This interview took place on March 31, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Mathew receives research support from the General Clinical Research Center, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health. Dr. Mathew has been named as an inventor on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Mathew could benefit financially.

 

Dr. Mathew is assistant professor of Psychiatry at the Mount Sinai School of Medicine (MSSM) in New York City. A board-certified psychiatrist, Dr. Mathew is also attending physician in the Mood and Anxiety Disorders Program at the Mount Sinai Medical Center.  In 2007, he received the American Foundation for Suicide Prevention Pfizer Travel Award as well as the Lamport Research Award from MSSM. In addition to therapeutic approaches for treatment-resistant depression and anxiety, Dr. Mathew’s research involves magnetic resonance imaging and spectroscopy applications to anxiety and mood disorders.

 

What is the basis for the undertaking of this research?

There has been approximately 30 years of research looking at ketamine as a probe for glutamate function and as a possible pharmacologic model for psychosis. In the early 1990s, John Krystal, MD, and several others discovered that ketamine can model the acute positive symptoms, negative symptoms, and cognitive disruptions observed in schizophrenia.1-3 As a result, injecting healthy volunteers with ketamine and having them perform a variety of cognitive tasks was believed to reflect schizophrenic pathology better than amphetamine-induced psychoses.

In the late 1990s, an attempt was made to further understand the ketamine response in major depressive disorder (MDD). At that time, studying patients with MDD was thought to expand understanding of the N-methyl-D-aspartate (NMDA) receptor hypofunction.

 

How does NMDA relate to the monoamine neurotransmitters in antidepressants?

Glutamate receptors can classified as ionotropic receptors, and NMDA is one of them. There are other ionotropic receptors, including kainate and a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA). Ionotropic receptors mediate fast receptor transmission and use-dependent changes required for brain plasticity. They are important for a host of normal functions such as cognition and learning.

It has been challenging to identify pharmacologic targets that do not result in seizure, stroke, or other sequelae of NMDA overactivity. However, newer drugs and approaches (eg, ketamine) have shown to be interesting and useful because NMDA and glutamate are found in 85% of circuits in the central nervous system (CNS). However, identifying subtype-selective and safe ligands of this system has been difficult. Glutamate is a ubiquitous system, but with its ubiquity comes the risk of overtoxicity.

 

What attracted people to ketamine?

Ketamine binds at the site of the NMDA receptor similarly to phencyclidine. Physicians are attracted to ketamine for numerous reasons. In psychiatric research, it was a good model for understanding glutamate and the NMDA receptor relevant to schizophrenia. In the 1960s, the drug was used for anesthetic purposes primarily in children. However, it was used in adults undergoing orthopedic procedures and in the field of gynecology as well. In addition, that ketamine is neither associated with significant side effects nor known to have a short half-life contributes to its popularity.

 

Was a psychiatric therapeutic response observed when ketamine was used as an anesthetic?

Yes. The doses were approximately 4–5 times higher than the current doses used to manage MDD. The most notable symptoms were emergence type reactions of dissociation, particularly in children emerging from the anesthesia. Ketamine was not systematically tracked to their mood, and that they were feeling better within the next 1–3 days was not systematically described. There have been reports in the pain literature that patients given ketamine for chronic refractory pain syndromes (eg, cancer-related pain) felt better in terms of their mood. However, tracking them long term for changes in depressive symptoms had not been conducted.

 

Is there a connection between the glutamate system and monoamine neurotransmitters?

Connections are directly observed in both animal models and human imaging models. For example, selective serotonin reuptake inhibitors (SSRIs) used in depression, anxiety, and obsessive-compuslive disorder (OCD) have been found to decrease glutamate regulation in specific areas.

Rosenberg and colleagues4 looked at glutamate signaling in caudate. They found overactivity in OCD and a down-modulation with subsequent SSRI treatment. The results showed that SSRIs and other serotonergic drugs could dampen overactivity of glutamate.

Conversely, γ-aminobutyric acid (GABA) is the major inhibitory amino acid that counterbalances some of the glutamatergic overactivity. SSRIs have been found to increase GABA.5 It is possible that established monoaminergic treatments work in both respects by decreasing overactivity and increasing the underactive GABA. In animal models, numerous examples show the connections between serotonin postsynaptic receptors (eg, 5-HT2A receptor) and specific components of the glutamate system.

 

Which drugs are major topics in research?

Of the Food and Drug Administration’s currently available drugs, investigators have been interested in acamprosate, lamotrigine, memantine, riluzole, and topiramate.

Riluzole is the only treatment approved for Lou Gehrig’s disease. It is a glutamate-release inhibitor that is believed to have AMPA receptor activity as well as the capability of increasing the reuptake into glial cells; the net effect could be neuroprotection. Topiramate is a well-described anticonvulsant with AMPA kainate receptor activity. The antiviral, amantadine, has been found to have weak NMDA activity, meaning it is a partial NMDA antagonist. Memantine, which is approved for Alzheimer’s disease, is an NMDA antagonist, but it is a lower affinity than ketamine. Acamprosate is believed to have glutamate activity. It works on the metabotropic glutamate (mGlu) receptor system as an antagonist. Lamotrigine, possibly the best-described drug for bipolar depression, has shown evidence of anti-glutamatergic activity.

 

Have the preliminary reports of D-cycloserine shown a pharmacologic spectrum different from other drugs in theory?

D-cycloserine is a partial NMDA agonist that works at the D-serine site on the NMDA channel. The theoretical rationale behind D-cycloserine is not an excitotoxicity neuroplasticity model, but an enhancement of extinction learning model. By itself, D-cycloserine does not appear to be anxiolytic or antidepressant. However, in conjunction with active forms of learning and extinction type psychotherapies (eg, prolonged exposure to social anxiety disorder, acrophobia, or height phobia), D-cycloserine co-administration results in more rapid improvements, particularly in extinguishing the stressor or the fear. The theory behind D-cycloserine capitalizes on the mechanisms of extinction learning as opposed to decreasing excitotoxicity and enhancing resilience.

 

Which FDA-approved drugs look most promising for clinical use?

The FDA-approved drug with the most momentum in terms of the data in treatment-resistant depression (TRD) is riluzole. At least two open-label studies in TRD involved patients who had not responded to ≥2 standard antidepressants.6,7 The National Institute of Mental Health (NIMH) is reviewing a grant that will determine whether or not there is a role for riluzole adjunctive therapy in unipolar depression.

A small study by Zarate and colleagues8 showed memantine to have negative effects in unipolar depression. However, there is still much interest in memantine, as this study involved a relatively small sample size and efficacy with dosing >20 milligrams was not measured. While acamprosate is being explored for off-label uses in depression and anxiety, ketamine is being looked at as an experimental model for acute treatment of depression. Ketamine is not being studied for its long-term potential outside of the hospital setting, but those studies are going to be ongoing.

 

Which patients would benefit from these treatments?

It is premature to discuss who would benefit from ketamine at this time as the numbers treated are extremely low. Further controlled investigations are necessary. Work is ongoing to uncover moderators and mediators of response to intravenous ketamine and similar approaches

In addition, the pilot data9 suggests that anxious and depressive patients would benefit from glutamate-modulating agents. According to results from the Sequenced Treatment Alternatives to Relieve Depression study,10 anxious depression is a risk factor for resistance and nonresponse to citalopram as well as augmentation strategies.

There is open-label evidence of efficacy of riluzole in OCD; however, there is no placebo-controlled data at this time.11,12
Topiramate has successfully treated patients for self-mutilation in OCD and borderline personality disorder, possibly due to topiramate’s benefits in the spectrum of compulsive-impulsive disorders (eg, binge eating disorder).

 

What are the risks associated with the use of these drugs?

The acute risks with intravenous infusion of ketamine include dissociation, described as having a sense of altered time, feeling light, or feeling outside a person’s body. These side effects tend to be transient and time limited. The patients we have studied have not had side effects beyond 2 hours following intravenous infusion.

There are some reports in the literature of frank psychosis and auditory hallucinations,13 but with the dose given (ie, approximately 25% the anesthetic dose), neither auditory nor visual hallucinations were seen. However, this is still something of which to be aware. As there are transient increases in blood pressure, patients with uncontrolled hypertension are not recommended for the treatment. In addition, this medication is given by anesthesia, meaning there is potential aspiration risk. Therefore, patients with inadequately treated gastroesophageal reflux disease are excluded.

 

Are neurokinin (NK)1 antagonists and corticotropin-releasing factor (CRF) antagonists moving ahead in as promising a way as glutamate?

Mount Sinai Medical Center is investigating both of those compounds. The NK1 receptor antagonist is being looked at in posttraumatic stress disorder (PTSD). The rationale pre-clinically and clinically is that substance P, which is a stress-related neuropeptide, is elevated in the cerebrospinal fluid of veterans with PTSD, and NK1 receptor activity has been co-localized in regions important in stress. The NK1 receptor is an attractive target in that it is a stress-related neuropeptide implicated in fear and anxiety as well as mood circuitry. Numerous companies have developed NK1 antagonists and are now hitting Phase II and even Phase III studies.14 CRF has been in the news and on the horizon for >10 years. A CRF-1 selective antagonist for the treatment of PTSD is being investigated, and numerous studies have examined this mechanism in patients with anxiety and depressive disorders.15 Although NK1 and CRF antagonists have been heavily considered, it has been difficult to have one of these drugs receive FDA approval. In fact, a Phase II study of a selective CRH-1 antagonist was just published and found lack of efficacy of this agent for major depression.16

 

Have other drugs been developed that are more practical in terms of administration or safety?

There has been a lot of interest in an experimental MGlu receptor agonist drug called LY2140023. In a recently published study, the drug performed better than placebo and was as effective as olanzapine, suggesting that LY2140023 has antipsychotic properties. This may have several implications in terms of new directions in schizophrenia and psychosis. Drugs similar to mGlu drugs have preclinical and clinical evidence of utility in depressive and anxiety disorders.

In terms of ease of use and safety, only time will tell. The preclinical safety data for one of the compounds was not favorable, and that development was halted due to seizures. However, more clinical testing needs to be conducted.

 

Do you expect any major study results on these drugs to be published or presented in the near future?

The mGlu family has numerous exciting and interesting compounds one should expect to hear about next year. In addition, ampakines, which are AMPA receptor potentiators, are being studied for cognitive deficits in schizophrenia, memory disorders, and MDD. One should also expect to hear about NMDA receptor 2B antagonists, which are subtype selective NMDA receptor antagonists, as Zarate and colleagues are performing studies on them at the NIMH.

 

Is there a number at Mount Sinai Medical Center to which anyone interested in exploring participation or referring a patient should call?

If anyone is interested, they can call 212-241-4480, and we would be happy to discuss any of the specifics of participation.

 

Is there anything you would like to add?

Although there is a lot of excitement about ketamine and the rapidity of onset, the NIMH has recently funded us to perform a definitive clinical trial comparing ketamine to an active control, as that has not been done to date. At this point, it is important to not go beyond the data and suggest ketamine is appropriate for treatment. Caution should be taken until more data emerges. PP

 

References

1.    Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301-1308.
2.    Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.
3.    Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13(1):9-19.
4.    Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry. 2000;39(9):1096-1103.
5.    Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry. 2002;159(4):663-665.
6.    Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61(6):822-825.
7.    Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
8.    Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153-155.
9.    Mathew SJ, Amiel JA, Coplan JD, Fitterling H, Sackeim HA, Gorman JM. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry. 2005;162(12):2379-2381.
10.    Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342-351.
11.    Grant P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2007;17(6):761-767.
12.    Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58(5):424-428.
13.    Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007;10(3):493-500.
14.    Mathew SJ, Manji HK, Charney DS. Novel drugs and drug targets for severe mood disorders. Neuropsychopharm. 2008. In press.
15.    Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry. 2008. In press.
16.    Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007;13(9):1102-1107.

 

Dr. Lysaker is a clinical psychologist at the Roudebush VA Medical Center and associate professor of clinical psychology in the Department of Psychiatry at Indiana University School of Medicine in Indianapolis. Ms. Buck is a clinical nurse specialist at Roudebush VA Medical Center.

Disclosure: Dr. Lysaker receives grant support from the Department of Veterans Affairs Rehabilitation Research and Development Service and the National Institute of Mental Health. Ms. Buck reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Paul H. Lysaker, PhD, Associate Professor of Clinical Psychology, Department of Psychiatry, Indiana University School of Medicine, 1111 W 10th St, Indianapolis, IN 46202; Tel: 317-988-2546; Fax: 317-988-3578; E-mail: plysaker@iupui.edu.

 


  

Abstract

Contrary to long-standing pessimistic views regarding the prognosis for people with schizophrenia, emerging literature suggests that many with this condition can meaningfully recover over time. Using increasingly complex models of recovery with clearly defined operationalized criteria, numerous longitudinal studies have provided data pointing out that progressive deterioration is more of an exception than a rule for people with this condition. To address the issues of the definition and likelihood of recovery from schizophrenia, this article reviews evolving definitions which stress that recovery must involve the development of a sense of hope, self-reliance, and a personalized awareness of current strengths and challenges. Empirical research indicates that while many with schizophrenia experience significant bouts of disability, more people experience long periods of relatively good functioning, including symptom remission, healthy levels of self-esteem, and meaningful community participation. Implications for how clinical practice can reinforce and promote recovery are discussed.

 

Introduction

In the mid- to late 20th century, many schizophrenia patients in the United States left long-term psychiatric institutions to return to their communities. During this era, schizophrenia was seen as having a poor prognosis, and goals were often conceptualized in terms of stability or the absence of negative events such as hospitalizations or symptom exacerbation. In stark contrast, the field of medicine is now seeking to embrace the view that many with schizophrenia can recover substantially, if not fully, over time.1-4 Progressive deterioration may be a hallmark for some, but it is more of an exception than a rule.5 Consequently, stability is no longer a sufficient endpoint. As a goal, stability may not only ignore recovery, but hamper it as well. Recovery is being urged as the goal and may include symptom remission, fully acceptable levels of function, and transformations in how people with schizophrenia think about themselves as individuals with the potential to have a meaningful life.6-10

Taken as a whole, the vision of recovery has been embraced in the US11 and has had a significant impact on mental health services internationally.12 While this has generated considerable enthusiasm, the idea of recovery has been received with resistance13 and, as an evolving concept, it has yet to be defined as an agreed upon matter.14,15 To clarify the concept and its implications for practice, this article offers a review of definitions, operational criteria, and studies of the incidence and correlates of recovery from schizophrenia. This is followed by a brief review of clinical practices that might be employed to promote recovery.

 

Recovery: Basic Definitions and Components

In response to questions of what recovery refers to, the Substance Abuse and Mental Health Services Administration (SAMHSA) hosted a meeting that included >110 expert panelists from multiple backgrounds. This group generated a list of 10 fundamental components of recovery, including self-direction, individualized, empowerment, holistic, non-linear, strengths-based, peer support, respect, responsibility, and hope.16 Taken together, these components offer a view of recovery as something that must be initiated by the person with the illness. To recover, people with mental illness must have faith in themselves and have a realistic sense that wellness is possible. Therefore, recovery is not used to connote the point of cure or a result of a medical intervention. Instead, recovery is framed as an individualized process that takes place across multiple facets of a life. The elements and path to recovery may vary between people, and it is a process facilitated by people with mental illness helping one another.

A second attempt to refine the key elements of recovery has been offered by Davidson and colleagues.17 The authors distilled nine common elements, including renewing hope and commitment, redefining self, incorporating illness, being involved in meaningful activities, overcoming stigma, assuming control, becoming empowered, managing symptoms, and being supported by others. While these elements parallel the SAMHSA components, they emphasize that individuals must develop an understanding of their illness and learn how to deal with aspects of it that may persist over time. This conceptualization highlights how subjective changes in the manner in which people understand and experience themselves as individual human beings may be an essential element of recovery.

 

Recovery: Objective and Subjective Dimensions

While the work of SAMHSA16 and Davidson and colleagues17 offers direction for the assessment and promotion of recovery, these authors have noted that it remains unclear how the different elements of recovery relate to one another. Does one have to attain certain milestones or elements of recovery before other elements can be achieved?

In response to these questions, it has widely been suggested that there are recognizable dimensions in recovery that are relatively separate from one another.15,18 Some labels offered for larger dimensions into which the many components of recovery can be grouped include process versus outcome, consumer oriented versus scientifically oriented, and social versus symptomatic.3,6,14 A dimensional view of recovery adopted and slightly refined for this article is one proposed by Resnick and colleagues.18 They suggest that the components of recovery are comprised of two distinct sets of phenomena, including one that reflects the reduction of objective problems linked to illness and another which reflects changes in the subjective experience of life.    

As portrayed in Table 1, Resnick’s objective dimension of recovery includes changes in identifiable and concrete problems such as returning to full-time work or the remission of symptoms. Other possible objective forms of recovery include enrolling in college or spending time comfortably with family. However, regarding subjective aspects of recovery, the authors of this article offer a slight refinement to the model and propose that the subjective domains of recovery can be divided into two dimensions, ie, the subjective appraisal of one’s life circumstances and opportunities and the subjective experience of oneself as an individual human being. Appraisal of life circumstances refers to an evaluation of external conditions, both in the present and in terms of possibilities for the future. People who are recovering in this domain, for example, might perceive their living situation as now safe and comfortable. They might have an optimistic sense of a future that holds economic promise and believe that they will be offered opportunities for advancement. The second subjective dimension, by contrast, refers to the experience of internal qualities, issues closer to matters of identity. To recover in this sense might mean to regain an experience of oneself as possessing basic human value.9 People recovering in this domain might see themselves now as entitled to make sense of their lives and begin to reshape a personal account of their strengths and weaknesses.

 

Distinguishing between objective and subjective domains of recovery has several advantages. It allows a person to see how changes in one domain may not transfer into changes in another. A reduction in symptoms might be unrelated to hope for a satisfying life. Renewing education might not change a sense of self as a marginalized person. In addition, distinguishing between the two subjective domains may have several advantages. First, it allows one to see how someone might appraise him- or herself as fully possessing a sense of worth, yet be dissatisfied with the quality of his or her job and apartment. Alternatively, one can see how someone might embrace a new role at his or her job but still feel essentially inadequate and may even attribute his or her good quality of life (QOL) to the actions of someone else. This is consistent with observations that perceptions of the external quality of one’s life is not equivalent to the experience of one’s root identity or the meaning one makes of those external qualities.9,10,19,20 It is also consistent with research suggesting that schizophrenia may involve diminishments in self-experience, including the loss of basic dignity, regardless of external circumstances.2,21,22 Viewing recovery as multi-dimensional also allows for an appreciation of the synergy that could ensue from growth across different dimensions, with changes in the life of the recovering person being greater than the sum of individual gains.

 

Operational Definitions and Methods for Assessing Objective and Subjective Aspects of Recovery

Initially, some of the ground-breaking work that challenged pessimistic views of schizophrenia employed general assessments of function.5 Since then, efforts have been made to more precisely define recovery. Beginning with symptoms, the Remission in Schizophrenia Working group convened in 2003 to reach a consensus definition of remission. This produced criterion for remission for each of the three major sets of symptom rating scales used in schizophrenia research,23 ie, the Scale for Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), and the Brief Psychiatric Rating Scale (BPRS). Using the PANSS as an illustration, this group suggested that symptom remission could be defined as maintenance for >6 months of mild or less levels (ie, a rating of ≤3 on a 7-point Likert scale) on symptoms such as delusions, unusual thought content, hallucinations, conceptual disorganization, mannerisms and posturing, blunted affect, social withdrawal, and lack of spontaneity.

In practical terms, remission from schizophrenia, as in a range of different medical illnesses, may reflect the complete absence or presence of persistent mild symptoms. Evidence supporting the validity of these proposed criteria include studies indicating that people meeting the PANSS remission criteria have significantly lower PANSS scores overall as well as significantly better function in other objective aspects of recovery.25-27 Another study28 using the Psychosis Evaluation tool for Common use by Caregivers, an instrument that closely parallels the PANSS, found that participants with remission that was sustained across multiple points had higher levels of QOL than participants with transitory periods of remission.

In contrast to these dimensions, Liberman and colleagues3 have proposed a more broadly based operational criteria for several of the objective elements of recovery, including ratings of moderate or less (≤4) on BPRS grandiosity, suspiciousness, unusual thought content, hallucinations, bizarre behavior, self-neglect, blunted affect and emotional withdrawal items coupled with appropriate role function, independent living, and active social connections over a 2-year period. This system allows people to be in recovery even if they have somewhat higher levels of symptoms than allowed by the Andreasen criteria,23 but only if acceptable levels of function are sustained for a relatively longer period of time. In an effort to validate this system, Liberman and colleagues3 report that the majority of participants interviewed in focus groups agreed with the proposed criteria. However, the authors note rates of agreement were higher among researchers than practitioners and consumers, with the latter groups concerned with recovery being considered as an ongoing process. After comparing these criteria to those of the Remission in Schizophrenia Working group, it has been noted by Leucht and Lasser29 that a strength of the Liberman criteria3 is that it tends to be more conservative, though not all the symptoms it uses are linked to schizophrenia by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.30

Turning to the subjective domains of recovery, a range of methods exist for assessing how satisfied people are with their external circumstances. Resnick and colleagues18 have reported on the responses of >800 people with schizophrenia to items assessing the personal appraisal of their QOL and future opportunities. These included measures of life satisfaction, hope, knowledge about mental illness, and empowerment. Importantly, in this study assessments of these phenomena were not only internally consistent but also linked to levels of subjective distress, including depressive symptoms. Echoing these findings are other studies linking hope with objective indicators of lesser distress and dysfunction.31,32

Regarding the second subjective domain of recovery (ie, self-appraisal) multiple methods exist for assessing how people with schizophrenia think about themselves as individual human beings. One of the more studied constructs closely related to self-experience in schizophrenia is self-stigma.33,34 Stigma refers to stereotypic beliefs about people with mental illness such as mental illness is synonymous with dangerousness and incompetence. Self-stigma refers to the acceptance of those ideas and resultantly a degraded sense of identity and self-worth.35 Bearing in mind the differences between the two subjective domains of recovery, it is recognized that an act of discrimination might reduce a person’s appraisal of his or her chances for closeness with others in his or her community while self-stigma could directly lead to the experience of a fundamentally diminished sense of self. While no cut-off scores have been established for recovery in this domain, several scales exist (eg, the Internalized Stigma of Mental Illness Scale)32 that generate indices of discrimination experiences and stereotype endorsement or degree of agreement with negative stereotypes of mental illness.

Recently, efforts have been undertaken to develop a recovery-oriented scale to quantitatively assess self-experience as it is expressed in the personal narratives of people with schizophrenia. The Scale to Assess Narrative Coherence (STAND)36,37 can be used to rate spontaneously generated speech samples in which people with severe mental illness talk about themselves. The STAND assesses the extent to which people have developed a coherent story of themselves and their psychiatric challenges, which includes the experience of themselves as possessing social worth, connections to others, and a sense of being able to meaningfully affect their own destiny. The STAND produces a total score by summing the scores of the four individual scales described in Table 2. Evidence of interrater reliability, internal consistency, and concurrent validity have been presented.36-38 Davidson2 has noted that the earliest phases of recovery may involve not seeing oneself as a person whose story is worthy of being told. Roe and colleagues39 note that the latter stages of recovery involve achieving mastery in the process of constructing and negotiating meaning. The STAND may offer a way to quantify movement along this most personal and subjective continuum.

 

 

 

 

Rates and Correlates of Recovery

Accompanying the development of more precise definitions of recovery are longitudinal studies that assess how often people can achieve recovery. Although no firm conclusions can be drawn yet, given the widely varying methods, numerous carefully controlled studies offer some essential information. One of the more comprehensive studies to date was conducted by Drake and colleagues.40 They examined five aspects of recovery for 130 participants from the US with co-occurring substance abuse and schizophrenia spectrum disorders. Over a 10-year period, they reported that 62.7% controlled symptoms as defined as mean BPRS scale scores of ≤3 (a definition similar to symptom remission offered by the Remission in Schizophrenia Working group), 62% were abstinent from substances, and 56.8% were living independently. Beyond that, 41.4% of participants had a competitive job in the last year, 48.9% had regular healthy social contacts and 58.3% reported acceptable satisfaction with their overall circumstances. Notably, participants in this sample often attained recovery in ≥1 domains but not necessarily in others, supporting the relative independence of different aspects of recovery.

A study41 of 1,010 participants from Spain reported that 44.8% achieved remission using the Remission in Schizophrenia Working group’s criteria for the SANS and SAPS. Of the 44.8% who had attained symptom remission, just under 25% (10.2% of the total sample) also attained full functional remission as defined by a Global Assessment of Functioning (GAF) score from the DSM-IV-TR of ≥81. Consistent with this is an earlier report42 which examined 15- and 25-year outcomes for a large international sample of participants with a range of psychotic disorders. Using more general ratings of outcome, including a 4-point Likert scale developed by Bleuler to assess recovery, the authors reported that approximately 50% of their sample with schizophrenia appeared to have a quite favorable outcome, achieving a rating of recovery. However, when more strict criteria were employed adding a GAF–Disability score of ≥60 and no treatment in the past 2 years, the rate of recovery fell to 16.3% for the schizophrenia participants.

Harrow and colleagues43 also reported data from a 15-year follow up that suggested 41% of their sample attained recovery as defined by no significant symptoms, adequate social function, and no hospitalizations for an identified period of time. However, only a small fraction of those that sustained recovery at one time met full criteria across all time points. Other researchers have suggested the same pattern of results for a variety of other samples including older adults with schizophrenia.44 Reports examining symptom remission alone over shorter follow-up periods of approximately 1 year still suggest significant percentages of symptom remission with rates hovering around one out of every three.26,28

Summarizing the work conducted prior to 2006, Bellack14 concluded that this literature suggests that while most people “with schizophrenia have a long period of intermittent or continuous disability… many if not most people with this illness have periods of relatively good function with increase in frequency as they move to middle age.” He also cautioned that the result of studies to date probably underestimate recovery rates given that many who attain wellness are naturally not included in studies. Studies that have appeared since support the same conclusions. Recovery from schizophrenia in the sense of a state in which people experience no difficulties associated with the illness can happen, but it probably does not occur at a rate greater than one in ten. Instead, the modal response to schizophrenia seems to be one in which difficulties, which are linked to symptoms, social function, and work appear periodically but can be successfully confronted. Furthermore, difficulties with symptoms may arise and be resolved, just as difficulties working and sustaining social relationships may arise and be resolved. Furthermore, difficulties with work could occur during the absence of symptoms and symptom exacerbations might occur despite ongoing satisfaction with work and relationships. This set of preliminary conclusions is consistent with in-depth interviews of smaller samples of people with schizophrenia45 as well as with controlled case studies showing fluctuations in STAND scores across 1.5–2.5 years.46,47

 

Implications for Practice

Taken together, the theoretical and empirical work reviewed above has several interrelated implications for practice. First, it may be inappropriate to wait for specific improvements before considering other aspects of recovery or to ignore some dimensions of recovery when people are doing well at others. The presence of active symptoms may not preclude the possibility of working and expressed satisfaction with housing does not mean it is not important to attend to self-stigma.

In addition, it may not be enough for practitioners to provide accurate education about symptoms and the possibility of recovery. People recovering from schizophrenia may need to develop a sense of hope and self-reliance before they can fully use any information a practitioner can offer them. What practitioners say and how they say it are both important. Helping people to take charge of their own recovery may require speaking in a consultative non-hierarchical way that does not authoritatively usurp their right to make their own sense of their needs and hopes. It may be essential at times to not only provide support to people with schizophrenia but to challenge them to not neglect opportunities to improve their lives as they see fit. In some cases, it may be that practitioners need to respectfully, but honestly, challenge self-defeating beliefs and explore with people alternative ways of thinking about themselves and their resiliency. With enhanced functioning across multiple roles, people may be able to attain goals well beyond what they initially anticipated. One recent movement which bears on this is peer counseling. Having people with severe mental illness become peer counselors, among other things, promotes changes in multiple roles and places mentally ill people in positions that enable them to become more responsible and to help one another.

It may be useful to think about services as interventions that offer more than treatments for problems (eg, supported employment for unemployment and medication for hallucinations). Recovery-oriented intervention can be as simple as the offer of consultation regarding different ways recovering people have thought about what their illness means in their lives. Interventions may offer both tools for coping and opportunities for recovering people to think about the meaning of what has happened to them along with what they may be grieving, hoping for, and what steps they think they should take next. People may need to tell (or continue to tell) their story, deepen that story, reposition themselves as the narrators of their own stories, and actively play the role of agents in everyday life.

 

Conclusion

Results of data from multiple sources suggest most people with schizophrenia can achieve long and meaningful periods of recovery. This recovery can include the resolution of problems associated with the illness, the development of an optimistic outlook on life, and the development of a sense of worth and intrinsic value. Recovery is a process. At times, gains may be followed by losses. While people with mental illness, their families, and practitioners strive to avoid relapse or movements away from health, when relapses occur they need not be seen as signs of failure nor call for demoralization on anyone’s part. Instead, as people evolve their own self-understanding, challenging times may call for renewed efforts at self-understanding and self-acceptance. While all of this points to the importance of evidence-based interventions and contraindicates authoritative stances on the part of practitioners, the authors of this article look forward to future studies of objective and subjective domains of recovery and the testing of interventions that address how people with schizophrenia come to evolve a different understanding of themselves and sustain wellness. PP

 

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First Annual Alzheimer’s Disease Summit Targeted Recent Advances in Diagnosis and Management

Alzheimer’s disease (AD) is expected to increase dramatically in the coming decades as a consequence of global aging. In response to the growing public health need for recognition and optimal treatment of dementia and cognitive impairment associated with AD, leading experts in the field established The Alzheimer’s Disease Summit (ADS). The inaugural convocation of the ADS, themed Translating Research Advances Into Clinical Practice, was held on May 3, 2008, in Washington, DC.

The ADS provided a comprehensive update of cutting-edge research and addressed application of knowledge to day-to-day practice. Led by co-chairs Jeffrey L. Cummings, MD, of the University of California at Los Angeles, and Pierre N. Tariot, MD, of the Banner Alzheimer’s Institute, a team of 13 internationally recognized experts in the field presented to an audience of geriatric psychiatrists, neurologists, geriatricians, and primary care physicians. Key topics were grouped into four educational sessions: Advances in Clinical Assessment; Advances in Neuroimaging and Biomarkers; Current AD Therapy; and The Future of AD Therapeutics. In a concluding panel discussion, guest panelist Russell Katz, MD, Director of Neurology Products at the Food and Drug Administration, gave perspective on disease-modifying agents.

“This program was both practical and forward-looking, providing a terrific update on how advances in the science of Alzheimer’s disease can be applied in practice, showing how best to use the currently available medications, and describing advances in the emergence of disease-modifying treatments” noted Dr. Cummings.

Approximately 84% of attendees reported enhanced knowledge of AD and approximately 75% found the information convincing and applicable enough to implement significant changes to their practice in the form of new screening techniques for MCI, changes to treatment protocol, and discussion of new treatment options with patients. Among the more specific topics addressed were new office-based techniques to simplify the detection of cognitive impairment and AD; imaging techniques for diagnosis of dementia and assessment of MCI in the earliest phases of AD; characterization of dementia syndromes using magnetic resonance imaging, FDG positron emission tomography, and amyloid imaging; new treatment targets; and compounds with therapeutic promise, such as anti-amyloid and neuroprotective agents.

This educational event was jointly accredited by the Mount Sinai School of Medicine and MBL Communications, Inc. The ADS proceedings will be available as a CME supplement to CNS Spectrums and Primary Psychiatry as well as a series of podcasts in October 2008 (http://cmepsychcast.mblcommunications.com). The next ADS will convene in 2009.

For more information, please visit www.mblcommunications.com/aspx/meetings.aspx.
This activity was supported in part by educational grants from Forest Pharmaceuticals, Inc., Eisai Inc., Medivation, Inc., and Elan Pharmaceuticals, Inc. –DH

 

Cognitive Remediation Improves Psychological Functioning in TBI Patients

Traumatic brain injury (TBI) occurs when sudden trauma causes damage to the brain, ie, when the head suddenly and violently hits an objects or when an object pierces the skill, thus entering the brain tissue. TBI patients suffer from impaired physical, cognitive, and psychological functioning that can impede their progress for the remainder their lives. Keith Ganci, BS, and Amy Rosenbaum, PhD, from the Park Terrace Care Center in Rego Park, NY, studied 94 patients between 17–80 years of age with an average length of treatment of 12.42 (SD=10.73) months. Patients were treated within 6 months of their initial injury and received intensive interdisciplinary treatment, including cognitive remediation and psychotherapeutic services. Patient brain injuries had focal and diffuse injuries in all areas of the brain.

“We were interested in the association between cognitive functioning and psychological status,” said Ganci. “We believe that much more research needs to be done with respect to recovery curves in TBI in order to provide the most comprehensive rehabilitation possible.”

The researchers used the Functional Independence Measure and the Functional Assessment Measure (FIM/FAM) to assess patients improvements in functioning. By using the cognitive and psychological adjustment subscales FIM/FAM, Ganci and Rosenbaum were able to test the patients memory, orientation, attention, safety judgment, and problem solving skills, and social interaction, emotional status, adjustment to limitations, and employability, respectively.

“What we did was create a variable called change scores. These scores were the individual patient’s discharge scores minus admission scores for both cognitive functioning and psych adjustment. Thus, we compared change in cognitive functioning to change in psych adjustment,” said Ganci.

Ganci and Rosenbaum believe that cognitive remediation helps to further facilitate psychological adjustment after brain injury.
“I was pleased with the findings because I believe that they illustrate the importance of cognitive remediation in TBI rehabilitation programs,” said Ganci. “In many cases, it is the cognitive deficits that preclude patients from returning to the community independently, not the physical deficits. Cognitive remediation is as important as physical therapy, occupational therapy, and speech therapy in TBI rehabilitation.”

Ganci and Rosenbaum also found that psychological functioning at discharge and patients that made greater improvements in cognitive functioning made greater improvements in psychological functioning.

“Much more research needs to be done in the field,” Ganci concluded. “Specifically, more studies need to look at what else we can do to help individuals with TBI return to their normal lives as safely and independently as possible.” (2008 Eastern Psychological Association Conference). –CN

 

Recent Drug Approvals from the Food and Drug Administration

The United States Food and Drug Administration recently approved several medications for various disease states. The Table outlines the new indications and dosage ranges as well as the side effects most commonly seen during clinical trials. For more information, please consult each medication’s respective prescribing information. –CN

 

 

 

Higher Risk of PTSD in Patients with History of Mood and Anxiety Disorders

Posttraumatic stress disorder (PTSD) is a comorbid condition affecting approximately 7.7 million American adults. Statistically, women are more likely to develop PTSD than men. According to a study by Barbara Andersen, PhD, and colleagues, women with a history of mood and anxiety disorders are at higher risk of suffering PTSD.

The study involved 74 breast cancer patients who were screened for cancer-related PTSD with diagnostic interviews over an 18-month period after cancer diagnosis or surgery. The researchers used the data to form three patient groups, including PTSD (n=12; ie, full diagnosis), subsyndromal PTSD (n=5; ie, show PTSD symptoms, but not to the extent of the full diagnosis), and no symptoms (n=47). Results revealed that women with PTSD were more than twice as likely as breast cancer patients without the condition to have had previous mood disorders and more than three times likely to have suffered anxiety disorders. In addition, past alcohol and substance abuse was linked to symptoms of PTSD in approximately 33% of women with PTSD, 20% of subsyndromal women, and 10% of women with no PTSD. A history of traumatic life events such as physical abuse was linked to 50% of PTSD patients and <17% of women in the other patient cohorts as well.

With 63.51% of cancer patients showing no symptoms of PTSD, the study reveals that breast cancer patients are not at risk for PTSD. However, women in the PTSD and subsyndromal groups were approximately four times more likely than breast cancer patients without the disorder to claim they were unable to work due to emotional distress. This suggests the importance of screening newly diagnosed breast cancer patients for past mood an anxiety disorders, as PTSD symptoms impact everyday life.

Research for this study was provided by grants from the American Cancer Society, Longaberger Company-American Cancer Society Grant for Breast Cancer Research, National Cancer Institute, National Institute of Mental Health, Ohio State Comprehensive Center, United States Army Medical Research Institute, and the Walther Cancer Institute. (J Trauma Stress. 2008;21(2):165-172.) –ML

 

Childhood Sexual Abuse Is a Risk Factor for Development of Bulimia Nervosa in Young Adulthood

Prior studies have shown that childhood incidence of sexual abuse is linked to a variety of mental health disorders and behavioral problems, including major depressive disorder, panic disorder, posttraumatic stress disorder, substance abuse (alcohol and drugs), and suicide. Eating disorders, such as anorexia and bulimia nervosa, have also been linked to childhood sexual abuse although data have been conflicting as to the association of each disorder to prior sexual abuse. Researchers at the Department of General Practice at the University of Melbourne in Australia sought to determine the relationship between childhood sexual abuse among females ≤16 years of age and the later development of anorexia and/or bulimia nervosa.

Lena Sanci, MBBS, PhD, FRACGP, and colleagues studied 1,936 female students from 44 public, private, and Catholic schools in Victoria, Australia from 1992 to 2008 to determine if a link between sexual abuse and development of an eating disorder exists. Among the 1,936 students (average age=15 years) who took part in at least one portion of the study, 999 continued the study through follow-up evaluation (average age of participants at follow-up=24 years).

All participants were assessed for anorexia or bulimia using the Branch Eating Disorders Test and identified with either disorder following Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Childhood sexual abuse that occurred ≤16 years of age was identified via self-report measures at follow-up. Childhood sexual abuse was measured at follow up due to the increased willingness among young adult participants to divulge incidents of abuse rather than children, and the duration between possible incident and follow-up being a shorter duration.

Thirty-five participants developed bulimia and 32 participants developed anorexia during the study period. Ninety-six participants reported one episode of childhood sexual abuse and 70 participants reported ≥2 episodes of abuse. When investigating the link between sexual abuse and eating disorder development, the incidence of bulimia was 2.5 times higher for those who reported one episode of sexual abuse and 4.9 times higher for those who reported ≥2 episodes of abuse, when compared to female students who did not report any episodes of sexual abuse.

There was no link between the development of anorexia and childhood sexual abuse. Sanci and colleagues adjusted for mediating or confounding factors including age, psychiatric morbidity, dieting behavior, and background factors, such as parental divorce. The authors concluded that childhood sexual abuse appears to be a risk factor for the development of bulimia nervosa in young adulthood and is not mediated by other psychiatric disorders. These findings are also similar to other studies that show both disorders related to childhood sexual abuse, although the link for bulimia is stronger.

Sanci and colleagues stated that these findings illustrate that the emotional style of patients with bulimia is similar to those who experience childhood sexual abuse, including feelings of emotional stress and secrecy. These patterns may be an important focus of interest to clinicians treating patients with bulimia.

Funding for this research was provided by the Australian Center for Excellence in Eating Disorders, the Australian National Depression Initative, and the Australian National Health and Medical Research Council. (Arch Pediatr Adolesc Med. 2008;162(3):261-267.) —CP

 

Amitriptyline in Low Doses Can Improve Quality of Life for Adolescents with IBS

Irritable bowel syndrome (IBS) is a comorbid functional disorder wherein the large intestine operates abnormally, resulting in abdominal pain, bloating, and diarrhea. As there is no cure for IBS, existing treatments only mitigate its symptoms. Past research suggests that the antidepressant amitriptyline is effective for the treatment of IBS in adults. However, a study by Ron J. Bahar, MD, and colleagues, suggests that low doses of amitriptyline can similarly and substantially improve the overall quality of life (QOL) for adolescents with IBS.

The double blind, placebo-controlled study involved 33 IBS patients (24 girls, 9 boys) between 12–18 years of age. It consisted of three phases, including 2 weeks of enrollment and symptom scoring, 8 weeks of therapy with either amitriptyline or placebo, and 3 weeks of post-medication washout and symptom scoring. Doses of amitriptyline were given according to the patient’s body mass; ie, 30–50 kg (one 10-mg capsule), 50–80 kg (two 10-mg capsules), and 80 kg (three 10-mg capsules). At 2, 6, 10, and 13 weeks, patient response to treatment was assessed using a symptom checklist, pain-rating scale, visual analog scale, and IBS-QOL questionnaire. The results found that patients receiving amitriptyline were more likely to experience improvement in QOL as well as reduction in right lower quadrant pain of the lower abdomen at 6, 10, and 13 weeks; reduction in IBS-associated diarrhea at 6 and 10 weeks; and reduction in periumbilical pain at 10 weeks.

“Most surprisingly, we were able to obtain statistically significant results with a relatively small number of subjects,” Dr. Bahar said. “Similarly, the biggest limitation to the study was the subject size, which did not allow us to stratify by sex.”
Greater than 50% of adolescents with IBS, or their parents or guardians, were deterred from enrolling in the study. They cited negative reports in the media and Food and Drug Administration warnings that discussed increased suicidal behavior in children using antidepressants. However, the researchers argue that such concerns are irrelevant as the dose in the study was lower than the dose used to treat depressive disorders. In this study, AMI is considered a treatment for neuropathic pain complemented by chronic pain symptoms, not an antidepressant.

Future research will determine who continues to stay well on amitriptyline, whose symptoms yield completely, and which medications can be substituted for amitriptyline so adolescents with IBS may safely use them.

Funding for this study was provided by AstraZeneca and the James L. Brooks and Diane Brooks Medical Research Foundation of the California Community Foundation. (J Pediatr. 2008;152(5):685-689.) –ML

 

Antidepressant Use Shown Not to be Cause for Suicide Rate Decline in Older Adults

Although 815,000 people die by suicide worldwide each year, in industrialized countries, the rate of suicide has progressively declined in recent years. Researchers in the psychiatric community have attributed the decline to the increased identification of mental health disorders such as major depressive disorder, and the increased use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). However, contrary to this claim, additional studies have not found an effect on suicide risk among patients taking SSRIs. Thus, the effect of patients taking SSRIs and/or other medications on the overall suicide rate has yet to be clearly determined.

Annette Erlangsen, PhD, of the National Centre for Register-based Research at the University of Aarhus in Denmark, and colleagues, studied the suicide and antidepressant use rate among people ≥50 years of age living in Denmark from 1996 to 2000 in order to determine if the decline in suicide rate (from 52.2 to 22.1 per 100,00 people between 1980 and 2000) was due to increased antidepressant use (from 8.4 to 52.2 per 1,000 people between 1990 and 2000). In Denmark, older adults receive antidepressants at higher rates than younger age groups and also have higher suicide rates than other age groups. Researchers evaluated suicide and antidepressant use rates for 2,100,808 adults.

Data were gathered from the Centralised Civil Register, the Register of Medical Product Statistics, and the Registry of Causes of Death. Antidepressants included in the analysis included SSRIs, such as citalopram and fluoxetine; tricyclic antidepressants (TCAs), such as clomipramine and nortriptyline; and other antidepressants, such as mirtazapine and nefazodone. Among all study participants, 299,440 filled ≥1 antidepressant prescriptions during the study period and were considered as “in treatment.” During the study period, 2,136 participants died by suicide.

Suicide rates for men fell by 9.7 per 100,000 people and rates for women fell 3.7 per 100,00 people during the study period. Regarding this decline in suicide rates among participants taking antidepressants, .94 suicides per 100,000 people were accounted for by men and .40 suicides per 100,000 people were accounted for by women taking antidepressants, which are approximately <10% of the total decline in suicide rates during the study time frame. Although rates were not significantly different among types of antidepressants taken, the authors found that men taking SSRIs had higher suicide rates than those taking TCAs.

Erlangsen and colleagues concluded that only a small portion of older adults who commit suicide are being treated with antidepressants at the time of death. According to the authors, this ratio was expected to be higher given the large reductions in treatment-specific suicide rates. The authors recommend that suicide prevention programs for older adults not only focus on the increased use of antidepressants. Study limitations included the potential influence on findings due to the method of defining “in treatment” as well as lack of information regarding prescription rates and actual drug administration and the possible influence of antidepressants taken without a prescription. 

Funding for this research was provided by the American Foundation for Suicide Prevention, the Danish Velux Foundation, and the National Institute of Aging. (J Epidemiol Community Health. 2008;62(5):448-454.) —CP

Psychiatric dispatches is written by Deborah Hughes, Michelisa Lanche, Christopher Naccari, and Carlos Perkins, Jr.

 

Dr. Opler is adjunct assistant professor in the Department of Psychiatry at New York University (NYU) and assistant professor of clinical neuroscience in the Department of Psychiatry at Columbia University in New York City. Dr. Perrin is assistant professor in the Departments of Psychiatry and Environmental Medicine at NYU. Dr. Kleinhaus is a Schizophrenia Research Fellow in the Department of Psychiatry at Columbia University. Dr. Malaspina is professor in and chairman of the Department of Psychiatry at NYU.

Disclosure: Drs. Opler, Perrin, and Kleinhaus report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Malaspina receives grant support from the National Institute of Mental Health.

Please direct all correspondence to: Mark G. A. Opler, PhD, Department of Psychiatry, New York University, 550 1st Avenue, MHB – 3rd Floor, New York, NY 10016; Tel: 646-234-3607; Fax: 646-758-8169; E-mail: mark.opler@med.nyu.edu.

 


 

Abstract

Schizophrenia is a brain disorder with a complex etiology believed to have both genetic and environmental risk factors. Although the precise pathology of the disease and the mechanisms that cause the emergence of symptoms remain elusive, understanding the causes of schizophrenia and its risk factors have evolved considerably over the past decade. The discussion has shifted from the reductionist “genes versus environment” debate to a more integrative approach, ie, the functions of susceptibility genes, epigenetics and paternal age, and toxic exposures throughout early development. This article discusses evidence for three major categories of risk factors, including genetic contributions, the role of paternal age and potential mechanisms by which it exerts its influence on risk, and new findings on the role of environmental exposures.

 

Introduction

Conventional wisdom holds that schizophrenia is a disorder of “unknown etiology,” and for many years, almost every review on the subject of causality began with some variation on that theme. However, as the end of the first decade of the 21st century approaches, the picture has begun to change. Several findings have now been confirmed (eg, nutritional deprivation) and a widely replicated risk factor, ie, advanced paternal age, has strongly implicated new mechanisms such as epigenetics. This article discusses current findings on the etiology of schizophrenia and related psychotic disorders. Divided into three sections, this article evaluates genes, particularly the evidence for genetic associations and the function of suspected susceptibility of genes; advanced paternal age and potential mechanisms by which it exerts its influence on pathology; and selected environmental exposures, including chemical exposures and nutritional deprivation during early development.

 

Genes

Twin, Family, and Adoption Studies

At the beginning of the 20th century, it was strongly suspected that some cases of schizophrenia were genetic in origin.1 This supposition was based on numerous twin studies performed in the intervening years that found monozygotic twins consistently had a higher concordance rate for schizophrenia than dizygotic twins.1 Among more recent studies, the concordance rate in monozygotic twins ranges from 44% to 79%, and among dizygotic twins the concordance rate ranges from 4% to 17%.2 Heritability estimates range from 71% to 85%.2

In an analysis of 40 family studies, Gottesman3 found that the grand average risk of being diagnosed with schizophrenia among relatives of cases was 2% for third-degree relatives, 4% to 6% for second-degree relatives, 9% to 13% for children and siblings, and approximately 46% for monozygotic twins. Adoption studies provided further support for a genetic contribution to schizophrenia risk. Adopted offspring of mothers diagnosed with a schizophrenia spectrum disorder (SSD) were at higher risk of SSD than the control adoptees (relative risk 4.67, 95% CI=2.24–9.77, P<.001),4 and there was a higher prevalence of SSD in the biologic relatives of an adoptee with SSD than in the adoptive relatives (14.4% versus 3%, P<.0001).5

 

Susceptibility Genes

Based on twin, family, and adoption studies there is clearly a strong genetic component to the risk of schizophrenia as well as an environmental and probable epigenetic component. Epigenetic processes can cause heritable changes in the genome. Although they do not involve changes in deoxyribonucleic acid (DNA) sequence, they can nonetheless alter gene expression. A common variant or polymorphism in a susceptibility gene may not in and of itself increase the risk of schizophrenia. However, in combination with other polymorphisms in other genes, it may increase the risk for rare variants. Furthermore, the increased risk associated with a particular polymorphism may only be relevant in conjunction with an environmental exposure. In the absence of an environmental exposure the polymorphism may have no effect on risk of schizophrenia.

In addition to polymorphisms, gene copy number and structural changes in chromosomes may play a role in schizophrenia. A recent study by Walsh and colleagues6 looked at rare structural variants through microarray comparative genomic hybridization. This study reported that rare deletions and duplications were significantly more common in schizophrenia cases than controls (15% versus 5%, P=.0008). In cases, rare structural variants were seen more frequently in pathways involving neurodevelopment, including neuregulin signaling, extracellular signal-regulated kinase/mitogen-activated protein kinase signaling, axonal guidance signaling, and glutamate signaling, among others. Further, the microdeletions and or duplications in 11 out of 24 genes were involved in the pathways referred to above. In controls, disrupted genes were not found to be predominantly in neurodevelopmental pathways or any other pathway.

The search for variants in genes detected in linkage studies or most recently through genome-wide scans have detected genes such as neuregulin (NRG1), dysbindin (DTNBP1), and disrupted in schizophrenia (DISC1). Studying these and other genes is a continuing process as is the study of the biologic import of their proteins. NRG1, DTNBP1, and DISC1 have generated a great deal of interest as putative susceptibility genes in schizophrenia.

NRG1
NRG1, which is located on chromosome 8p, was identified as a potential candidate gene for schizophrenia by a study in Iceland that reported a haplotype on NRG1 was present two times as frequently among cases compared to controls.7 These results were later confirmed in a Scottish study (Table 1).7-14 Expressed isoforms of NRG1 are associated with a multitude of biologic processes, some of which include neuronal migration and specification; neuron-glial signaling; glial development and differentiation; synapse formation; myelination; and regulation of NMDA, γ-aminobutyric acid-A, and nicotinic receptors.15

 

 

Many studies,15 but not all, have reported positive findings between different single nucleotide polymorphisms (SNPs) and haplotypes of NRG1 and schizophrenia. A meta-analysis performed in 2006,9 however, reported that though there was no association between the most frequently studied SNP, SNP8NRG221533, there was an association between NRG1 and schizophrenia based on a haplotype analysis. An update study10 published in 2008 found that the previous association between NRG1 and schizophrenia using haplotype analysis was attenuated compared to the 2006 study. Another meta-analysis11 showed an association for four SNPs and two microsatellite markers and risk of schizophrenia, though the results differed somewhat by ethnicity. Haplotype analysis also showed a significant association among Europeans. However, the largest single study to date12 found no link between NRG1, SNPs, and schizophrenia (Table 1).7-14

DTNBP1
DTNBP1 is located on chromosome 6p22.3 and its overexpression is linked to increased basal glutamate levels.16 It is believed to be protective of neuronal viability via P13-kinase-Akt signaling.17 In a postmortem brain study, there was 20% to 40% reduction in DTNBP1 messenger ribonucleic acid expression in patients with schizophrenia compared to controls (F=4.69, df=1, 18 P=.04). There was decreased expression in dentate granule cells (t=-1.90, P=.04) and dentate polymorph cells (t= -2.32, P=.02) and in CA3 (t=-1.99, P=.03) but not CA1 (t=-1.33, P>.05) regions of the hippocampus among those with schizophrenia compared to controls.17 It is hypothesized that lower levels of DTNPB1 may alter synaptic connectivity and glutamate signaling,17 possibly impacting the risk of schizophrenia.

Research in healthy individuals suggests that DTNPB1 genotype affects prefrontal brain function18 and general cognitive ability in schizophrenia patients and controls.19 In 11 out of 14 samples there was a significant association between SNPs in DTNPB1 and schizophrenia.20 The results of more recent studies are presented in Table 2.12-14,21-23

 

 

 

DISC1
A balanced translocation in t1:11 (q43, q21) was found in large Scottish family which occurred in 16/34 members with a psychiatric diagnosis and 5/43 without.24 This translocation results in damaged DISC1 on chromosome 1.23 It has been suggested that DISC1 is a “hub” protein interacting with many different proteins. For example, DISC1 and phosphodiesterase 4B (PDE4B) together regulate cyclic adenosine monophosphate signaling.25 DISC1 and fasciculation and elongation protein 1 are thought to act in concert with one another in axon guidance and outgrowth. In the mouse, DISC1 is developmentally regulated and is particularly associated with peaks prenatally, postnatally, and during puberty. DISC1 interacts with other proteins critical to neurodevelopment25 and has been implicated in centrosomal-based functioning and kinesin-mediated intracellular transport.26 Thus, alterations in DISC1 expression during early development due to events such as SNPs and rare mutations could be one of the factors that increase the risk of schizophrenia years later. Some,27-29 but not all, studies12 have been largely supportive of DISC1 as a susceptibility gene for schizophrenia (Table 3).12-14,27-29

 

The genetic contribution to schizophrenia is clearly complex and involves more genes than those discussed here. Genome-wide scans are currently ongoing and their results, ie, the genes they identify, are eagerly anticipated. The next step is identifying SNPs and haplotypes in the genes that the genome-wide scans detect and determining their effect on protein product and expression. This will be challenging research as the risk associated with variants in a detected gene may affect the risk associated with variants in other genes in a particular pathway. In addition, copy number and structural changes in genes may also play a role. Complicating the research further is that schizophrenia is a heterogeneous disorder and the pathways to schizophrenia diagnosis likely differ among individuals. Finally, these pathways plausibly include not only genetic but environmental and epigenetic components as well.

 

Parental Age

There is conclusive evidence that advancing paternal age is associated with an increased risk of schizophrenia. In 2001, Malaspina and colleagues30 published the first analysis of data from a large prospective cohort that showed the strong relationship between paternal age and risk of schizophrenia. It established that the findings were not confounded by maternal age, family history, or other socio-demographic factors such as birth order, social class, and birth weight. Offspring of fathers 45–49 years of age and ≥50 years of age had twice and three times the risk for schizophrenia, respectively, as the children of men <25 years of age.30 The observations in Malaspina and colleagues’ landmark study have been confirmed multiple times in the literature.31-33 Maternal age has not been associated with the risk of schizophrenia after accounting for effects of paternal age.30,32 It was considered whether the link between a father’s age and the risk of schizophrenia was due to psychiatric problems in parents delaying childbearing. Offspring of older fathers would then be more likely to inherit these psychiatric disorders, and paternal age would be only a mediator in the causal pathway to disease. However, effects of paternal age are not attenuated by family history of psychiatric illness.31

Paternal age is associated with other negative reproductive outcomes. Spontaneous abortion, autism, adolescent intelligence quotient, and the need for special education have each been related to paternal age independently of maternal age.34-37 Older men have an increased risk of fathering offspring with achondroplasia, Apert’s syndrome,38 and breast cancer, presenting before the child reaches 40 years of age.39 There is also convincing evidence that as men age they experience a statistically significant decline in fertility, independent of women’s age, coital frequency, and lifestyle effects.40

 

Genetic and Epigenetic Mechanisms

It is hypothesized that increased rates of genetic mutation in the sperm of older fathers may constitute an underlying mechanism for the link of advancing paternal age with an increased risk of schizophrenia as well as other negative reproductive outcomes.41 Current opinion is that replication errors are a major cause of such mutations as a consequence of the ongoing division of spermatogonial stem cells throughout a man’s reproductive life.42 An increase in point mutations has been linked with advancing paternal age43 as has the number of repeated DNA sequences and the rate of chromosomal breakage.44,45 The 22q11 deletion syndrome is associated with congenital anomalies, neurocognitive deficits, and increased risk of schizophrenia.46,47

Epigenetic changes might also contribute to increased risk.48 Epigenetic processes (eg, DNA methylation) change gene expression without changing gene sequence. In schizophrenia, parental imprinting is thought to be an important epigenetic process.48 In parental imprinting, either the maternal or paternal allele is silenced, leaving the other to be expressed. It is possible that changes in epigenetic regulation of gene expression occur over time in rapidly dividing spermatogonia cells due to either the effects of aging or the cumulative exposure to environmental insults over time in the father.48 Imprinted genes function in the growth of the central nervous system and might increase the risk of schizophrenia through direct effects on the expression of genes related to its pathology.48

The link between paternal age and schizophrenia might also be considered in relation to observations in achondroplasia. Offspring of older fathers have an increased risk of achondroplasia. It is theorized that age-related lesions may have occurred in sperm that disable DNA repair by oocyte components in the newly formed zygote; this disabling of DNA repair then results in disease in offspring.49 The most common mutation observed in sperm of fathers who have offspring with achondroplasia is also the most common mutation following oxidative damage to DNA, and lesions responsible for the initiation of aberrant DNA repair in the oocyte are oxidative in nature.49 Human spermatozoa are capable of generating Reactive Oxygen Species (ROS), and this activity is of physiologic significance in promoting sperm capacitation.50 If the process is disrupted, endogenous ROS generated by human spermatozoa can damage sperm function and DNA integrity.49 It is conceivable that paternal age-related mutations in regulation of ROS in sperm might also contribute to other negative outcomes associated with advanced paternal age.51

Schizophrenia is a disease with a complex genetic background, and environmental factors contribute to risk. Environmental exposures during fetal and childhood development could interact with genetic mutations or changes in epigenetic regulation. While social status does not account for paternal age effect in schizophrenia,30 older fathers may create different home environments during pregnancy or different rearing environments for their children in ways that are not easily measured. These environments could contribute to the increased risk for schizophrenia in the offspring of older fathers.

Paternal age is an important risk factor for schizophrenia in offspring. There is increasing evidence that epigenetic errors as well as gene mutations may contribute substantially to this effect, while gene environment interactions may also be involved in the association.52-54 The mechanisms responsible for its strong association with the risk for schizophrenia warrant further study.

 

Environmental Exposures

The role of in utero and pre-conceptual exposures in the etiology of schizophrenia has expanded considerably in the past decade. Recent investigations using prospective cohorts identified prior to birth have assessed the impact of known or suspected neurodevelopmental disruptors. Several ascertain prenatal exposure through laboratory measures, eg, analysis of archived maternal biologic samples collected prior to birth. Various hypotheses have been advanced and numerous studies have produced suggestive results.

 

Maternal Nutritional Deprivation

The role of maternal nutrition has been associated with the risk of schizophrenia. Both lack of specific micronutrients and general nutritional deprivation have been previously implicated as risk factors for broad developmental disruption and for schizophrenia specifically. In one landmark study of prenatal nutritional deprivation known as the Dutch Famine Study,55 neurodevelopmental outcomes following severe caloric restriction were measured. Rates of schizophrenia were approximately doubled for individuals conceived under conditions of nutrient deprivation during early gestation.56 This finding has been re-examined and replicated by St. Clair and colleagues.57

 

Maternal Body Mass Index

Recently, high maternal body mass index (BMI) has become a focus of concern as the number of women of reproductive age with above average or high BMI has increased in industrialized societies.58 It has been studied in a prospective birth cohort, the Prenatal Determinants of Schizophrenia (PDS) study. The PDS is a cohort of 12,097 pregnancies in California that occurred between 1959 and 1967.59 Over the 40 years of follow up, 71 cases of schizophrenia spectrum disorder were identified by standardized procedures, including in-person diagnostic interviews. The PDS study used measures of prepregnant maternal BMI that were categorized to low (<19.9), average (20.0–26.9), above average (27.0–29.9), and high (≥30.0). As compared with average maternal prepregnant BMI, high BMI was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk=2.9; 95% CI=1.3–6.6).60

Influenza and Markers of Infection

Previous work describing associations between prenatal exposure to a variety of viral agents has been considered for some time and extensively reviewed elsewhere.61-63 Studies by Brown and colleagues64 demonstrate that first trimester exposure to influenza (determined serologically) was associated with a seven-fold increase in risk of schizophrenia spectrum disorder, while second and third trimester exposure showed no increase in risk. Additional analyses examined exposure during the first and second halves of pregnancy defined as 0–142 days (in effect, 40–142 days post-last menstrual period [LMP]) and from 143 days post-LMP until termination of pregnancy, respectively. Exposure in the first half of pregnancy conferred a threefold increase in risk, while no increase was seen following exposure during the second half of pregnancy or when second trimester exposure was considered.64

 

In-utero Lead Exposure

The first study65 on prenatal lead exposure and schizophrenia was conducted as a case-control study, nested within a prospective birth cohort—the previously mentioned PDS. Maternal serum samples were analyzed for δ-aminolevulinic acid (ALA), which is a biologic marker of Pb exposure using high pressure liquid chromatography with fluorescence detection. Validity studies were conducted and showed that serum δ-ALA levels >9.05 ng/mL were predictive of Pb exposure; δ-ALA levels >9.05 ng/mL were associated with a non-significant increase in risk of schizophrenia (odds ratio=1.54, 95% CI=0.86–2.86). This study provided preliminary evidence that prenatal exposure to Pb may be a risk factor for schizophrenia spectrum disorders in later life, but was restricted by sample size. A second analysis incorporating data from the New England Cohort of the National Collaborative Perinatal Project is consistent with earlier findings and the results will be forthcoming (M Opler, PhD, unpublished data, April 2008).

 

Parental Tetrachloroethylene Exposure

In an effort to expand research from lead into other parental chemical exposures and schizophrenia, tetrachloroethylene (PCE) exposure was examined. PCE (also referred to as perchloroethylene and tetrachloroethene, or PERC), is a common organic solvent, frequently appearing as a ground water contaminant.66 Dry cleaners are occupationally exposed to PCE since it has been used as a cleaning agent since the 1950s.67

The Jerusalem Perinatal Study of Schizophrenia,30,68,69 is a cohort study of 88,829 individuals born in Jerusalem, Israel, from 1964–1976 and followed to January 1, 1998; at this point, they were 21–33 years of age. Demographic data on parents, including their occupations, were linked to data on schizophrenia in offspring obtained from national registries. Six-hundred thirty-seven offspring were diagnosed with schizophrenia or related conditions. An estimate of the relative risk of schizophrenia in offspring of parents who were dry cleaners was calculated, taking into account confounders such as parental age, social class, duration of marriage, residence (urban or rural), religion, ethnicity, parental immigration status, birth order, sex, birth weight, and month of birth. The cohort available for study included 88,060 offspring, 637 with schizophrenia-related diagnoses, and 144 with one or more parents who were dry cleaners. Of these, four were diagnosed with schizophrenia over the 21–33 years of follow-up. The offspring of dry cleaners had a significantly increased risk of schizophrenia compared to offspring of parents in all other occupations (relative risk 3.4, 95% CI=1.3–9.2). This relationship was unexplained by parental age, social class, duration of marriage, urban versus rural residence, religion, ethnicity, or immigration status, or by the offspring’s birth order, sex, birth weight, and month of birth.

These results suggest that pre-conceptual, prenatal, or childhood exposures to PCE could play a meaningful role in the risk for schizophrenia, particularly in populations with occupational or environmental exposures. Similar to findings on lead exposure described above, the role of paternal exposure cannot be confirmed or refuted on the basis of this study. However, the results provide a further rationale for conducting basic and clinical research studies to investigate parental chemical exposure.

 

Conclusion

This article illustrates the diverse nature of the findings on the etiology of schizophrenia, including genetic, environmental, and epigenetic. One important question that has yet to be addressed is whether or not these multiple risk factors contribute via a single common pathway that leads to a single disease, or rather, if they act via multiple pathways, causing similar but separate disorders. It has been known for many decades that schizophrenia is highly variable in clinical presentation and in the relative efficacy of treatments across patients. The multiple pathways to schizophrenia that have been reviewed here may be reflected in neurobiologic differences, in the heterogeneous clinical presentation of the disease, and in differential responses to treatment. New research efforts must now be undertaken to determine if the heterogeneity of schizophrenia can be organized in terms of etiology. Communicating research findings between disciplines and incorporating both systematic and serendipitous clinical observations will be crucial as clinicians learn to apply this growing body of knowledge to improving the effectiveness of their treatments and reduce the incidence of new cases worldwide. PP

 

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34.    Kleinhaus K, Perrin M, Friedlander Y, Paltiel O, Malaspina D, Harlap S. Paternal age and spontaneous abortion. Obstet Gynecol. 2006;108(2):369-377.
35.    Reichenberg A, Gross R, Weiser M, et al. Advancing paternal age and autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.
36.    Malaspina D, Reichenberg A, Weiser M, et al. Paternal age and intelligence: implications for age-related genomic changes in male germ cells. Psychiatr Genet. 2005;15(2):117-125.
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Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.

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

 


 

E-mail has quickly become a preferential mechanism of communication today as evidenced by the growing numbers of smartphones, iPhones, and Blackberry communication devices used in both personal and work environments. Patients today are much more tech savvy, and have begun to rely upon health information on the Internet as well as utilize various Internet-based tools (eg, to assess themselves for depression, check their body mass index, and check their medications for drug interaction). The combination of soaring gasoline prices and increasing demands at the workplace for productivity has created a climate where electronic communication between physicians and patients will become more the norm rather exception. This column reviews privacy and security issues in health information technology in several modalities of electronic communication.

 

Security and Privacy Issues

One of the foremost concerns with any electronic communication or record is the issue of privacy and confidentiality. When a laptop computer was stolen from the Department of Veteran’s Affairs (VA) medical facility in Birmingham, Alabama in 2007,1 this sparked a major overhaul in the VA health system with regards to management of security.2 The Health Insurance Portability and Accountability Act (HIPAA) of 1996 was written to improve the Medicare program by encouraging the development of health information systems through the establishment of standards and requirements for electronic transmission of certain health information.3

As many physicians know already, HIPAA mandates that security measures and policies be implemented to ensure privacy and confidentiality of protected health information, but it does not specify what type of security mechanism. It recommends a combination of administrative, physical, and technical safeguards to protect the confidentiality, integrity, and availability of protected health information. These safeguards are designed to protect stored information from the risks of improper access and prevent interception during electronic transmission.

One way to avoid the regulations in HIPPA is to not be a covered entity such as a healthcare clearinghouse, health plan, or a healthcare provider who conducts certain financial and administrative transactions electronically. It may appear that a cash pay practice and a paper-based medical record are sufficient to bypass the rigors of HIPAA; however, such a perspective ignores the benefit of electronic records and transactions, which include ease of backup, portability, ease of transmission, multi-site availability, and ability to monitor and prevent access.

 

E-mail

Today’s patient is much more technologically savvy and regularly uses e-mail. Communicating via e-mail is not just for the young professional; even patients who have retired have begun to use e-mail.4 Slack4 noted that a patient saw e-mail as a benefit because it enabled him to write a question directly to his physician, instead of going via the telephone which would add additional layers to route the call. The patient only wrote once every 2 weeks, but found that being able to print out his question and responses helped him refer to them later. The patient’s physician believed that e-mails often replace conversations that would have happened on the phone anyway, and he felt that fortunately, there were no “rambling novels” of e-mails. The physician indicated that an e-mail exchange often takes less time than a phone conversation because the patient thinks ahead of time what specific question to ask in an e-mail. In this scenario, both patient and physician logged into a secure Internet site for patients.

Guidelines by Kane and Sands5 in 1998 for the clinical use of e-mail with patients outlined principles developed by the American Medical Informatics Association Task Force on Guidelines for the Use of Clinic-Patient Electronic Mail. Communication guidelines include establishing what types of transactions, such as appointment scheduling and subject matter sensitivity are permitted; turnaround time; informing patients about privacy issues such as who has access to these messages and that they are part of the medical record; and placing such communication in the paper chart. Medicolegal and administrative guidelines include obtaining informed consent for e-mail, using password-protected accounts, separating professional e-mail from personal e-mail, using encryption, and not forwarding patient identifiable information to third parties without the patient’s permission.

Today, e-mail encryption is still a cumbersome process that is not easy to implement. On the Microsoft Windows operating system, PKZIP offers a product called SecureZip for Desktop, which integrates with Microsoft Office applications such as Outlook, Word, Excel, and PowerPoint.6 This product compresses e-mail and encrypts it automatically to provide a seamless experience; however, the e-mail recipient must know and understand how to decrypt and decompress the file.

Another similar product on the Windows platform is PGP Desktop Email from Pretty Good Privacy (PGP) corporation.7 PGP was developed in 1991 by Phil Zimmermann8 as an e-mail encryption software package to promote human rights on the Internet. It has become a standard for encryption, and an open source version, OpenPGP, is available as well.9 An implementation of OpenPGP into a mail client is freely available at Gnu Privacy Guard,10 called Gpg4win.11 One of the caveats of installing Gpg4win is that knowledge of e-mail account type (post office protocol versus internet message access protocol), server name (incoming and outgoing), and account name and password is necessary for setup. PGP Desktop does offer a freeware version, which is only for non-commercial use, such as patients.

On the Mac operating system, there are several ways to provide encrypted e-mail. PGP offers a Mac version of its PGP Desktop E-mail product, and CryptoHeaven12 also offers both a Mac and PC version of its product. Mac GNU Privacy Guard13 is a free OpenPGP software program similar to Ggp4win. One of the challenges of installing encryption for e-mail is to understand that the PGP or Open PGP are merely encryption code, and must be implemented by software clients such as Gpg4win or Mac GNU Privacy Guard.

With the potential confusion with regards to installing OpenPGP clients, an alternative is to use a digital signature to “sign” e-mail.14 In this manner, what happens is that a “public key” is used to sign e-mails sent to a recipient, but only the recipient has the “private key” to decrypt that message. The challenge is that although individual users can create and send their own “keys,” it is insufficient to trust that they are who they are since it is easy to impersonate someone else in e-mail. Third party “certification authorities” such as Thawte15 establish trust by verifying one’s identity and then issuing the private and public keys. After obtaining the keys from Thawte, they must then be integrated into the mail client.

It appears that to implement an encryption method for one’s regular e-mail client is a process left to either the most technically savvy physician or the enterprise. A much simpler alternative is to utilize a secure Internet-based communication platform such as Network Research Labs S-Mail.16 Unlike many Internet browser-based e-mail systems, S-Mail implements the public key encryption system discussed above, but instead of requiring that the user manage the keys, S-Mail installs and manages them by creating them on the Java Virtual Machine on one’s computer. S-Mail is not encrypted when mail is sent to any other e-mail account, but it remains encrypted when both sender and recipient, eg, a patient and physician, are on S-Mail. It is important to understand that the company does not have access to e-mails, passwords, or private keys since these are on the user’s computer and not the company server. This system is not ideal for large groups or healthcare enterprise but may be perfect for individual practices since the service is free. The paid version offers larger mailbox as well as other encrypted storage.

The simplest option is to use a service such as RelayHealth,17 which requires no installation at all and it is entirely Internet-browser based secured via 128-bit Secure-Socket-Layer 3.0 encryption. Providers set up an account and may give administrative access to staff to initially read messages. In addition to secure electronic messaging, the system offers non-urgent asynchronous consultations, appointments, medication refills, and preventive care reminders. Patients sign up for free and may register their family members as well. Liederman and Moorefield18 at University of California, Davis Primary Care Network surveyed eight providers, their staff, and patients utilizing this system. Of registered users, 36.9% (238/645) responded to the survey, which demonstrated that both providers and patients preferred the Internet messaging system over phone calls for the communication of non-urgent problems. Almost all of the patients found it easy to use and were satisfied because their provider had a timely response. Clinicians were also favorable to the system despite concerns that they would be inundated with messages and therefore impacted in terms of productivity. Aetna has expanded its use of RelayHealth to include specialty providers and will reimburse for online consultations and other secure messaging services.19

 

Other Forms of Electronic Communication

Although e-mail has become the most common form of electronic communication between patients and physicians, instant message (IM) software may be used instead of e-mail. One of the advantages of IM is that it is centrally managed from a server and therefore is more stable compared to voice over Internet protocol (VOIP). Questions and responses are managed in real time and appear much less asynchronous. However, IM’s central management also is its weakness in terms of privacy as the system is an open network. There are numerous companies, such as Sigaba Secure IM, that will provide secure instant messaging. Security is provided either at the server level or as an encrypted tunnel through the public network.20 In all likelihood, the instant and intrusive nature of IM does not lend itself well to medical practice, but such a secured service could provide some benefit to patients who otherwise would not participate in health treatment, such as teenagers, who prefer text messaging and IM services. Once the “session” is over, a word for word transcription can be captured if the text session has not exceeded the buffer capacity or if the session has not been interrupted.

VOIP is another possibility for electronic communication since many therapists use a telephone session in lieu of an in-person session if patients are out of town or in transition to another location. Skype is a well-known VOIP service and it has both authentication and encryption to ensure the privacy of a session.21 This service is free to use from computer to computer over the Internet, but it also offers low-cost computer-to-landline and landline-to-computer calls. If desired, Skype calls can even be recorded onto the computer with audio recording programs.22 Even a computer is not necessary as mobile devices such as a personal digital assistant, the PlayStation Portable, and even Wi-Fi–enabled phones can use the Skype system.23 Many professional users may shy away from Skype since it is so well known, and therefore should try the Zfoneproject, which is encrypted by PGP and developed by Philip Zimmerman.24

Conclusion

Electronic communication with patients comes in many forms, both text based, voice, and perhaps even video. Without question, there are disadvantages to this form of communication such as privacy and security, in addition to its asynchronous nature. Simple yet robust e-mail security can be managed by both provider and patient, but may require both patience and technical support. The secure Internet-based communication hub appears to be favored by not only patients and providers, but insurance plans as well. In today’s digital age, despite the technological and HIPAA hurdles, both the busy patient and busy physician can benefit from electronic communication. PP

 

References

1.    Hubler D. New House VA Committee Chairman Laments Latest Laptop Loss. February 6, 2007. Available at: www.fcw.com/online/news/97587-1.html. Accessed May 13, 2008.
2.    Mosquera M. VA Security Still in Recovery Mode. April 7, 2008. Available at: www.fcw.com/print/22_8/policy/152134-1.html. Accessed May 13, 2008.
3.    Health Insurance Portability and Accountability Act of 1996. Available at: http://aspe.hhs.gov/admnsimp/pl104191.htm. Accessed May 13, 2008.
4.    Slack VW. A 67 year-old man who e-mails his physician. JAMA. 2004;292(18):2255-2561.
5.    Kane B, Sands DZ. Guidelines for the clinical use of electronic mail with patients. The AMIA Internet Working Group, Task Force on Guidelines for the Use of Clinic-Patient Electronic Mail. J Am Med Inform Assoc. 1998;5(1):104-111.
6.    SecureZip for Desktop. Available at: www.pkzip.com/software-data-security. Accessed May 13, 2008.
7.    PGP Desktop Email. Available at: www.pgp.com/products/desktop_email/index.html. Accessed May 13, 2008.
8.    Philip Zimmermann. Available at: www.philzimmermann.com/EN/background/index.html. Accessed May 13, 2008.
9.    Open PGP Alliance. Available at: www.openpgp.org. Accessed May 13, 2008.
10.    GnuPG. Available at: www.gnupg.org. Accessed May 13, 2008.
11.    Ggp4win. Available at: www.gpg4win.org/. Accessed May 13, 2008.
12.    CryptoHeaven. Available at: www.cryptoheaven.com. Accessed May 13, 2008.
13.    Mac GNU Privacy Guard. Available at: http://macgpg.sourceforge.net/. Accessed May 13, 2008.
14.    de Kermadec FJ. How to Set Up Encrypted Email on Mac OS X. Available at: www.macdevcenter.com/pub/a/mac/2003/01/20/mail.html?page=1. Accessed May 13, 2008.
15.    Thawte Personal E-mail Certificates. Available at: www.thawte.com/secure-email/personal-email-certificates/index.html?click=DoYouNeedTo-SecureMail. Accessed May 13, 2008.
16.    Network Research Lab S-Mail. Available at: www.nrlab.com/main.php?pg=s-mail&subpg=overview or www.s-mail.com. Accessed May 13, 2008.
17.    RelayHealth. Available at: www.relayhealth.com. Accessed May 13, 2008.
18.    Liedeman EM, Morefield CS. Web messaging: a new tool for patient-physician communication. J Am Med Inform Assoc. 2003;10(3):260-270.
19.    Aetna Expands Availability Of RelayHealth‘s Secure Online Messaging And Consultations Nationwide, Includes Specialists. Available at: www.aetna.com/news/2007/1219.htm. Accessed May 13, 2008.
20.    Sigaba Secure IM. Available at: www.sigaba.com/sec_products/secure_im/index.shtml. Accessed May 13, 2008.
21.    Skype. Available at: www.skype.com/security/security/. Accessed May 13, 2008.
22.    How to Record Skype Phone Calls. Available at: www.how-to-capture-streaming-media.com/record_skype_phone_calls/record_skype_phone_calls.htm. Accessed May 13, 2008.
23.    Skype on Your Mobile Device. Available at: www.skype.com/mobile/. Accessed May 13, 2008.
24.    Zfone. Available at: http://zfoneproject.com/prod_zfone.html. Accessed May 13, 2008.

 
Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Johnson and Johnson, PGxHealth, Pfizer, Schering Plough, Somerset, and Takeda.

 


Alzheimer’s disease is a progressive neurodegenerative disorder of increasing prevalence, clinically manifested by memory impairment and declining cognition. Approximately 25 million people worldwide suffer from dementia as a result of Alzheimer’s disease.1 Greater than 50% of individuals with Alzheimer’s disease experience agitation, aggression, delusions, or hallucinations during the course of their illness.2 These behavioral disturbances of Alzheimer’s disease pose difficult management problems because existing agents are not fully effective and safe; better pharmacotherapy is needed. Antipsychotics are widely prescribed to treat behavioral disturbances in Alzheimer’s disease patients, although recent safety concerns with the atypical antipsychotics have led to more restrictive labeling imposed by the Food and Drug Administration.

 

 

Prevalence of Agitation in Alzheimer’s Disease Patients

Long-term observation of patients with mild-to-moderate Alzheimer’s disease randomized to placebo treatment as part of a 1-year double-blind, controlled trial found agitation to be the most common symptom.3 Agitation/aggression occurred in 54% of patients over 1 year of observation, followed next in incidence by depression (50%) and psychosis (36%). Agitation was associated with greater cognitive impairment. Presence of psychotic symptoms correlated both with more rapid cognitive decline and with age. In a 2-year observational study tracking behavioral and psychological symptoms in Alzheimer’s disease patients, agitation and aggression were the most frequent as well as persistent symptoms and, in addition to psychotic symptoms, were harbingers of more rapid progression of the disorder.4  

Numerous health economic surveys5 implicate behavioral symptoms in Alzheimer’s disease as significant independent predictors of  need for institutionalization and higher patient care costs. The magnitude of the cost differential associated with behavioral problems in Alzheimer’s disease patients averaged an additional $10,000 to $15,000 per year compared with those without these clinical manifestations of Alzheimer’s disease.

 

Antipsychotic Therapy in Alzheimer’s Disease

Antipsychotics are widely used to treat dementia in elderly patients. According to a statewide survey of Medicare beneficiaries in nursing homes, >25% of patients received treatment with an antipsychotic.6 Antipsychotics have been a mainstay of pharmacologic therapy for agitation and aggressive behavior despite limited effectiveness and recent safety concerns.7,8

Over the last decade, atypical antipsychotics largely replaced first-generation antipsychotics as the preferred treatment for behavioral disturbances in elderly patients with dementia because of  perceived safety advantages over traditional antipsychotics and other psychotropic drugs, including the benzodiazepines and anticonvulsants. Safety advantages include less orthostatic hypotension or adverse effects on cardiac repolarization (prolonged QT), less sedation, and decreased liability for movement disorders.

The unexpected findings of higher mortality and incidence of stroke during atypical antipsychotic treatment of Alzheimer’s disease patients in placebo-controlled trials led to warnings and restrictions in product labeling of antipsychotics imposed by the FDA.6,8 There was a consistent pattern of small but significant increases in mortality and strokes in trials of each of the atypical antipsychotics compared with placebo treatment.8,9 The Committee for the Safety of Medicines in the United Kingdom has imposed similar constraints on the use of atypical antipsychotics in dementia patients.

Trials have shown that atypical antipsychotics provide only modest benefits for the behavioral symptoms of Alzheimer’s disease. In the absence of aggressive behavior, there were no differences in improvement of agitation between antipsychotic and placebo treatment.8 Both risperidone and quetiapine lacked efficacy compared with placebo treatment for treating agitation in patients receiving institutional care.8,9 Quetiapine treatment was associated with greater cognitive decline than with placebo treatment, and its anticholinergic properties may contribute to poorer therapeutic response.

In addition, there is evidence in one clinical trial that neuroleptic drug treatment may actually accelerate cognitive decline and induce pathologic changes characteristic of Alzheimer’s disease.10  It is also postulated that suppression of neurotropic factor by antipsychotics may accelerate accumulation of pathologic substrates in brains of Alzheimer’s disease patients.8  

 

Memantine for Agitation and Aggression in Advanced Alzheimer’s Disease

Memantine is the first of a new class of agents for the treatment of Alzheimer’s disease acting on the glutamatergic system. Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist approved for treatment of patients with moderately severe and severe Alzheimer’s disease. Dysfunction of glutamatergic neurotransmission, manifested by neuronal excitotoxicity, is implicated in the etiology of Alzheimer’s disease. Memantine acts as a non-competitive, low potency antagonist at NMDA receptors and inhibits prolonged influx of calcium ions, causing neuronal excitotoxicity.11,12 In general, memantine therapy is well tolerated clinically because it has low potency as an NMDA receptor antagonist and differs from treatment with the more potent NMDA antagonists, which offer neuroprotective effects but often have unacceptable side effects.

The efficacy and tolerability of memantine was established in a series of placebo-controlled trials that show significant, albeit modest, therapeutic benefits in Alzheimer’s disease.13-15 Memantine treatment produces improvement in multiple domains, including global, cognitive, functional, and behavioral. A recent retrospective meta-analysis of pooled data from the efficacy trials examines outcomes in patients with agitation, aggression, or psychosis before trial entry.16 Patients who scored ≥1 on any of three Neuropsychiatric Inventory (NPI) items assessing agitation/aggression, delusions, or hallucinations within 4 weeks of entry into the trial were analyzed separately. Of the 983 patients in the total study population, 593 (60%) manifested agitation, aggressive behavior, or psychosis prior to treatment (placebo=287, memantine=306). This subgroup with pre-existing behavioral symptoms resembled the overall patient sample in demographics, Mini-Mental Status Exam scores, and symptom severity (except for NPI score).

Across the trials, 454 patients had pre-existing agitation/aggression, 336 delusions, and 172 hallucinations.13-15 Improvement on the NPI behavioral symptom cluster was significantly better with memantine than with placebo treatment at both 3 months (P=.0014) and 6 months (P=.0004). At 6 months, memantine treatment showed significant benefit compared with placebo on measures of cognition (P<.001), activities of daily living (P<.001), and clinician/caregiver impression of change in clinical status (P<.001). In addition, memantine treatment was tolerated better than placebo treatment, with fewer discontinuations from the study treatment over the 6 months. The incidence of withdrawals due to agitation and psychosis among placebo-treated patients was 3-fold higher than with memantine treatment (7.5% versus 2.6%, respectively, P<.01).

For patients randomized to placebo treatment in the trials, behaviorally disturbed patients at trial entry experienced significantly greater decline in clinical status and activities of daily living than placebo-treated patients without pre-existing symptoms. For those patients with neither prior agitation/aggressive behavior or psychosis, significantly fewer memantine-treated patients (P<.01) went on to develop behavioral symptoms during the 6 months of treatment compared with placebo, indicating preventive benefit with memantine therapy.

 

Conclusion

Behavioral disturbances and psychotic symptoms in Alzheimer’s disease are associated with rapid disease progression and increased costs of care. Although safety concerns about increased mortality and stroke and changes in product labeling have tempered their use, antipsychotics remain the mainstays of drug therapy for these symptoms of dementia in the elderly. A pooled analysis of efficacy trials of the NMDA antagonist memantine indicates that it is superior to placebo for treating and preventing behavioral symptoms in Alzheimer’s disease patients; however, the therapeutic benefit appears to be modest. PP

 

References

1.    Ferri CP, Prince M, Brayne C, et al. Global incidence of dementia: a Delphi consensus study. Lancet. 2005;366(9503):2112-2117.
2.    Schneider LS, Tariot PN, Dagerman KS, et  al. Effectiveness of atypical antipsychotics in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525-1538.
3.    Levy ML, Cummings JL, Fairbanks LA, et al. Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer’s disease. Am J Psychiatry. 1996;153(11):1438-1443.
4.    Haupt M, Kurz A, Janner M. A 2-year follow-up of behavioral and psychological symptoms in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2000;11(3):147-152.
5.    Murman DL, Chen Q, Powell MC, Kuo SB, Bradley CJ, Colenda CC. The incremental direct costs associated with behavioral symptoms in AD. Neurology. 2002;59(11):1721-1729.
6.    Robinson DS. Mortality risks and antipsychotics. Primary Psychiatry. 2008;15(4):21-23.
7.    Margallo-Lana M, Swann A, O’Brien J, et al. Prevalence and pharmacological management of behavioural and symptoms amongst dementia sufferers living in care environments. Int J Geriatr Psychiatry. 2001:16(1):39-44.
8.    Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934-1943.
9.    Schneider LS, Dagerman KS, Insel  PS. Efficacy and adverse effects of atypical  antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14:191-210.
10.    Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomized, double-blind, placebo-controlled trial. BMJ. 2005;330(7496):874-878.
11.    Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003;9(3):275-308.
12.    Lipton SA. The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: low affinity, uncompetitive antagonism. Curr Alzheimer Res. 2005;2(2):155-165.
13.    Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003;348(14):1333-1341.
14.    Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317-324.
15.    Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999;14(2):135-146.
16.    Wilcock GK, Ballard CG, Cooper JA, Loft H. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: a pooled analysis of 3 studies. J Clin Psychiatry. 2008;69(3):341-348.

 

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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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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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.

 

FDA Approves Desvenlafaxine Succinate for Treatment of Major Depressive Disorder

The United States Food and Drug Administration approved desvenlafaxine succinate (Pristiq, Wyeth Pharmaceuticals), a serotonin norepinephrine reuptake inhibitor, to treat adult patients with major depressive disorder (MDD). The recommended dosage for an adult with MDD is 50 mg/day. This dosage does not require titration, which allows patients to start immediately at the recommended dosage.

The efficacy of desvenlafaxine was established through four, 8-week randomized, double-blind, placebo-controlled, fixed-dose studies of adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD. Approval was based on several post-marketing commitments, including conducting and submitting data from several studies—a new long-term maintenance relapse-prevention study; a sexual dysfunction study; a lower dosage study; pediatric studies and a non-clinical toxicity study.

The discontinuation rate due to adverse events for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%). The most common adverse events observed in MDD patients in fixed-dose, short-term studies were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders.

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

 

Symptom Severity of Generalized Social Phobia Not Likely to Determine Success of Cognitive Behavioral Group Therapy

Primary care physicians may hesitate to refer an individual with severe generalized social phobia (GSP) for cognitive-behavioral group therapy (CBGT) because the patient may either not benefit from it or will stop treatment. Approximately 26% of patients who attend CBGT sessions do not complete treatment, and completers do not always show improvement. According to a study by Dave Davies, PhD, of the Royal Ottawa Mental Health Centre in Ontario, Canada, and colleagues, CBGT can benefit patients with GSP, but the severity of symptoms associated with GSP does not necessarily predict patient completion of or response to CBGT.

The 12-week study involved 78 patients between 18 and 61 years of age diagnosed with GSP in accordance with criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision and as assessed by the Social Phobia Diagnostic Questionnaire. Patients were randomly divided into groups of five to eight individuals, and each group attended 12 CBGT sessions hosted by two CBT-trained therapists. The program consisted of psycho-education, cognitive restructuring, within-session exposure, in vivo exposure homework, and relapse prevention. Using Social Phobia Inventory (SPIN) scores to determine response to treatment, 30 of the 51 participants who completed therapy (ie, attended ≥7 sessions and completed follow-up surveys) positively responded with a reduction of ≥9 points on the SPIN. Completers demonstrated a substantial decrease in social anxiety, avoidance, and cognitions. Their scores on both the Beck Anxiety Inventory and Beck Depression Inventory-II declined as well. Results suggest that CBGT can reduce social anxiety symptomatology among a majority of individuals with GSP, but they do not necessarily indicate symptom severity as a factor for determining completion of CBGT.

In addition, the researchers unexpectedly found that anxiety and associated avoidance were not the primary reasons for participants’ discontinuation of CBGT.

“[Participants] who completed therapy were not different from their counterparts who discontinued treatment in terms of any anxiety-related variables (eg, symptom severity, avoidance, strength of negative cognitions, and depression) assessed prior to treatment,” Dr. Davies said.

That the research primarily focuses on social anxiety symptomatology before and immediately after group treatment limits the study, as whether or not treatment responses are consistent in the long-term is not assessed. Lack of follow-up with participants who did not complete therapy limits the study as well, leaving the reason for patient discontinuation unknown.

“Ascertaining reasons for discontinuing would be helpful for planning future interventions that would increase retention of participants,” Dr. Davies said. (2008 ADAA, Poster 122). –ML

 

Increased Prevalence of Anxiety and Internalizing Problems in Children with OCD and Comorbid Depression

In adults, depressive and anxiety disorders often occur as comorbid conditions with obsessive-compulsive disorder (OCD). Studies have shown that approximately 33% of patients with OCD report comorbid depression, which has also been shown to negatively affect overall treatment response. Although researchers have investigated the efficacy of pharmacologic indications for the treatment of OCD and depression in children, few studies examine the prevalence of comorbid depression in children and adolescents with OCD. Research is also lacking in determining possible risk factors for comorbid depression in children and adolescents with OCD.

Kristin E. Canavera, MS, at the Virginia Polytechnic Institute and State University in Blacksburg, and colleagues, evaluated 56 children and adolescents with OCD to determine the prevalence and potential risk factors for comorbid depression. They hypothesized that comorbid depression in patients with OCD may be correlated with the comorbidity of other anxiety disorders, more severe symptomology, and presence of parental depression. They also sought to extend current understanding of comorbid OCD and depression in adults to the child and adolescent population.

Patients were 10–17 years of age (mean age=14.5 years). All participating families received the Anxiety Disorders Interview Schedule, which assessed symptoms of anxiety and depression. Patients were divided into two groups, ie, those who met diagnostic criteria for OCD and did not have comorbid depression (n=28), and those with OCD and a comorbid depressive disorder (n=28). The prevalence, severity, and risk of comorbid depression among patients in the study were measured using the Children’s Depression Inventory, the Penn State Worry Questionnaire for Children (PSWQ-C), and the 39-item Multidimensional Anxiety Scale for Children (MASC). Parental self-reports including the Child Behavior Checklist (CBCL) and the Depression, Anxiety, and Stress Scales were also used to determine depression rates for both children and parents.

Canavera and colleagues found that among children and adolescents with OCD, there were significant differences in symptomology for those with and without comorbid depression. Patients with OCD and comorbid depression showed significantly higher rates of pervasive worry (PSWQ-C score of 38.1 for OCD patients with depression compared to 28.6 for those without depression) and internalizing problems, as measured by the CBCL, than patients without comorbid depression. Anxiety disorders, including social anxiety disorder and generalized anxiety disorder, were commonly associated with presence of OCD with comorbid depression. Although differences in MASC and clinical severity were not significant, differences were present among patients with and without comorbid depression. Contrary to their hypotheses, the authors found that OCD severity was not significantly higher for children and adolescents with comorbid depression, and that mothers’ rates of depression and anxiety were not significantly higher for patients with comorbid depression.

These results show that children and adolescents with OCD and comorbid depression may experience more internalizing problems than those without depression, which may alter the treatment course to include both OCD and depressive symptoms. Although cognitive-behavioral therapy (CBT) has shown to be effective for adults with OCD and depression, the authors suggest that a CBT approach that includes family support may be more effective with children and adolescents. The authors recommend that future research investigate whether comorbid depression is related to specific obsessive or compulsive symptoms of OCD. (2008 ADAA, Poster 72). –CP

 

PCMAD: A Self-Report Scale for Improved Detection of Mood and Anxiety Disorders

Unrecognized or misdiagnosed mood and anxiety disorders have a taxing effect on the social and economic well being of society. Such strains may be reduced by heightened vigilance and improved detection of mood/anxiety disorders by primary care physicians (PCPs), but all private practices have limited resources, and, certainly, limited time to interact with patients directly.

Monica Vermani, BSc, MA, PsyD, at the START Clinic in Toronto, Canada, and colleagues, assessed the need for and created a self-report measure for diagnosing mood disorders.
“Our goal was to develop a psychometric screening tool that was self report driven and could allow for a primary care practitioner to identify earlier, patients in their clinic, who suffer from an anxiety disorder, major depressive disorder, or bipolar disorder,” Dr. Vermani said.

The Primary Care Mood and Anxiety Diagnoser (PCMAD) was devised to facilitate diagnosis and enhance proper communication of one’s symptoms, with the intention of recognizing psychological causes for physical symptoms patients suffer from. In turn, this would facilitate patients to receive appropriate treatment care and reduce unnecessary physician/lab visits. PCMAD is a 38-item, self-report measure designed as a sensitive assessment tool for the presence of mood and anxiety disorders, with a high positive predictive value to enhance PCPs’ ability to detect features that correlate with the presence of various anxiety and mood disorders. PCMAD was developed from questions in 10 existing psychometric scales, including the Beck Depression Inventory and the Mood Disorder Questionnaire.

To evaluate the clinical accuracy of PCMAD, Vermani and colleagues administered the Mini-International Neuropsychiatric Interview (MINI) to 1,007 recruits in Phase I. From the MINI results, the investigators gauged the presence of generalized anxiety disorder (GAD), panic disorder, social anxiety disorder (SAD), bipolar disorder, and major depressive disorder (MDD). Subjects who demonstrated the presence of a mood and/or anxiety disorder(s) after the MINI were permitted into Phase II, in which the PCMAD was administered. Phase III included a patient’s chart review to determine whether each patient had a record of the mood disorder(s) detected during Phases I and II. Finally, in Phase IV, PCPs were asked to administer a clinical questionnaire pertaining to the specific subject.

When examining the outcome diagnoses after Phase IV, percentages of subjects with a mood/anxiety disorder(s) not detected by PCPs were as follows: 51.1% of patients with MDD, 87.4% with bipolar disorder, 62.2% with GAD, 73.6% with panic disorder, and 97.1% with SAD.

“A variety of factors contribute to the difficulty that physicians had in detecting these illnesses in their patients,” Dr. Vermani said. “Specifically, the constraints included time limited medical appointments, in sufficient resources and poor communication of physical/psychological symptoms and significant life stressors or life altering events by the patient."

According to the authors, PCMAD will promote communication between doctors and patients, leading the way to uncover symptoms that appear to be physical but are sometimes psychologically based, decreasing the occurrence of repeated physician visits and enhancing patients’ quality of life.

“Overall,” Dr. Vermani said, “since majority of the population with mood and anxiety disorders are likely to visit their primary care physician, it is crucial to enhance detection in order to minimize individual, economic, medical and societal costs incurred by such illnesses.”

It is Vermani and colleagues’ hope that the self administered psychometric screener they are developing will allow PCPs to go beyond examining a patient’s physical symptoms and seek for psychological triggers and stressful life events eliciting physical responses.

“This will hopefully allow for earlier detection, mis/overuse of medical services, earlier provision of treatments, and an overall decrease in patient sufferings,” Dr. Vermani said.

Funding for this study was provided by an unrestricted educational grant from Wyeth Canada (Poster presented at the 2008 ADAA). –LS

 

Increased Cell Phone Use May Heighten Symptoms of Anxiety

Cell phones and other handheld communication devices allow people to contact each other more easily and more often. However, such communication facility may cause people to feel obligated to remain connected and available to others. A study by Lisa Merlo, PhD, and Amanda Stone of the University of Florida in Gainesville, FL, found that individuals with higher levels of trait anxiety likewise have higher levels of cell phone abuse and dependence.

This preliminary investigation involved 183 individuals between 18 and 75 years of age from diverse backgrounds (approximately 76% Caucasian, 10% Asian, 9% Latino, 2% African-American, and 3% “other”). The participants owned a cell phone for an average of 7.2 years and were evaluated using three measures, ie, Cellular Technologies Addiction Scale (CTAS), State-Trait Anxiety Inventory (STAI), and International Personality Item Pool (IPIP-NEO). The CTAS consisted of two subscale questionnaires that gauged cell phone dependence and abuse. The Trait Anxiety subscale of the STAI assessed trait anxiety symptoms, and the Anxiety subscale of the IPIP-NEO measured anxiety. The negative correlation between age and the scores on the CTAS Abuse and Dependency scales suggest that cell phone addiction symptoms are more common in the younger participants regardless of gender. Scores on the STAI-Trait Anxiety scale were highly correlated with scores on the IPIP-NEO Anxiety scale, providing evidence of the association between anxiety symptoms and increased obstructive cell phone use.

The most interesting finding from this study was participant response to the CTAS Dependence subscale item, “I sometimes think that I might be ‘addicted’ to my cell phone.” Approximately 18% (one in five) of individuals admitted that they somewhat or strongly agreed.

“Though cell phone addiction has become a more prominent topic in pop culture, I was surprised that such a large number endorsed feeling this way,” Dr. Merlo said. “It appears that this may be a more prevalent issue than I initially thought.”

Due to the relatively small sample of healthy volunteers, research was unable to assess whether symptoms of cell phone addiction are more common among people with diagnosable anxiety disorder, especially in consideration of race and gender. In addition, whether individuals who manage anxiety disorders well report fewer symptoms of cell phone addiction than individuals who poorly manage anxiety disorders was not addressed.

Despite limitations, the study suggests that excessive cell phone usage may reflect maladaptive attempts at coping, especially among patients with high anxiety.

“Primary care physicians may wish to ask patients about cell phone usage, particularly about ways that cell phone usage may cause distress, impairment, or other negative consequences,” Dr. Merlo said. “Individuals who endorse significant problems would likely benefit from a referral to a mental health professional in order to learn more adaptive coping strategies.” (2008 ADAA, Poster 123). –ML

 

Environmental Cues and Rituals Often Trigger Hairpulling for Patients with Focused-Type Trichotillomania

Classified as an impulse-control disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, trichotillomania has also been classified as a stress and tension-releasing habit disorder as well as a variant of obsessive-compulsive disorder (OCD), which has led to debate as to the conceptualization of the hairpulling disorder. Research has shown that trichotillomania occurs on a continuum of two types, automatic and focused hairpulling, which each highlight different aspects of the disorder’s varied classifications. While automatic hairpulling occurs when the patient is unaware of the behavior (eg, occurring during other activities, such as reading or watching television), focused hairpulling is caused by intense urges to perform the behavior and satisfaction when the behavior is being performed, which is more representative of the diagnostic criteria for the disorder.

For both forms of trichotillomania, cues associated with the hairpulling are important to identify in order to begin effective treatment and optimize outcomes. Rebecca Nichols at the University of Florida in Gainesville, and colleagues, sought to investigate hairpulling symptoms in a non-clinical population of 527 people to examine the phenomenology of trichotillomania among different populations because such understanding would benefit clinicians in the recognition and treatment of trichotillomania.

Study participants were assessed for presence of trichotillomania using the two-part Florida Hairpulling Scale, which includes the qualitative and quantitative assessment of hairpulling cues and six questions related to the type and severity of hairpulling behavior. Researchers found that among the 527 study participants, between 17–47 years of age, 0.74% engaged in hairpulling behavior with the age of trichotillomania onset being 13.57 years. Among participants with trichotillomania, 80.4% were female and 19.6% were male; 68.7% engaged in automatic hairpulling while 31.3% exhibited focused hairpulling behavior.

Nichols and colleagues compared rituals associated with hairpulling among those who engaged in automatic and focused types of the behavior. They found that participants who were in the focused hairpulling group had a greater frequency of rituals associated with the behavior (56.3% for the focused group, 20% for the automatic group). Rituals included pulling hair from the root, examining the hair root, using certain fingers to pull hair, and dropping hair to the floor.

In addition, those in the focused group reported engaging in hairpulling behavior in more environments than those in the automatic group. Environmental cues included “reading,” “lying in bed,” “looking in the mirror,” “when alone,” and “watching television.” Overall, participants in the focused group reported more rituals and environmental cues triggered hairpulling behavior. The authors concluded that people who engage in focused hairpulling view the activity as a target of their attention, leading to more severe incidence. They added that these results show that there is a difference between focused and automatic hairpulling among those with trichotillomania, and may indicate the differences among current classifications for the disorder with focused hairpulling representing a more severe subtype of the condition. (2008 ADAA, Poster 85). –CP

 

Biologic Factors May Play a Role in the Development of Eating Disorders in Females

Eating disorders, exhibited mostly in females, are often attributed to environmental factors such as thinness ideals. However, a new study suggests that biologic factors may play a role as well. Kristen Culbert, MA, at Michigan State University in East Lansing, and colleagues, studied the effects of testosterone in twin pairs enrolled at the Michigan State University Twin Registry. The study found that females who were in the womb with a male twin have a lower risk for eating disorders than those with a female twin.

The study consisted of 304 same-sex female twins, 59 opposite-sex female twins, 54 opposite-sex male twins, and 165 same-sex male twins. Levels of disordered eating were measured by the Minnesota Eating Behavior Survey, which measures body dissatisfaction, preoccupation with weight, binge eating, and behaviors to control weight such as purging. As hypothesized, linear trends of disordered eating were found. Same-sex female twins exhibited the highest level of disordered eating, followed by opposite-sex female twins, opposite-sex male twins, and same-sex male twins. This trend was not accounted for by anxiety levels or social factors.

“Given that sociocultural differences, such as pressures for thinness in women, have typically been used to explain sex differences in eating disorder prevalence, findings from this study are most interesting in suggesting a biological explanation,” Culbert said. “Specifically, our findings provide evidence that increased levels of prenatal testosterone exposure may protect against the development of disordered eating attitudes and behaviors.”

The findings also ruled out socialization effects of being reared with a brother. Opposite-sex female twins exhibited lower (ie, more male-like) levels of disordered eating than non-twin females with at least one brother.

As the twins with the most male exposure in the womb were less likely to develop disordered eating, the authors concluded that biologic factors such as masculinization of the central nervous system by prenatal exposure to testosterone may affect the prevalence of disordered eating. Culbert said that in the long term, the identification of neurobiologic processes underlying risk for eating disorders might enhance treatment.

“If prenatal testosterone is protective and acts to organize anatomical and functional brain differences between males and females, then we can begin to identify areas of the brain that might be altered by prenatal testosterone, such as those involved in food intake or satiation,” Culbert said. “This information would be important for understanding how prenatal testosterone confers protection against disordered eating and could ultimately be used to develop new pharmacological treatments that could mimic these protective effects.”

The practical application of this study is that healthcare professionals can help to reduce parental or personal guilt by highlighting that eating disorders are biologically based and that the risk for eating disorders results from socio-cultural and familial factors that act in combination with biologic and genetic vulnerabilities.

The biggest limitation to this study was the inability to directly assess levels of prenatal testosterone exposure. Additional research examining more direct assessments of prenatal testosterone exposure is warranted. However, at present, only prohibitively invasive methods, such as amniocentesis, exist.

“While such methods would be invaluable for directly examining levels of prenatal testosterone exposure, researchers are limited by the lack of access to and difficulties collecting these data,” Culbert said.

Funding for this study was provided by the National Institute of Mental Health. (Arch Gen Psychiatry. 2008;65(3):329-336). –DC

 

First-Trimester Maternal Stress During Pregnancy Linked to Later-Life Schizophrenia in Offspring

During pregnancy, an elaborate biologic system protects fetuses from the physiologic effects of maternal stress during crucial neurodevelopment—particularly during the first trimester. That system, known as a “fetal-placental barrier,” is hardly impenetrable, however, and a recent study reveals several fetal risk factors associated with antenatal maternal stress. The study weighed the claim that maternal stress during the first trimester of pregnancy was especially associated with the risk of congenital malformations.

Ali S. Khashan, MSc, of the Centre for Women’s Mental Health Research at the University of Manchester, and colleagues, compiled data from several national databases in Denmark. In a cohort of 1.38 million Danish births, born between the years of 1973 and 1995, mothers were considered exposed to stress if ≥1 close relatives died or were diagnosed with cancer, acute myocardial infarction, or stroke syndrome either 6 months before conception or during pregnancy. The offspring were tracked from 10 years of age until their death, migration, or onset of schizophrenia, or until June 2005. Maternal relatives were also tracked for outcomes including death, serious illness, or terminal diagnoses. Of the 1.38 million births included in this investigation, the mothers of 36,193 offspring were exposed to the death, serious illness, or terminal diagnosis of a close relative, of which 21,987 mothers were exposed to the death of a family member. Finally, 14,206 mothers were exposed to a relative with serious illness.

These birth records were compared with psychiatric inpatient and outpatient data in order to assess the relationship between maternal exposure to severe stress and adverse mental health outcomes in their offspring. The most significant finding was that the offspring of mothers who were exposed to the death of a close relative during the first trimester were more likely to develop schizophrenia later in life (adjusted relative risk=1.67 [95% CI]). This increased risk was not associated with maternal stress during the 6 months preceding conception or during other trimesters.

Funding for this study was provided by Tommy’s The Baby Charity and the Stanley Medical Research Institute. (Arch Gen Psychiatry. 2008;65(2):146–152). –LS

Posters were drawn from the 28th Annual Conference of the Anxiety Disorders Association of America (ADAA; March 6–9, Savannah, Georgia). Psychiatric dispatches is written by Dena Croog, Jaime Cunningham, Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.