blood urea nitrogen, creatinine), hepatic panel (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin), thyroid-stimulating hormone, viral markers (HIV, hepatitis B, hepatitis C), qualitative urine drug screen (amphetamines, benzodiazepines, tetrahydrocannabiol, cocaine, opiates), and urine pregnancy test.

 

Eligibility Determination

A family physician performed medical clearance of anxiety patients and determined eligibility of healthy controls based on all available information including H&P, SCID, laboratory assessment, and NIH medical record review of subjects who previously participated in NIH studies. The NIH maintains a comprehensive medical record for all potential research participants who have volunteered in any NIH-IRP study. Questionable cases were discussed with principal investigators (experimental psychologists) and study psychiatrist.

All studies used identical criteria to rule out conditions that might influence interpretation of study results. However, relative to noninvasive fMRI studies, medical eligibility criteria were more stringent in provocative fear conditioning studies and studies involving medication exposure, due to safety concerns. For example, liver function test abnormalities present on at least two occasions were exclusionary only in studies with medication exposure, and murmurs and mitral valve prolapse were exclusionary only in provocative studies with electric nerve stimulation. No subjects were excluded based on only one-time abnormal laboratory result, as one-time laboratory abnormality could be transient or caused by a laboratory error.

 

Data Analysis

Fisher’s Exact test, χ2, chi-square, and t-tests, were used to compare healthy controls and patient volunteers on dichotomous, polychotomous, and continuous measures, respectively. Means and standard deviations are reported. Significance was evaluated at P<.05, two-tailed.

 

Results

Anxiety patients were older (34±12 years) than healthy controls (27±8 years; P<.0001) and underwent more comprehensive evaluations. Laboratory assessment was completed in 37% of participants, ie, 89% of anxiety patients versus 30% of healthy controls (P<.0001). A SCID was administered in 66% of participants, ie, 97% of patients and 62% of healthy controls (P<.0001).

A total 110 of 540 subjects (20%) were excluded, 102 (19%) for medical or psychiatric reasons. Exclusion rates were similar for healthy controls and anxiety patients (Table).

 

The most common reasons for exclusion were psychiatric conditions (6.3%), positive toxicology screen (5.4%), abnormal liver function tests (4.5%), cardiovascular abnormalities (3.9%), positive viral markers including hepatitis C, hepatitis B, and HIV (3.5%), anemia (2.5%), neurologic disorders (1.6%), and electrolyte abnormalities (1.0%) (Table). Excluded subjects were older (mean=30.9, SD=10.3) than subjects accepted to protocols (mean=27.3, SD=8) (P<.001). As expected given differences in study criteria, exclusion rates were significantly higher in medication challenge studies (32%) compared to fMRI (18%) and fear conditioning studies (17%; X=13.57, df=2, P=.001).

Proportions of exclusions found during various methods of in-person evaluation are shown in the Figure. Forty-one subjects were excluded by history or history and SCID, while seven subjects were excluded by SCID only (Figure). Significant proportion of exclusions (59/107 or 55%) was detected by physical exam, laboratory testing, and NIH medical record review, ie, screening methods that rely on information beyond volunteer-provided history. Some examples of significant findings on physical exam include scarring from intentional self injury, very low body mass index (BMI) of 14.5, severe hypertension, tachycardia, conjunctivitis, and loud heart murmur probably indicating valvular heart disease.

 

The importance of laboratory testing for both healthy controls and patients is illustrated in the following examples. A 42 year-old healthy control had unremarkable H&P and SCID, but tested positive for cocaine and hepatitis C. Two anxiety patients tested positive for amphetamines. It is possible that their anxiety disorder was substance induced.

With the exception of one anxiety patient, all volunteers with positive toxicology screen denied any recent illicit drug use during phone screening, SCID, and H&P. For example, one healthy volunteer who had negative SCID had conjunctivitis on exam. He was drinking water from a large container during the interview. His toxicology screen was positive for tetrahydrocannabinol. Volunteers who tested positive for viral markers were significantly older (41±9 years) than those who were negative (21±9; P=.001).

NIH medical record review resulted in exclusion of seven volunteers whose H&P and SCID were unremarkable. For example, a healthy control who denied history of mental illness during the SCID and H&P had participated 1 year earlier in an NIMH treatment study as a patient with recurrent major depressive disorder. Medical record review of a 50-year-old healthy control who denied any medical problems revealed severe anemia with hemoglobin of 6.8 documented 6 months prior to current evaluation; she had applied for fear-conditioning study that did not require laboratory testing. An anxiety patient denied a history of substance abuse, but medical record review revealed a past history of polysubstance dependence. As this was not exclusionary in the study for which he applied, he underwent laboratory testing that later identified hepatitis C infection.

In eight healthy controls that were excluded for psychiatric reasons, the SCID revealed no Axis I diagnosis. However, observations during the H&P in concert with consultation with the study psychiatrist and principal investigators led to exclusion for psychiatric reasons. For example, exclusion followed the observation during physical exam of extensive scarring due to self injury. In another case, history identified attention deficit/hyperactivity disorder that had been previously diagnosed and treated by a psychiatrist outside the NIMH. None of these psychiatric conditions are routinely assessed by the SCID.

Ten subjects had more than one medical exclusion. For example, one healthy control had severe obesity with a BMI of 60, hypertension, and one-sided blindness. Another had history of meningitis with consequent hearing loss, hypothyroidism, and severe migraine headache treated with tryptan.

 

Discussion

The current report is the first that specifically addressed findings on medical evaluation in healthy controls and anxiety patients who volunteer in research on mental illness. Although the study population in this cohort was young and relatively healthy, conditions were detected that could have a profound influence on the safety of participants and validity of research results, including severe hypertension, extreme weight disturbances, electrolyte abnormalities, viral infections, and positive toxicology screen. As in previous investigations,1-5 these results confirm that phone screens fail to identify sizable proportion of subjects who are ineligible for research on mental illness. For example, Shtasel and colleagues1 reported 47% of exclusions for medical and psychiatric illness but did not describe medical exclusions. Consistent with previous reports,1-7 the current cohort also displayed relatively high rates of psychiatric disorders and drug use in healthy controls. As the authors of this article did not include subjects who were excluded by the SCID prior to medical evaluation, the prevalence of psychiatric conditions in this cohort was significantly lower than in previous reports. Methods to improve the yield of eligible volunteers and increase the cost-effectiveness of the screening process have been previously reported2 and are not examined in this study.

Exclusion rates were different in various protocols due to differences in eligibility criteria and the extent of evaluation. For example, more stringent eligibility criteria and more extensive evaluation with laboratory assessment explain higher rejection rates in medication challenge studies.

Study results confirm previous observations that histories are often not reliable in assessment of eligibility of research volunteers, possibly due to financial incentive.6-10 Moreover, denial is common in some psychiatric conditions such as substance abuse and eating disorders.

Despite the fact that only 37% of subjects underwent laboratory testing and toxicology screen, 55% of exclusions in this study were found by physical exam, laboratory testing, or medical record review, ie, procedures relying on methods other than volunteer-provided history.

Study procedures in some research protocols required healthy controls to receive less extensive assessments than patients with anxiety disorders, and thus only 30% of healthy controls underwent laboratory assessment and toxicology screen. Gibbons and colleagues14 suggested the importance of screening healthy participants with a level of care equal to that applied to patients as inadequate screening of controls may adversely impact research results.

While healthy controls usually have no complaints, anxiety patients often present with a variety of physical symptoms. For example, dizziness, weakness, and palpitations may indicate anxiety, anemia, cardiac abnormality, substance abuse, or any combination of these conditions. Therefore, medical evaluation is equally important in patients.

Some findings on medical evaluation may represent complications of psychiatric disorders that had been minimized by volunteers during interview. For example, hypertension, tachycardia, abnormal liver function tests, infection with hepatitis B or C, or HIV may be consequences of substance abuse. One of the healthy controls whose blood pressure was 202/87 denied prior history of hypertension but admitted recent cocaine use after further questioning. Other findings in this cohort may represent manifestation of eating disorders, such as hypo-estrogenic amenorrhea, extremely low BMI, and electrolyte abnormalities. In cases where research volunteers may be motivated to conceal their problems, physical exam, laboratory assessment, and medical record review increase the sensitivity of in-person evaluation. However, some potentially serious preexisting medical conditions such as severe hypertension, valvular heart disease, and viral infections may remain unrecognized without a medical evaluation.

There are some limitations in this study inherent to its retrospective design. The variability in exclusion criteria and extent and order of in-person evaluation makes it somewhat difficult to interpret the results.

As some potential medical exclusions were not pre-specified, the research team reached decisions concerning eligibility on a case-by-case basis using all available information including subject’s age, other risk factors, and study procedures and invasiveness. However, it is impossible to pre-specify all potential exclusions. Moreover, there is insufficient knowledge and no consensus regarding many conditions and medications that may impact some forms of psychiatric research. Unlike psychiatric eligibility criteria, medical eligibility criteria and extent of medical evaluation are rarely discussed in psychiatric literature and deserve further study.

 

Conclusion

Medical screening identified a relatively high rate of conditions in both healthy controls and patients that potentially impacts mental health research. Perhaps most importantly, these findings demonstrate the complementary nature of medical and psychiatric evaluations and underscore the need to develop further standards in medical screening procedures for volunteers in psychiatric research. PP

 

References

1.    Shtasel DL, Gur RE, Mozley PD, et al. Volunteers for biomedical research. Recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;48(11):1022-1025.
2.    Schechter D, Lebovitch R. Normal controls are expensive to find: methods to improve cost-effectiveness of the screening evaluation. Psych Res. 2005;136(1):69-78.
3.    Huang DB, Koo H, Dougherty D, Hassan Y. Psychopathology among persons responding to participation as normal controls in behavioral research. Compr Psychiatry. 2003;44(2):83-87.
4.    Halbreich U, Bakhai Y, Bacon KB, et al. The normalcy of self –proclaimed “normal volunteers.” Am J Psychiatry. 1989;146(8):1052-1055.
5.    Bunce SC, Noblett KL, McCloskey MS, Coccaro EF. High prevalence of personality disorders among healthy volunteers for research: implications for control group bias. J Psych Res. 2005;39(4):421-430.
6.    Struve FA, Straumanis JJ, Manno JE, Fitzgerald MJ, Patrick G, Leavitt J. Inadequacies of self-report data for exclusion criteria detection in marihuana research: an empirical case for multi-method direct examination screening. J Addict Dis. 2000;19(3):71-87.
7.    Swerdlow NR, Geyer MA, Perry W, Cadenhead K, Braff DL. Drug screening in “normal” controls. Biol Psychiatry. 1995;38(2):123-124.
8.    Apseloff G, Swayne JK, Gerber N. Medical histories may be unreliable in screening volunteers for clinical trials. Clin Pharmacol Ther. 1996;60(3):353-356.
9.    Watson N, Wyld PJ. The importance of general practitioner information in selection of volunteers for clinical trials. Br J Clin Pharmacol. 1992;33(2):197-119.
10.    Kolata GB. NIH shaken by death of research volunteer. Science. 1980;209(4455):475-476,478-479.
11.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
12.    First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition. (SCID-I/NP). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
13.    First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition with Psychotic Screen (SCID-I/P W/PSY SCREEN). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
14.    Gibbons RD, Davis JM, Hedeker DR. A comment on the selection of “healthy controls” for psychiatric experiments. Arch Gen Psychiatry. 1990;47(8):785-786.

 

Dr. Randall is postdoctoral fellow in the Sleep Disorders and Research Center at the Henry Ford Hospital in Detroit, MI. Dr. Roehrs is director of research at the Sleep Disorders and Research Center at the Henry Ford Hospital and professor of psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University School of Medicine in Detroit. Dr. Roth is director of the Sleep Disorders and Research Center at the Henry Ford Hospital and professor of psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University School of Medicine.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Surilla Randall, PhD, Henry Ford Hospital Sleep and Research Center, CFP-3, 2799 West Grand Blvd, Detroit, MI 48202; Tel: 313-916-5301: Fax: 313-916-2508; E-mail: srandal1@hfhs.org.

 


  

Abstract

Insomnia is defined as difficulty initiating or maintaining sleep and/or nonrestorative sleep which impairs daytime function. Self treatment with over-the-counter (OTC) sleep aids, herbal and dietary supplements, and/or alcohol is common. Problems associated with insomnia self treatment are ineffectiveness, tolerance, dependency, and potentially harmful side effects. Studies of OTC sleep aids and other non-prescription sleep aids such as antihistamines, valerian, melatonin, and L-tryptophan have inconsistent results and lack objective data on both their efficacy and safety. Lastly, alcohol should never be used as a sleep aid due to its abuse liability.

 

Introduction

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,1 defines primary insomnia as difficulty initiating or maintaining sleep and/or poor quality (nonrestorative) sleep for at least 1 month, which has some daytime consequences. The duration of insomnia can be transient (days to several weeks) or chronic (≥1 month). Insomnia is associated with impairments in social, occupational, and other areas of functioning. Sleep disturbances can have a significant negative impact on daytime function, evident by mental slowing, reduced concentration, memory lapses, and decreased motivation. Insomnia can be associated with medical conditions, medication use, psychiatric disorders, substance abuse, or other primary sleep disorders (eg, sleep apnea, restless leg syndrome). However, primary insomnia is a disorder independent of these other conditions.

Epidemiologic studies report varying estimates of insomnia prevalence. The estimates are dependent upon whether the data come from patient care settings; female, elderly, or general populations; or the study’s definition of insomnia.2 Taking into consideration the various adult insomniac populations, prevalence estimates range from approximately 10% to 50%. When including only chronic insomnia the prevalence range decreases from 10% to 15%.3-6

Insomnia predisposes one to psychiatric disorders, aggravates medical conditions, decreases the quality of life, and increases the risk of drug and alcohol abuse.7 Greater than 50% of those with depression, psychosomatic disorders, anxiety disorders, neuroses, dementia, and schizophrenia have insomnia complaints.8 In some cases, treating the underlying mental disease may not improve the insomnia.

Self treatment with over-the-counter (OTC) sleep aids, herbal and dietary supplements, and/or alcohol is common among insomniacs. It is thought that the availability of these products, decreased cost compared to prescription sleep aids, and importantly, perceived safety results in the great usage of OTC sleep aids.9-11 A metropolitan Detroit study10 showed that 25.9% of respondents reported using some substance to aid their sleep. Of those who used medications (either prescription, OTC sleep aids, or both) to improve sleep, 57% reported using OTC sleep aids. In a recent study,12 approximately 25% of patients with insomnia used OTC sleep aids, and 5% used these drugs several times a week. A study of insomniac women ≥85 years of age noted that the respondents reported they did not see a physician or nurse practitioner for insomnia until the self treatment (with alcohol, OTC sleep aids, or both) was no longer effective.13 The problems associated with insomnia self treatment are use at higher than recommended doses, tolerance resulting from loss of efficacy, and the development of dependency in at-risk populations. There are even greater concerns with alcohol used as a sleep aid. Ineffective and potentially harmful self treatment is not fully appreciated as a risk of not treating insomnia medically with drugs exhibiting efficacy and safety profiles. This article provides an overview of what is known regarding the efficacy and safety of popular nonprescription products used for insomnia.

 

Antihistamines

Antihistamines consist of a broad class of pharmacologic agents that include the first-generation, central acting histamine (H)1 receptor antagonists. The primary action of this drug class is to block the effects of histamine, which reduces congestion, sneezing, coughing, and allergy symptoms. Centrally, these drugs block histamine receptors, histamine being one of the major alerting central neurotransmitters. Due to the sedative action of antihistamines, they are widely used as non-prescription sleep aids. Evidence appears to suggest that antihistamines may be useful for insomnia for 1–2 nights, but not efficacious in treating chronic insomnia.

 

Diphenhydramine

In 1982, the Food and Drug Administration authorized the initial marketing of diphenhydramine HCl and diphenhydramine citrate as active ingredients in non-prescription sleep aids. Other general medical uses include relief of allergies, motion sickness, and coughing. Table 1 lists the various OTC products and their doses. For sleep, the available dose range of diphenhydramine is 25–50 mg, with 50 mg being the maximum dose to be taken 30–60 minutes before bed.14,15 While marketed for allergy relief, Benadryl, which contains 12.5 or 25 mg of diphenhydramine depending on the formulation, is commonly used for sleep. Diphenhydramine citrate is often combined with an analgesic; together they are advertised to provide pain relief and induce sleep (Table 1).

Diphenhydramine has a half-life of 5–12 hours and has significant anticholinergic activity. Consequently, its use is associated with next-day mild-to-moderate side effects, namely residual morning sedation, dry mouth, grogginess, and malaise.15,16 Importantly, it has not been determined which aspects of its pharmacologic activity are mediated by H1 receptors and which are mediated by cholinergic receptors. Despite the reported side effects of diphenhydramine, virtually all OTC sleep aids contain diphenhydramine as the active ingredient (Table 1).

 

 

The use of diphenhydramine is common, but the number of controlled trials that support its efficacy are limited and many lack objective data. Several studies show evidence of sedative properties. One-week administration of diphenhydramine (50 mg) significantly decreased self-reported sleep latency and improved sleep depth and quality.16 Similar results were reported in psychiatric patients with insomnia following nightly administration of 12.5–50 mg of diphenhydramine for 2 weeks. Sleep quality, duration of sleep, and severity of insomnia symptoms significantly improved as measured by self reports.15 Interestingly, global improvements in sleep were significantly greater in those who had not received previous treatment for insomnia.15 This finding suggests drug tolerance, cross-drug tolerance, or that the efficacy of diphenhydramine is not as robust as other pharmamocologic treatments. Tolerance to the hypnotic effects of diphenhydramine was evident on both objective and subjective measures of sleepiness following 3–4 days of administration.17 Thus, only short-term use is recommended since physical tolerance, can develop.17,18

For several reasons, it is advised that those with chronic medical conditions should not take diphehydramine, and specific precautions should be considered in those with cardiovascular disease, hypertension, or lower respiratory disease. Diphenhydramine produces additive central nervous system effects when taken concomitantly with alcohol, hypnotics, anxiolytics, narcotic analgesics, and neuroleptic drugs. Similarly, significant interactions may occur if the drug is taken concomitantly with anticholinergic agents or tricyclic antidepressants.

 

Doxylamine

In 1978, the FDA approved doxylamine succinate as an active ingredient for OTC sleep aid use. Doxylamine succinate mediates its activity through the H1 receptor. Doxylamine has minimal effects on sleep onset due to its relatively long time to maximum plasma concentration. The time for sleep to be achieved is 45–60 minutes after oral administration. The peak plasma concentration is not reached until 90 minutes after administration. Using patient report outcomes, doxylamine (25 mg) for 1 week significantly decreased sleep latency.19 The authors of this article are unaware of any further published OTC efficacy studies for doxylamine. The elimination half-life is 10.1 hours. Thus, upon waking, plasma levels of doxylamine are present; consequently, residual daytime sedation is a documented side effect. Doxylamine is also potentially dangerous in accidental or intentional overdose. Rhabdomyolysis and secondary acute renal failure are rare but potentially serious complications, making early recognition and treatment essential.20 H1 antihistamines are not recommended for the elderly due to potential adverse effects and drug interactions. Doxylamine shares the same mechanism of action as diphenhydramine and the potential for tolerance to doxylamine’s sedative effects exists.

 

Supplements and Herbs

In the United States, usage of complementary and alternative medicines showed a secular upward trend from 33.8% to 42.1% for treatment of any health condition between 1990 and 1997. In comparison, treatment for insomnia rose from 20.4% in 1990 to 26.4% in 1997.21 Supplements and herbs are perceived as “natural” and, therefore, a safe alternative to prescription medications and some OTC products. The FDA does not rigorously test or regulate manufacturing of supplements and herbs. Currently, no FDA regulations specific to dietary supplements require a minimum standard for manufacturing of dietary supplements. Thus, the manufacturer is responsible for the strength, purity, composition, and safety of their products. According to FDA regulations, supplement manufacturers are forbidden to market their product as a treatment, prevention, or cure, for any medical disorder, including insomnia.

Supplements and herbs have reported side effects and inconsistent clinical findings, so the risk to benefit is questionable. Care should be used when taking these substances because they still cause physiologic changes in the body and can interact with other medications (Table 2).

 

 

 

Valerian

Valerian is a flowering plant that includes >200 species. The species Valeriana officinalis is most often used in the treatment of anxiety and insomnia. Valerian preparation methods vary with several different extraction methods used. The aqueous extraction method produces doses range from 270–900 mg and ethanolic valerian extraction doses range from 300–600 mg.22 Other valerian species (V. edulis and V. wallichii) have active ingredients that are minimally present in V. officinalis. The chemical ingredients in valerian products vary depending on the plant species and the extraction method. Valerian roots are prepared as teas and dried plant material and extracts are compounded into capsules or incorporated into tablets. A possible mechanism in which valerian causes sedation is by inhibition of the breakdown of γ-aminobutyric acid (GABA) or GABA-like metabolites.23

The sleep research evaluating the efficacy of valerian as a sleep aid has produced inconsistent results. Variations in study participants, study design, and methodology; valerian preparation; dose; and sleep assessment measures likely account for the mixed results for valerian.

Valerian 400 mg administered on three nonconsecutive nights produced a significant decrease in self-reported sleep latency, which was notable in people >40, men, and those who considered themselves poor or irregular sleepers. Poor or irregular sleepers and those who considered themselves as having long sleep latencies also reported significant improvements in sleep quality.24 Significant decreases in self-reported sleep latencies were also found in healthy subjects without major sleep disturbances following one valerian dose of either 450 or 900 mg. Only the 900 mg dose reduced wake time after sleep onset using self reports. The self ratings of sleep quality were not significantly different among treatments (0, 450, and 900 mg).

In an uncontrolled case study, insomniacs receiving mental health services took valerian for 14 days to supplement their psychotropic regimen. Doses of valerian started at 470 mg (one pill) on nights 1–3 and the insomniacs could increase their dose to a maximum of 1,410 mg (three pills) after week 1. Dose escalation occurred if lower doses proved to be insufficient. After 1 week of treatment, 11 of the 20 participants reported that valerian “moderately” improved their insomnia at the 940 mg dose (two pills). By week 2, all increased their dose to 1,410 mg, nine rated their insomnia “moderately to extremely” improved, and six rated their insomnia “extremely” improved.25 There was no discussion as to what aspect of their sleep disturbances was improved.

Chronic insomniacs were given valarian 450 mg for 1 week and were required to maintain sleep diaries. Valerian was not shown to be appreciably better than placebo adminstration in a series of randomized n-of-1 trials.26 Similarly, valerian (6.4 mg) for 28 days did not relieve insomnia or anxiety to a greater extent than placebo in an Internet-based study. Adverse events occurred with similar frequency between the treatment group and the placebo group except that significantly more reports of diarrhea (18% of 114) occurred in the valerian group compared to those receiving placebo (8%).27

Polysomnography (PSG), the concurrent recording of electroencephalograph (EEG), electromyogram, and electrooculogram, is the standard method of objectively assessing sleep. It is often combined with computer analyses of EEG frequency and power (ie, spectral analyses). PSGs and spectra analyses of sleep EEG showed no significant differences between a 900 mg valerian dose and placebo administration in healthy volunteers. No adverse events or side effects were reported.28 Results of objective assessments of sleep latency have varied. Actigraphy, recording movements of arms or legs, is a less labor-intensive and intrusive method of assessing sleep than PSG. Actigraphs, worn by eight mild insomniacs, showed decreases in sleep latencies following valerian 450 mg for 4 nonconsecutive nights. In contrast, 900 mg did not produce a further improvement in sleep latencies and the higher dose had significantly greater morning sleepiness associated with it.29 In a PSG study, no significant decrease in sleep latency was demonstrated following 8 consecutive days of valerian (405 mg on day 1 and 1,215 mg on days 2–8) in 14 elderly female insomniacs. On other sleep measures, this dosing produced selective effects on non-rapid eye movement (REM) sleep stages. Non-REM is characterized by slower brain activity, divided into sleep stages 1–4, and is not associated with dreaming. Relative to baseline, valerian decreased the percentage of stage 1 sleep on night 1 and further decreased it on night 8. No systematic change occurred in the placebo group. Slow wave sleep (SWS; sum of sleep stages 3 and 4) significantly increased from baseline to night 8. REM sleep (sleep stage characterized by active brain waves and dreams) was unaltered by valerian.30

Sixteen insomniacs given valerian 600 mg for 14 days showed significant decreases in SWS latency in comparison to placebo, and a significant increase in the percentage of SWS compared to baseline as measured by PSG. Other sleep parameters were not significantly altered. Only three independent side effects or adverse effects occurred following valerian administration, which included one episode of gastrointestinal complaints, migraine, and an accident associated with the PSG procedures. Subjective measures of sleep and other sleep parameters were not significantly altered.31 Overall, these double-blind data suggest that although valerian is safe it does not improve the symptoms of disturbed sleep.22 It would be interesting to pursue the question of the increase in slow-wave sleep, its clinical significance, and the degree to which this is mediated by GABA.

Valerian is frequently combined with other herbal extracts such as hops and lemon balm, each purportedly having their own sedative or tranquilizing effects. A valerian preparation (valerian 400 mg, hops 375 mg, and lemon balm 160 mg) was rated better than control following one night of administration. No side effects were reported with this preparation.32 In contrast, for 3 nonconsecutive nights a commercial preparation of valerian 120 mg and hops 60 mg produced no significant change in sleep latency or sleep quality on subjectively rated sleep measures in healthy normal volunteers. This valerian preparation resulted in significantly greater reports of “more sleepy than usual” responses in comparison to the placebo group.33 Similar results were reported in mild insomniacs administered a valerian (374 mg)-hops (83.8 mg) combination for 28 days. This dosing and duration failed to produce a significant effect in sleep parameters using sleep diaries and PSG.

 

St. John’s Wort

St. John’s wort (hypericum perforatum) is the medicinal herb used for a variety of ailments including depression, anxiety, and fatigue. The active components are thought to be hyperforin and hypericin, although different formulations vary in their level of constituents.34 Most clinical studies focus on the treatment of depression rather than insomnia. No published double-blind placebo controlled studies were found using St. John’s wort to ameliorate primary insomnia.

 

Kava

Kava (or kava kava) comes from the roots of the Polynesian plant Piper methysticum is indigenous to the South Pacific. Supplements containing kava are marketed to alleviate menopausal symptoms, anxiety, and insomnia. Liver damage may be a risk factor associated with kava, and the FDA issued an advisory to consumers of this important potential risk. A meta-analysis of kava in the treatment of anxiety reported adverse events such as stomach complaints, restlessness, tremor, headache and tiredness (Table 2).35

Stress-induced insomnia was ameliorated after 6 weeks of 120 mg of kava and further improved by 6 weeks of valerian (600 mg) as measured by sleep questionnaires. There was a 2-week wash-out period between both treatments and, importantly, sleep during the washout did not differ from baseline. Side effects of kava included, diarrhea, gastric disturbances, and dry mouth.36

A frequent symptom associated with anxiety disorder is sleep disturbances. Kava 300 mg for 28 days did not significantly relieve anxiety or insomnia symptoms using the Insomnia Severity Index and State-Trait Anxiety Inventory, respectively.27 In contrast, significant improvements relative to placebo in sleep quality and the recuperative effects of sleep as well as decreases in anxiety were demonstrated in patients with sleep disturbances associated with anxiety of non-psychotic origin following kava 200 mg (WS®1490) for 4 weeks.37 Sleep questionnaires such as the Hamilton Rating Scale for Anxiety, self-rating scales of well being, and the Clinical Global Impressions scale showed improvements in sleep and anxiety. No drug-related adverse events or changes in clinical or laboratory parameters were noted.

As is the case in many of these products, there are some non-controlled data suggesting efficacy. However, objective and/or other placebo controlled trials that further suggest efficacy for insomnia are limited. Further, the benefit has to balanced against the risk, and the potential of liver toxicity in the case of kava cannot be dismissed.

 

Neurohormones and Transmitter Precursors

Melatonin

The pineal gland produces the neurohormone melatonin (N-acetyl-5-methoxytryptamine). Synthesis and secretion occurs nocturnally by darkness and is inhibited by environmental light, which suggests that melatonin is involved in modulating circadian rhythm. Melatonin secretion starts at approximately 9:00pm and peaks between 2AM and 4AM.38 Melatonin supplements are commonly used to combat jet lag and sleep disturbances, to protect cells from free-radical damage, and for enhancement of immune function. The mechanism by which melatonin affects sleep, beyond its circadian signaling capability (phase shifting), is unknown, but it likely involves stimulation of melatonin receptors.8

The half-life of melatonin ranges from 0.54–2 hours; with doses ranging from 0.3–5.0 mg, melatonin is less likely to cause residual daytime drowsiness. Side effects reported in the literature included headache, odd taste in mouth, and poor sleep quality (Table 2).39 Melatonin supplements are relatively safe when used short term over days or weeks. However, the safety of melatonin over months has not been studied.

Riemann and colleagues40 showed significant decreases in nighttime melatonin concentrations in insomniacs, and others have shown delays in melatonin secretion. However, several double-blind, placebo-controlled studies have failed to show the effectiveness of supplemental melatonin in treating primary insomnia. Melatonin in doses that range from 0.3–5 mg showed no significant differences over placebo in sleep measures such as sleep efficiency; total sleep time; latency to sleep; number of nocturnal awakenings; average length of the non-REM-REM cycle; percent of stage 1, 2, delta sleep, and REM sleep; total minutes of each sleep stage; and in the latency to REM sleep. The lack of hypnotic activity was evident when measured by self reports or by PSG measures.39-43 MacFarlane and colleagues44 found a significant improvement in subjective assessments of sleep and daytime alertness in insomniacs given a much larger dose, 75 mg, in a single, crossover placebo-controlled study. It is important to recognize that this dose is dramatically higher than the physiologic doses of melatonin (0.5–1 mg) and hence the safety of this dose requires study.

Melatonin appears to ameliorate secondary and age-related insomnia. Increased sleep efficiency was noted in both populations after administration of melatonin.43 Improved sleep efficiency occurred in an elderly population with doses of 0.1–3.0 mg which elevated plasma levels within normal range.45,46 Overall, the present data would suggest that melatonin is not an effective treatment for the management of primary insomnia. However, it has clear phase shifting properties and hence it may have efficacy in elderly insomniacs with decreases in endogenous melatonin and insomnia associated with sleep circadian rhythm disorder.

 

Tryptophan

L-tryptophan is an essential amino acid that comes from food. Once absorbed, it can be converted to serotonin and melatonin. In the brain, serotonin is synthesized from tryptophan, which is the major metabolic route.47 Low levels of serotonin have been reported to be associated with depression, anxiety, and insomnia, and L-tryptophan supplements have been used to treat these disorders despite the absence of convincing data of its benefit.

The tryptophan-depletion model has been used to determine the association between tryptophan and sleep. Tryptophan depletion, following an ingestion of a tryptophan-free amino acid drink, significantly increased stage 1 sleep and decreased stage 2 sleep. However, indices of sleep induction and sleep efficiency were not affected. Indices of REM density (the frequency of eye movements per unit of time during REM sleep) were significantly increased, whereas REM latency remained unaltered.40

L-tryptophan supplements appeared to be effective hypnotic agents in chronic insomniacs with sleep maintenance disturbances that were characterized by 3–6 discrete awakenings during the night. Insomniacs self-reported 100% improvement following 1 g nightly administration for 1 week.48 No consistent significant effects of L-tryptophan on sleep parameters determined by PSG were found in doses <1 g. Significant decreases in sleep latencies were observed following 1–3 g of tryptophan but inconsistent findings were noted on total sleep time, SWS, and REM sleep.49

In a study by Schneider-Helmert and Spinweber,50 chronic insomniacs characterized by both sleep onset and sleep maintenance problems showed therapeutic improvement occurring over time with repeated administration of low doses of L-tryptophan. The hypnotic effects appeared late in the treatment period or, as shown in some studies, even after discontinuation of treatment. L-tryptophan is also effective in reducing sleep onset time on the first night of administration in doses ranging from 1–15 g in young situational insomniacs.50

The treatment of depression with the selective serotonin reuptake inhibitor fluoxetine can exacerbate insomnia. The hypnotic effects of tryptophan in conjunction with an antidepressant were used to potentiate an improvement in insomnia. Tryptophan (2–4 g) and fluoxetine (20 mg) administrated for 8 weeks significantly decreased depression scores and had a SWS protective effect. A significant decrease in SWS was noted in the fluoxetine placebo group but not in the fluoxetine-tryptophan group.51

L-tryptophan administration has not been linked with impairments in visuomotor, cognitive, or memory performance.50 Some side effects of tryptophan can include drowsiness, tiredness/fatigue, nausea, loss of appetite, dizziness, headache, and dry mouth (Table 2).

 

Alcohol

In 2001, approximately 30% of chronic insomniacs in the general population reported using alcohol to induce sleep and 67% of those reported that alcohol was effective.52 However, in PSG studies insomniacs who used alcohol had significantly impaired measures of sleep continuity and had more severe alcohol dependence and depression.53 Males and those never married or those separated or divorced/widowed are approximately 1.5 times more likely to use alcohol as a sleep aid than females or those who are married.10

Alcohol consumed at bedtime may decrease the time required to fall asleep and increase SWS. Because of alcohol’s sedating effect, many people with insomnia consume alcohol to promote sleep. However, alcohol consumed within an hour of bedtime appears to disrupt the second half of the sleep period.54,55 Alcohol affects the proportions of the various sleep stages with dose-dependent suppression of REM sleep. Higher doses of alcohol increased nocturnal awakenings and/or lighter stages of sleep (stage 1) during the second half of the night. The second-half disruption of sleep continuity is referred to as a “rebound effect,” occurring as alcohol is metabolized or eliminated from the body.54

Overall, the use of alcohol as well as the discontinuation of alcohol is associated with disturbances of sleep. This is most clearly seen in alcoholics who exhibit profoundly disturbed sleep during active drinking and after months of abstinence. Finally, the relation of alcohol consumption to improve sleep to the evolution of chronic alcoholism warrants study.

 

Conclusion

Much of the data on the efficacy and safety of OTC sleep aids is inconclusive and is associated with problems such as too few participants in the studies, little demographic and diagnostic information regarding study participants, inconsistency in demographic and diagnostic information among studies to allow comparisons, lack of placebo-control groups, subjective reports with a lack of objective data, and short-term treatment with study medication which provides little indication about long-term usage.56

Treatment of insomnia with antihistamine-containing OTC sleep aids may help occasional mild insomnia. Prolonged use of some if not all antihistaminic drugs may result in tolerance and/or dependence and produce daytime sleepiness. The data on other non-prescription sleep aids is too limited or inconsistent in results to consider their use. While alcohol may have initial sedative effects, it is associated with rapid tolerance development and dose escalation (Table 2). PP

 

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Needs Assessment:
Psychotic depression is a more common illness than previously believed. It differs from other psychotic disorders in the type and manifestation of psychotic symptoms. The purpose of this article is to synthesize the available literature on the phenomenology and treatment of psychotic major depression.


Learning Objectives:

• Understand the unique symptoms of psychotic major depression.
• Learn the limitation of clinical trials in the treatment of psychotic depression.
• Learn about investigational treatments for psychotic depression.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

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 posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. DeBattista is associate professor of Psychiatry and Behavioral Sciences, director of Depression Research and Psychopharmacology Clinics, and director of Medical Student Education in Psychiatry; and Dr. Lembke is senior research associate and clinical instructor, both at Stanford University School of Medicine in California.

Disclosure: Dr. DeBattista is on the speaker’s bureaus and/or consultant to Bristol-Myers Squibb, Cephalon, Corcept, Cyberonics, Eli Lilly, Forest, Pfizer, and Wyeth; receives grant support from AstraZeneca, Boehringer-Ingelheim, Cephalon, Cyberonics, Eli Lilly, Forest, Neuronetics, Novartis, Pfizer, and Wyeth; and is a stockholder of Corcept Therapeutics (Corcept is the developer of mifepristone for use in psychotic depression). Dr. Lembke receives research support from the National Institutes of Health.

Please direct all correspondence to: Charles DeBattista, MD, Stanford University School of Medicine, 401 Quarry Rd, Stanford, CA 94305; Tel: 650-723-8324; Fax: 650-723-8331; E-mail: debattista@stanford.edu.

 


 

 

Abstract

Psychotic major depression appears to be a unique subtype of depression with its own phenomenology and treatment response. However, the symptom profile of psychotic depression is not well described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the psychotic symptom features of psychotic depression may be distinct. While treatments such as electroconvulsive therapy and the combination of antidepressants and antipsychotics appear effective, data that supports the efficacy of these treatments have substantial limitations. The symptoms and treatment of psychotic major depression are critically reviewed in this article.

 

Introduction

Psychotic major depression (PMD) is classified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),1 as a severe form of depression characterized by meeting the full criteria for major depressive disorder (MDD) plus the presence of delusions or hallucinations. Growing evidence suggests that PMD is more common than once believed. It is estimated that at least 14% to 20% of depressive episodes have psychotic features.2,3 Psychotic depression may represent a unique subtype of MDD with a distinct phenomenology and treatment response.4 Psychotic features are not necessarily the only symptoms that distinguish PMD from non-psychotic major depression (NPMD) For example, cognitive deficits may also distinguish PMD form NPMD.5 Furthermore, the psychotic features of PMD may not completely parallel the kinds of symptoms seen in other psychotic disorders such schizophrenia. In fact, specialized scales have been proposed for assessing psychosis in PMD.6,7 Given that the symptoms of PMD differ from other types of depression, it is not surprising that PMD may require different treatment than NPMD. However, relative to NPMD, very few trials have ever been completed in the treatment of PMD, and those trials have significant limitations.

 

Phenomenology

The DSM-IV describes the psychotic features of PMD as predominately delusions that are mood congruent, such as delusions of guilt, delusions of poverty, somatic delusions, or nihilistic delusions.1 Furthermore, the DSM-IV suggests that mood incongruent delusions such as persecutory delusions (without a depressive theme) are less common as are hallucinations. When present, hallucinations are described as transient, auditory, and likely to be mood congruent.

The rate of paranoid delusions in PMD samples has varied considerably. Lykourous and colleagues8 found that paranoid delusions were the most common, with nine of eleven patients presenting with delusions of impending disaster, guilt, and somatization. Likewise, a subsequent study by Lykourous and colleagues9 found that all 22 PMD patients had delusions, with ideas of reference and persecution being the most common. Breslau and Meltzer10 found that delusions of reference occurred in 23% of the PMD, 62% of the schizoaffective, and 32% of the bipolar patients. Persecutory delusions occurred in 38% of the PMD, 56% of the schizoaffective, and 53% of the bipolar patients. Other types of depressive delusions occurred in 49% of the PMD, 41% of the schizoaffective, and 51% of the bipolar patients.

The delusions in PMD may be more subtle than those seen in schizophrenia. Many patients with depressive disorders have ruminations that may not quite meet the threshold of delusion. However, these “near delusions” tend to predict poor response to antidepressant monotherapy.11

Hallucinations have been characterized as being less common in PMD than in schizophrenia but may still be quite common. For example, Breslau and Meltzer10 found that visual hallucinations were somewhat more common in psychotically depressed unipolar than bipolar or schizoaffective patients, occurring in 31% of unipolar patients. In contrast, auditory hallucinations were much less common in unipolar psychotic patients (28%) than in schizoaffective (62%) patients. Lykourous and colleagues8 found that 50% of patients with PMD had hallucinations, but that these only occurred in patients who also had delusions and with whom the content of the hallucinations was consistent with those of the delusions. In general, the hallucinations in PMD have been thought to be less severe than those found in schizophrenia.

Thought disorder has historically been most associated with schizophrenia spectrum illnesses. However, disorders of thought may be even more common in mood disorders such as bipolar disorder. The rate of thought disorder in PMD has been considered low. For example, Breslau and Meltzer10 found that only 10% of patients with unipolar depression with psychotic depression had evidence of a thought disorder, versus 40% of bipolar and 50% of schizoaffective patients. Wilcox and colleagues12 found that thought disorders were also predictive of a greater relapse rate over 7 years than other psychotic symptoms in PMD.

While a formal thought disorder may be less common in unipolar patients with psychotic depression, cognitive deficits in general appear quite common. Patients with psychotic depression have more difficulty processing, manipulating, and encoding new information5 than do NMPD patients. Other types of deficits seen in psychotic versus nonpsychotic depressed patients include difficulty with attention, response inhibition, and verbal declarative memory.13 In fact, the cognitive deficits seen in PMD appear to resemble those seen in schizophrenia more than those in patients with non-psychotic depression.14

Treatment

Antidepressant Monotherapy

Given the unique phenomenology of psychotic depression, it is not surprising that the standard treatment for MDD may not be as consistently useful in PMD. For example, monotherapy with antidepressants is thought to be less useful in PMD. Many of the treatment studies of psychotic depression have employed tricylcic antidepressants (TCAs). While TCA monotherapy has been an established treatment for MDD, studies of amitriptyline, imipramine, and other TCAs in the treatment of PMD have shown poor response. For example, Avery and Lubrano15 considered the DeCarolis study, where 437 patients with and without psychotic features were prospectively treated with imipramine. Only 40% of PMD patients responded to imipramine treatment versus 60% of the non-psychotic depressed patients. Similarly, an analysis of 12 studies by Chan and colleagues16 found that only 35% of PMD patients responded to TCAs versus 67% of NPMD patients. In the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression, 32% of patients with psychotic features responded to amytryptyline or imipramine compared with 37% of nonpsychotic severely depressed patients and 67% of patients with moderate nonpsychotic depression.17 However, the differences between PMD and severely depressed NPMD patients was not significant. Other TCA studies also have not necessarily shown a difference between response to TCAs in PMD versus NPMD patients.18

More recent monotherapy studies have reported efficacy with SSRIs in the treatment of PMD. For example, Gatti and colleagues19 reported that 84% of 57 patients treated for 6 weeks with fluvoxamine responded to treatment. In subsequent PMD trials, fluvoxamine was found to be at least as efficacious as venlafaxine in the treatment20 and even more rapidly efficacious in combination with pindolol.21 Long-term treatment with fluvoxamine was also reported to prevent relapse in PMD patients treated for 18 months.22 The pharmacologic profile of fluvoxamine differs from other SSRIs in that it has substantial effects on the Sigma receptor which is also thought to play a role in the pathophysiology of psychosis.23

Other SSRIs have also been proposed to be effective in the monotherapy of PMD. Zanardi and colleagues24 found that sertraline was more effective than paroxetine in the treatment of 46 patients hospitalized with PMD. In contrast, Simpson and colleagues25 found that sertraline was much less effective in PMD patients than NPMD patients treated with up to 200 mg/day. Thus, the utility of sertraline monotherapy in the treatment of PMD is unclear. As with the TCA studies, methodologic problems limit conclusions that can be surmised from the SSRI studies. Among the limitations of the SSRI studies in PMD include the lack of a placebo group, the lack of a comparison with response NPMD patients, and possibly differences in the criteria for defining PMD.

Amoxapine, a tetracyclic antidepressant related to loxapine and rarely used currently, was also reported to be effective as a monotherapy in the treatment of PMD. Anton and Burch26 compared amoxapine to the combination of amitriptyline and perphenazine in the treatment of PMD. After 4 weeks of treatment, >80% of patients in both the combination group and the amoxapine group exhibited a moderate or marked response without significant differences between treatments. However, the combination treatment was more poorly tolerated. While the Anton and Burch26 study was a double-blind randomized study with a placebo wash out, there was no placebo comparison group in the study.

Thus, there is some evidence that monotherapy with amoxapine and perhaps SSRIs may be effective in the treatment of PMD, and that TCA monotherapy has generally not been effective. However, the methodologic problems of the monotherapy trials are many and it is uncertain whether monotherapy is a reasonable treatment or whether combination treatment with an antipsychotic is generally necessary to achieve response.

 

Combination Treatment: Antidepressants and Antipsychotics

Numerous studies that found monotherapy with TCAs ineffective in the treatment of PMD found that the addition of a standard antipsychotic significantly improved efficacy. For example, Minter and Mandel,27 in a retrospective chart review of 54 PMD patients, found patients generally did not respond to monotherapy with a TCA but became responders when an antipsychotic was added. Similarly, Charney and Nelson,28 in a retrospective review of 120 PMD and NPMD patients, found that the PMD patients responded poorly to TCAs but well to the combination of TCAs and typical antipsychotics.

In one of the few prospective randomized trials to compare combination treatment with monotherapy, Spiker and colleagues29 compared the efficacy of amitriptyline alone, perphenazine alone, and the combination of amitriptyline and perphenazine in PMD patients. The response rate to treatment after 35 days was as follows. Amitriptyline alone was 41%, perphenazine alone was 19%, and combination of amitriptyline and perphenazine was 78%. Patients who failed to respond to monotherapy tended to respond when the second agent was added.

The combination of fluoxetine and olanzapine has also been evaluated in larger and more rigorous studies than previous combination trials. Patients who met DSM-IV criteria for PMD were randomized to either the combination of olanzapine and fluoxetine, olanzapine alone, or placebo.30 Two studies (study 1 with 124 patients, study 2 with 125 patients) were conducted in parallel at 27 sites under the same protocol. In study 1, the combination treatment was superior to placebo and olanzapine on the primary outcome, which was defined as change from baseline on the Hamilton Rating Scale for Depression (HAM-D). In addition, the categorical response rate (50% improvement on the HAM-D) was significantly higher in the combination treatment in study 1 (63%) compared to olanzapine alone (35%) or placebo (28%). There were no differences between groups in the second trial on the primary outcome measure, response rates, or remission rates. Furthermore, the pooled data of trials 1 and 2 did not apparently show a benefit of combination treatment over placebo or olanzapine. Both studies had much higher placebo response rates than have been typically reported for PMD. The long hospitalization allowed in the study may have contributed to this high placebo response rate. In addition, the lack of a fluoxetine alone arm also prevented a comparison with antidepressant monotherapy.

 

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) has been reported to be among the most effective treatments for PMD. The American Psychiatric Association Guidelines for the treatment of depression endorse ECT as a first-line treatment only for PMD.31 As with other treatments for PMD, there are few prospective randomized or sham-controlled trials. Retrospective reviews and open trials have generally shown ECT to be highly effective in the treatment of PMD.27,28,32-35 The DeCarolis study, as noted by Avery and Lubrano,15 found that while only 40% of PMD patients responded to TCA monotherapy, 83% of these nonresponders subsequently responded to ECT. While a large prospective trial, the DeCarolis study is an older trial without a control group or clear entry or response criteria.

There are few sham-controlled studies that specifically include PMD patients. In the Northwick Park Electroconvulsive therapy trial, both delusional and nondelusional depressed patients were evaluated.36 Seventy patients who met endogenous depression criteria were randomized to a series of eight ECT treatments or eight sham treatments. While the treating psychiatrists tended to consider the active ECT patients to be better responders than the sham treated patients, the differences between groups were small and there were no differences between groups at 1 and 6 months after treatment. Delusional patients were not separately evaluated in the initial analysis. However, when the results of the Northwick Park ECT trial were combined with results of the subsequent Liecester ECT trial, patients with delusional depression and/or psychomotor retardation appeared to have more benefit than sham-treated patients at 4 weeks.37 Patients without delusions or psychomotor retardation did not show a difference between active ECT treatment and sham treatment. In addition, there were no differences between the active and sham groups at 6 months. The conclusion in both sham-controlled trials was that ECT did not appear effective because there were no sustained benefits. These randomized trials have been criticized as using an ECT stimulus dose that might be considered ineffective currently,38 and as not providing a standardized treatment option after 4 weeks of twice weekly ECT. It has been more recently established that most patients can be expected to relapse within 6 months of successful ECT without effective follow-up treatment.39 Thus, the conclusion that ECT was ineffective because no difference could be observed 6 months after the ECT was discontinued appears invalid in retrospect.

More recent ECT trials comparing response in PMD compared to NPMD patients have suggested that there may be a more favorable response to ECT in PMD patients. Petrides and colleagues40 prospectively compared the efficacy of ECT in 176 patients with NPMD and 77 patients with PMD. Approximately 95% of PMD patients experienced a full remission with acute ECT compared to 83% of patients with NPMD on the HAM-D. Remission also occurred earlier in the PMD patients. Birkenhager and colleagues41 found a 92% response rate (defined as 50% improvement on the HAM-D) in PMD patients compared with only a 55% response rate to ECT in NPMD patients. PMD patients who respond to ECT also may be somewhat less likely to relapse than NPMD patients who respond to ECT. Birkenhager and colleagues42 prospectively followed 29 PMD and 30 NPMD patients who responded to ECT for 1 year. Only 15% of PMD patients relapsed at 12 months compared to 58% of NPMD patients. Since relapse to ECT may be related to factors other than psychosis (eg, number of previous episodes, number of failed previous medication trials),39 it is uncertain in this study whether the PMD and NPMD groups were comparable. Other trials have not found an advantage of ECT treatment in PMD patients compared to NPMD patients, and some trials have suggested a poorer response to ECT in PMD patients.43 Numerous factors might lead to disparate results in the evaluation of ECT for PMD. For example, ECT variables including stimulus dose, lead placement, frequency and number of treatments, and seizure duration tend to differ from trial to trial. In addition, assessment scales and inclusion criteria are also not uniform in ECT studies.

Despite the limitations of the ECT data, there has been a consistent theme in the literature over the past 40 years that suggests that ECT is an effective acute treatment for PMD with reported response and remission rates that are generally higher than those reported in pharmacotherapy trials. However, there are a lack of randomized, head to head comparison trials between ECT and pharmacotherapy in PMD patients, and such trials would be difficult to design and control given the obvious disparities between treatments.

 

Experimental Treatments

Among the treatments under investigation for PMD include the use of the glucocorticoid receptor antagonist mifepristone and transcranial magnetic stimulation (TMS). The glucocortiod/progesterone receptor antagonist mifepristone has been explored in the treatment of PMD with the rationale that some symptoms of PMD may be driven by abnormalities in the hypothalamic-pituitary-adrenal axis.44 Early open and controlled studies by the authors of this article have suggested that there might be benefits of mifepristone in the treatment of the psychotic symptoms of PMD.45,46 However, the most recent controlled studies of mifepristone failed to replicate these findings. Among the methodologic limitations of the mifepristone trials might include the representativeness of the patient sample, the adequacy of the endpoints, the high placebo response rates, and whether the optimal dose and duration of mifepristone treatment was employed. A summary of the mifepristone studies completed to date in the treatment of PMD can be found elsewhere.47 Additional controlled studies of mifepristone in the treatment of PMD are currently underway.

Another experimental treatment that has been examined in PMD is TMS, which uses a focused electromagnetic field to stimulate very specific areas of the cortex.48 Numerous studies have suggested efficacy for TMS, including a recently completed multi-center American trial of TMS in treatment-resistant depression.49 However, TMS, while more benign than ECT, appears to be substantially less effective than the latter.50-52 In addition, psychotic features of depression appear to predict poorer response to TMS.48 Thus, most recent studies of TMS exclude patients with PMD. It is possible, however, that different stimulation parameters might improve the efficacy of TMS of both PMD and NPMD.

 

Conclusion   

PMD remains a relatively poorly understood illness. The unique symptom profile of PMD is consistent with the finding that standard treatments for NPMD are often not as effective in the treatment of PMD. The increased prevalence of delusions, hallucinations, and more severe cognitive symptoms in PMD might require different strategies for effective treatment. The current standard of care for PMD is either combination treatment with an antidepressant plus an antipsychotic, or ECT. However, this standard is based on relatively limited data. While anecdotal experience tends to support the efficacy of combination treatment and ECT in PMD, there is a paucity of randomized controlled data evaluating these strategies. Furthermore, the few randomized controlled trials have not necessarily supported these strategies as the optimal treatments.
Trends in the treatment data suggest that TCAs alone are not effective in the treatment of PMD. It is conceivable that the anti-muscarinic effects of TCAs such as amitriptyline might exacerbate some of the more severe cognitive deficits in PMD.53 As suggested earlier, the unique pharmacology of some SSRIs, such as the effects of fluvoxamine on the sigma receptor, might be of specific benefit in PMD patients.23 The role of investigational treatments including glucocorticoid antagonists and TMS await further investigation. Given the substantial side-effect burden that antipsychotics may produce, further study is needed to evaluate whether combination treatment, especially with newer atypical antipsychotics, is the optimal pharmacotherapy.

Future treatment studies in PMD are hampered by the lack of adequate measures to assess outcome. It is not at all clear that the HAM-D, which has been used in most PMD studies, is the ideal scale for evaluating improvement in PMD patients. The HAM-D does not capture the unique phenomenology of PMD. Likewise, most scales employed to evaluate psychosis in PMD, such as the Brief Psychiatric Rating Scale, were designed to evaluate symptoms in schizophrenia. The psychotic symptoms in PMD do not necessarily parallel those in schizophrenia. Until better measures are developed and randomized comparison trials are completed with newer agents, the optimal treatment for PMD in most patients cannot be established with confidence. In clinical practice, most clinicians appear to be more likely to treat PMD with an antidepressant alone and seem hesitant to add an antipsychotic.54 The available data would at least suggest that patients who do not respond initially to an antidepressant alone should be treated with the combination of an antidepressant and an antipsychotic or ECT. PP

 

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FDA Approves Aripiprazole for Acute Treatment of Manic and Mixed Episodes in Pediatric Patients

The United States Food and Drug Administration approved aripiprazole (Abilify, Bristol-Myers Squibb, Otsuka America Pharmaceuticals) for the acute treatment of manic and mixed episodes affiliated with bipolar I disorder with or without psychotic characteristics in adolescents between 10–17 years of age.

Approval was based on results from a double-blind, placebo controlled study involving 296 pediatric bipolar patients enrolled at 54 US centers and evaluated over a 4-week period using the Young-Mania Rating Scale (Y-MRS) total score. Aripiprazole was initially administered at 2 mg/day. Patients who scored ≥20 on the Y-MRS were randomly assigned to aripiprazole doses of either 10 mg/day (n=98) or 30 mg/day (n=99). By week 4, both aripiprazole doses exhibited statistically significant improvement (P<.001) in bipolar symptoms when compared to placebo as measured by the mean change in the Y-MRS Total Score from baseline to week 4.

The most common adverse reactions to treatment were somnolence, extrapyramidal disorder, fatigue, nausea, akithisia, blurred vision, salivary hypersecretion, slight weight gain (ie, ≥7% change from baseline), and dizziness. The efficacy of aripiprazole for the maintenance treatment of bipolar I disorder in pediatric patients was not evaluated.

The recommended oral aripiprazole dose for the pediatric bipolar population 10–17 years of age is 10 mg/day.

For more information, please consult the medication’s full prescribing information (www.abilify.com). –ML

 

FDA Approves Fluvoxamine Extended Release for Treatment of SAD and OCD in Adults

The United States Food and Drug Administration approved once daily fluvoxamine maleate (Luvox CR, Jazz Pharmaceuticals) extended-release (ER) capsules for the treatment of social anxiety disorder (SAD) and obsessive-compulsive disorder (OCD) in adults. Fluvoxamine in the form of immediate-release tablets was previously approved in late 2007 for the treatment of obsessions and compulsions in patients with OCD.

Effectiveness for fluvoxamine ER capsules for the treatment of SAD and OCD was demonstrated in three 12-week, multicenter, placebo-controlled studies of adult outpatients. In each study, patients were titrated in 50 mg increments over the first 6 weeks on the basis of response and tolerance from a dose of 100 mg/day to that of 100–300 mg once daily. In the two SAD studies and one OCD study, the capsules demonstrated statistically significant superiority over placebo at the 12-week primary endpoint as assessed by the Liebowitz Social Anxiety Scale total score and Yale-Brown Obsessive Compulsive Scale, respectively.

Fluvoxamine ER capsules will be available in 100 mg and 150 mg dose strengths. The most common adverse reactions were nausea, somnolence, asthenia, diarrhea, anorexia, tremor, and sweating.

For more information, please consult the medication’s full prescribing information. (www.JazzPharmaceuticals.com.) –DC

 

Activity Rhythms May Serve as Bipolar Disorder Indicators in Various Illness States

Patients with bipolar disorder often exhibit physiologic or behavioral symptoms such as increased or decreased activity or amount of sleep, in addition to the manic symptoms like euphoric mood and depressive symptoms that occur during the course of the disorder. However, as most of these physiologic indicators are present only during acute illness, their use during other phases of the disorder or when a patient experiences positive treatment response is limited. In addition, a state-independent physiologic indicator would allow clinicians to anticipate possible mood changes in patients throughout different phases of the disorder. 

Paola Salvatore, MD, of the Schizophrenia and Bipolar Disorder Program and International Consortium for Bipolar Disorder Research at the McLean Division of Massachusetts General Hospital in Belmont, and colleagues, investigated activity rhythms among 36 patients with bipolar disorder in acute states as well as clinical recovery and rhythms among 32 participants without bipolar disorder. Typically, activity rhythms are highly abnormal in patients with bipolar disorder. Salvatore and colleagues hypothesized that such abnormalities may persist in other bipolar states, making activity rhythms a state-independent indicator of bipolar disorder.

The authors evaluated patients with bipolar disorder during acute mania or mixed states as well as during full and sustained clinical recovery, and healthy participants using wrist-worn piezoelectric actigraphic monitoring for 72 hours. Piezoelectric actigraphic monitoring measured changes in motility levels and circadian activity rhythms during the 24-hour day and night cycle.

Salvatore and colleagues found that there were significant differences in motility patterns between patients with bipolar disorder in acute phases and healthy participants. Patients with bipolar disorder showed a lower total proportion of activity in the daytime, decreased amplitude of circadian activity, increased amounts of daytime sleeping, and an earlier peak of daily motor activity rhythm (acrophase) as compared to health participants. Patients in sustained recovery also differed from those in acute phases of bipolar disorder.

Recovered patients showed lower daily activity average, increased motility amplitude, higher percentage of nocturnal sleep, and reduced amounts of daytime sleep when compared to patients with acute illness. When compared to healthy participants, euthymic bipolar disorder patients showed 8% less daytime activity, 18% more total sleep with 11% more nocturnal sleep, and an acrophase >1 hour earlier. Results from euthymic patients remained consistent when researchers controlled for ratings of mania as measured by the Young Mania Rating Scale, depression as measured by the Hamilton Rating Scale for Depression, subjective distress, as well as the type and dosage of psychotropic medication currently being taken.

The authors concluded that the presence of an earlier acrophase for bipolar disorder patients in acute illness and those experiencing treatment response may demonstrate a stable psychobiologic trait of bipolar disorder that can act as an indicator of illness in various states. The authors added that if such an indicator is verified, it may be useful in supporting clinical diagnosis. (Bipolar Disord. 2008;10(2):256-265.) —CP

 

Mild Cognitive Impairment Disrupts Everyday Life and Relationships

Memory loss, contrary to common belief, is not a normal part of the aging process. A study by Rosemary Blieszner, PhD, of Virginia Polytechnic Institute and State University, and colleagues, suggests that memory loss associated with mild cognitive impairment (MCI) interferes with the everyday lives of family members and their relationships with individuals suffering from MCI.

The 3-year study consists of three parts. The first part involved two interviews with 99 economically diverse, 3-member families. The member experiencing MCI was ≥60 years of age; the second member was a non-professional caretaker (eg, spouse); and the third was a non-professional, secondary care partner such as an adult child, friend, or sibling. The first round of interviews identified three types of responses from people with MCI (ie, acceptance and desire to manage their condition, uncertainty and lack of recognition of memory changes, and denial and rejection of their condition) while the second interview analyzed how families coped with the affected individual’s condition. With the addition of 40 ethnically and racially diverse families, the second phase of the study focused on how family members dealt with the transition from MCI to Alzheimer’s disease in the affected member. The third part, which is currently underway, continues to follow and interview the families. Results thus far have found that the family members of elders with MCI had to alter their daily activities and responsibilities, contributing to distress that affects the relationships between them. This reflects patients and families’ need for ongoing information and support targeted to the patient’s particular level of incapacity and symptoms.

“[Families and patients with MCI] do not find information and support groups for Alzheimer’s disease and other dementias to be relevant or useful,” Dr. Blieszner said. “Many do not have good information about what changes are occurring in the brain and do not understand the sources of the problems they are experiencing.”

That the findings are not based on a national sample is a significant limitation, as they are from three memory clinics located in one state. However, the availability of data from the patient and two other family members in addition to interviews repeated three times over 3 years provide multi-perspective results about changes over time that are otherwise not available for MCI.

Funding for this research was provided by the Alzheimer’s Association. (Family Relations. 2007;56(2):196-209.) –ML

 

Depression Improvement and Five Secondary Outcomes

According to a recent study, patients receiving selective serotonin reuptake inhibitor (SSRI) treatment for depression may see a shorter time to alleviation of depressive symptoms than for some secondary symptoms of depression, such as hopelessness or lingering somatic symptoms.The study tracked the improvement of secondary deficits associated with depression and then compared those outcomes with the outcome of the actual depressive symptoms.

James E. Aikens, PhD, at the University of Michigan in Ann Arbor, and colleagues, noted that secondary outcomes tend to worsen after depression onset and improve with its remission. Secondary outcomes have been assumed to not only depend upon improvement in depressive symptoms, but to also follow identical trajectories of change. Accordingly, Aikens and colleagues tested this convention based on two alternative hypotheses: first, that secondary outcomes could respond independently of depressive symptoms, or secondly, that secondary outcomes could respond somewhat independently of depressive symptoms.

The data for this study are from A Randomized Trial Investigating SSRI Treatment (ARTIST). The purpose of ARTIST was to evaluate clinical response to SSRIs in a primary care environment with as little research interference as possible. The two most significant ways in which ARTIST study protocol differed from primary care were randomization to one of three initial SSRIs and participation in telephone-based outcome reports during follow up.

The main outcome measure for depressive symptoms was the Symptom Checklist–20 (SCL-20). Each of the remaining five secondary outcomes—positive well-being, social functioning, hopefulness, physical symptoms, and work functioning—were assessed with separate, individual scales.

Seventy-nine percent of the baseline study population (n=573) were women (mean age=46.2 years) and 73% had a diagnosis of major depressive disorder (MDD). An average of 191 patients were randomized to one SSRI group each, including paroxetine (189), fluoxetine (193), and sertraline (191) groups. At study outset, 74% of patients met criteria for MDD, which decreased to 26% of patients by month 9. The mean SCL-20 symptom severity measure decreased as well from 1.66 to 0.78. There was no significant difference between the three SSRIs. Positive well being, one of the five secondary outcomes, and depressive symptoms followed a nearly identical outcome trajectory, improving along the same timeline.

The most significant finding, according to the authors, was that improvement in somatic complaints plateaued earlier than improvement in depressive symptoms. That is, improvement in overall somatic complaints occurred mainly during the first month of therapy, whereas depressive symptoms continued to improve through month 9 (1.2±1.0). Moderate effects were also noted in social functioning (0.9±1.1), work functioning (0.6±0.8), hopefulness (0.7±1.0), and somatic complaints (0.6±1.1).

According to Dr. Aikens, such rapid leveling of the improvement in somatic complaints was rather unexpected.

“I think we have suspected for quite some time that hopelessness cognitions may respond slower to treatment than mood symptoms,” he said. “But to see medical complaints reduce so sharply, especially at a time when initial medication side effects would be peaking—that was surprising.”

Hopelessness is sometimes associated with suicidality, but Dr. Aikens cautions that “the linkage between [the] results and suicidality can only be inferred indirectly” because the trial was not designed to assess suicidal ideation or related constructs. Instead, it was suggested that the results of this trial could guide clinicians when monitoring depressive patients who exhibit pronounced traits of hopelessness or physical pain. In addition, future investigations may determine why the improvement of somatic complaints and depressive symptoms diverge soon after treatment onset.

Funding for this research was provided by Eli Lilly. (Gen Hosp Psychiatry. 2008;30(1):26–31.) –LS

 

Increased Risk for Postpartum Depression in Low-income and African-American Women

Postpartum depression (PPD) is prevalent in approximately 10% to 20% of women in the United States. Studies by Lisa Segre, PhD, of the University of Iowa, and colleagues, suggest that women of low income are at a higher risk of experiencing PPD than their more affluent counterparts and African-American women are more likely to suffer from PPD than both Latino and white women.

The first study focused on the income, education, marital status, number of children, and occupational prestige of 4,332 women who gave birth 4.6 months prior to the research evaluation. They completed sociodemographic interviews and the Inventory to Diagnose Depression, which is a scale used to identify a major depressive episode according to standards in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision. Data revealed that 40% of the women who were suffering from PPD had a low household income of <$20,000. These results indicate that social status is a significant predictor of PPD, with income as the strongest predictor.

The second study examined race and ethnicity as a factor for PPD. The Iowa Barriers to Prenatal Care Project Survey asked 26,877 English-speaking women with newborns whether they felt excessively miserable over the 2 weeks after they gave birth. Data from the survey revealed that 15.7% of the women exhibited a single depressive item, with African-American women as the most likely candidates to report a depressive mood compared to white women. Hispanic women were least likely to report a depressive mood compared to both African-American and white women.

Both studies emphasize the need for early PPD identification programs and strong social support for women with newborns. (Social Psychiatry and Psychiatric Epidemiology. 2007;42(4):316-321; Journal of Reproductive and Infant Psychology. 2006;24(2):99-106.) –ML

Dispatches is written by Dena Croog, Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.

 

Dr. Ghanizadeh is assistant professor of Child and Adolescent Psychiatry and director of the Research Center for Psychiatry and Behavioral Sciences and Dr. Kianpoor is assistant professor of psychiatry, both at Shiraz University of Medical Sciences at Hafez Hospital in Iran.

Disclosures: Drs. Ghanizadeh and Kianpoor report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Ahmad Ghanizadeh, MD, Assistant Professor of Child and Adolescent Psychiatry, Shiraz University of Medical Sciences, Hafez Hospital, Shiraz, Iran; Tel: +98-711-627-93-19; Fax: +98-711-627-93-19; E-mail: ghanizad@sina.tums.ac.ir.


 

Focus Points

• There are several cases of risperidone-induced incontinency.
• There is no treatment for risperidone-induced incontinency except for two cases reports that suggested desmopressin.
• Further studies might show the possible effect of valproate for management of this problem.

 

Abstract

Risperidone is effective and well tolerated for treatment of some behavioral problems in children. Risperidone might double the rate of urinary incontinency. There are several cases of risperidone-induced incontinency (ie, in autistic children). Some studies report enuresis in patients who were taking risperidone plus selective serotonin reuptake inhibitors. Desmopressin was suggested in only two case reports as treatment for risperidone-related enuresis. No alternative medication has been suggested to manage this problem. The following is a case report of possible association of risperidone and urinary incontinency in a young male with pervasive developmental disorder; the case report also discusses cessation of the incontinency by taking valproate. Although there are some explanations for the possible association of risperidone and enuresis, the authors have no explanation for the possible effect of valproate on cessation of incontinency. The adverse effect of risperidone-related enuresis should be discussed with parents and children before a child takes risperidone, as the side effect might be disturbing and persistent. Controlled trial data are required to determine the possible efficacy and safety of sodium valproate in the management of risperidone-related incontinency.

 

Introduction

Risperidone, an atypical antipsychotic, is effective and well tolerated for the treatment of some of the behavioral problems in children with autistic disorder.1 Risperidone doubled the rate of enuresis in a clinic population.2 The enuresis is most commonly reported in children treated with risperidone in combination with serotonergic antidepressants or in combination with mood stabilizers.3,4 The rate of risperidone-related enuresis is <1%.4 One study found that enuresis is under-reported by 50%.5 Another study reported the rate of risperidone-related enuresis as 31% in children with autistic disorders taking risperidone. The rate in the control group was 29%, which does not support a causal relation.1 Andrenergic blockade via α1 and blockage of pudendal reflexes via antagonism of serotonin (5-HT)2 or 5-HT3 are possible mechanism of risperidone-related enuresis.6 Risperidone is an antagonist of both dopamine2 and serotonin (5-HT2A and others) receptors.7 Risperidone has little or no affinity for the muscarinic receptor.8 It increases bladder capacity only at the highest dose and decreases the micturition volume and expulsion time of the bladder. It decreases the activity of the external urethral sphincter.6 Valproate is an important anticonvulsant currently in clinical use for the treatment of seizures as well as for autism.9

There are several cases of risperidone-induced enuresis, including in children with autistic disorder.10,11 One study reported enuresis in individuals who were taking risperidone plus selective serotonin reuptake inhibitors.12 Only two case reports of desmopressin treatment for risperidone-related enuresis were found by the author of this article.3,13 No alternative medication has been suggested for management of this problem.

 

Case Report

A boy, 4 years and 3 months of age, was presented to the author’s outpatient clinic to be treated for behavioral problems, including limited social relationship, eye to eye contact, and facial expression; stereotypic behavior; aggression; failure to develop appropriate peer relationships, preferring solitary activities; marked impairment in the ability to initiate or sustain a conversation with others; restricted patterns of interest; nonfunctional routines or rituals; destructive behavior; and hyperactivity. The boy had childhood disintegrative disorder. His disruptive behaviors improved on risperidone monotherapy 1 mg QHS for 9 months. Family history was negative for primary enuresis. Medical history and workups, including neurologic exam, fasting glucose, urinalysis, and thyroid stimulating hormone were unremarkable. He had no history of urinary incontinency.

Incontinency occurred while taking risperidone but ceased after discontinuation of the medication. It reappeared 3 days after taking risperidone approximately 3–5 times/day. This trial happened many times in 9 months. The boy never experienced nighttime incontinency during this period; incontinency was only limited to daytime. The family discontinued the medication because of daytime incontinency. The child was referred again approximately 6 months later. He had not taken risperidone and did not suffer from incontinency during those 6 months. Risperidone was started again to achieve a better control of his disruptive behaviors, including aggressiveness, stereotypic behavior, hyperactivity, agitation, and destructiveness. Just after initiating the medication, daytime incontinency occurred. Incontinency continued for approximately 2 weeks. Another physician added sodium valproate to control the patient’s behavior problem. Interestingly, in addition to the behavioral problem being controlled, the incontinency ceased. There was no nocturnal incontinency even while taking risperidone. The patient never experienced incontinency while taking sodium valporate. In a rechallenge, incontinency reappeared after discontinuation of valproate. Incontinency never resolved spontaneously while he was taking risperidone alone. Although his intelligence was not assessed, clinically it appeared to be borderline. While taking valproate, he had never lost bowel control, there was no specific finding after taking an electroencephalograph, and urologic evaluation was negative.

 

Discussion

The temporal sequence of incontinency and medication, cessation of incontinency after discontinuation of risperidone, lack of other medication, and lack of any medical cause are suggestive of a possible causal effect of risperidone. However, it is a single cross-sectional case study. Thus, it is impossible to definitively link risperidone with incontinency in this report.

Changing risperidone to another antipsychotic with a lower α-adrenergic blockade effect (eg, quetiapine, olanzapine) is suggested by another study.10 Also lowering the dose may be another strategy. For disruptive behaviors, valproate is not a commonly used drug. However, valproate was added to control the patient’s behavior problem by another physician.

The pathophysiology of risperidone-induced persistent incontinency remains unclear. However, numerous mechanisms including α1-adrenergic blockade, dopamine blockade, and antimuscarinic effects has been suggested.10 Urinary incontinency associated with antipsychotics is more likely due to detrusor overactivity.14 In the case presented, it seems it was a stress or urge incontinency. The author does not have any explanation for this possible effect of valproate on cessation of incontinency.

There is still a controversy about the risperidone-valproate interaction. Some studies show that risperidone increases the blood level of valproate,15,16 but some reports found no interaction.17,18 In the case provided, it seems that valproate may lower the level of risperidone.

This adverse effect should be discussed with parents and children before children take risperidone, as it might be disturbing and persistent. Early identification and treatment of this side effect might increase treatment adherence.

The study is limitated in that it includes only a patient with pervasive developmental disorder and a mental handicap; it is also one case design and drug blood levels are lacking.

To the author’s knowledge, this is the first report of cessation of risperidone-related incontinency with valproate. The mechanism of antipsychotic-induced incontinency is not fully understood. Moreover, treatment of this side effect is not clearly reported. Fuller and colleagues19 proposed ephedrine (α agonist) for the treatment of clozapine-induced incontinency. Only two case reports proposed desmopressin for the treatment of risperidone-induced incontinency.3,13 It is impossible to conclude the usefulness of valproate in the treatment of risperidone-induced incontinency. Additional case reports and open-label studies to support this finding must occur before randomized studies are created.

 

Conclusion

Risperidone-induced incontinency should be discussed with parents and children before risperidone is administered to a child. Controlled trial data are required to determine the possible efficacy and safety of sodium valproate in the management of risperidone-related incontinency. PP

 

References

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