Dr. Kimhy is assistant professor of clinical psychology in the Department of Psychiatry at Columbia University, Ms. Durbin is research assistant at the New York State Psychiatric Institute, and Dr. Corcoran is director of the Center of Prevention and Evaluation clinic at the New York State Psychiatric Institute, all in New York City.

Disclosure: Drs. Kimhy and Corcoran receive grant support from the National Institute of Mental Health. Ms. Durbin reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: David Kimhy, PhD, Department of Psychiatry, Unit 55, Columbia University, 1051 Riverside Dr, New York, NY 10032; Tel: 212-543-6817; Fax: 212-543-6176, E-mail: dk553@columbia.edu.


 

Focus Points

• Psychosis onset has been associated with cannabis use.
• The causal relationship between cannabis and psychosis remain unclear.
• Retrospective assessments cannot determine the temporal direction of this link.
• Daily diaries can clarify the directionality of this link during “real world” daily functioning.

 

Abstract

The association between cannabis use and the initial development of psychotic symptoms has attracted increased interest over the past decade. In particular, researchers have attempted to elucidate whether cannabis use increases the risk of psychosis among vulnerable individuals or may just represent attempts to self-medicate distressing symptoms. While a growing literature suggests that cannabis use may contribute to the development of psychotic symptoms, these findings are based primarily on retrospective assessments that have limited ability to clarify the temporal link between cannabis use and psychotic symptoms. The authors review the literature regarding the link between cannabis use and psychotic symptoms; point out the limitations associated with retrospective assessments; and discuss advantages of incorporating daily diary methods, such as Experience Sampling Method (ESM), to study cannabis use and symptoms during daily functioning in “real world” environments. The authors also discuss potential future applications of ESM in research and clinical practice that may inform the identification of individuals vulnerable to develop psychotic symptoms, as well as the development of treatments that target this population.

Introduction

The association between cannabis use and psychotic symptoms has attracted increased interest over the past decade.1-3 A multifarious body of research has been conducted to characterize this link, including cohort, epidemiologic, challenge, and genetic studies. A primary focus of these inquiries has been the potential causal role cannabis use may play in the initial development of psychotic symptoms and schizophrenia. In particular, researchers have attempted to elucidate whether cannabis use increases risk of psychosis among vulnerable individuals or may just represent attempts to self-medicate distressing symptoms.4 The increased interest in this link is rooted, in part, in cannabis being potentially one of a few modifiable risk factors of schizophrenia,5 with an estimated 8% of the attributable risk for this disorder being accounted for by cannabis use.

Previous reports indicate that the prevalence of cannabis use in a first episode of psychosis (~20% to 40%)6-8 is comparable to rates reported among individuals at high risk of psychosis (17% to 41%).9-12 Cross-sectional studies in genetic high-risk individuals indicate a link between cannabis use and positive symptoms, with an increase in use and symptoms during the months leading to the development of frank psychosis.13,14 Similarly, individuals with psychosis vulnerability were more likely to report abnormal perceptions and thought influence when they used cannabis4,15 and were more likely to develop psychosis.2,16 Evidence from challenge,17,18 genetic,19-21 and epidemiologic studies22 provide further support for this link. However, the support for cannabis playing a causal role in the development of psychosis is not universal. Opponents of this position point to evidence of increased use of cannabis in the general population (eg, Australia) without corresponding elevations in cases of schizophrenia,23 as well as a lack of association between cannabis use and later development of psychosis in some clinical high-risk cohort studies.9  While a growing literature suggests that cannabis use may play a role in the development of psychosis, these findings are based primarily on retrospective assessments that have limited ability to clarify the temporal link between cannabis use and psychosis. The use of daily diary methods may potentially elucidate this link. Thus, the primary aims of this article are to review the literature regarding the link between cannabis use and psychotic symptoms; identify the limitations associated with retrospective assessments; and discuss advantages of incorporating daily diary methods, such as Experience Sampling Method (ESM), to study cannabis use and symptoms during daily functioning in “real world” environments.

Link Between Cannabis Use and Initial Development of Psychotic Symptoms: Methodologic Limitations

A growing body of literature suggests cannabis is associated with the initial development of psychotic symptoms. However, the literature remain inconclusive regarding the causal direction of this link due to numerous methodologic limitations. First, most studies to date in high-risk individuals have employed single assessments or cross-sectional designs. Thus, evidence of the co-evolution of cannabis use and symptoms over time remains unclear. Corcoran and colleagues12 recently published the first prospective longitudinal report on cannabis use and symptoms in individuals at clinical high risk of psychosis. Subjects were assessed prospectively every three months for up to 2 years. Data indicated that periods characterized by increased cannabis use were associated with significantly more perceptual disturbances and worse functioning, controlling for medications and use of other drugs. However, the 3-month assessment intervals in this study did not permit time-lag analyses, precluding the evaluation of causality between cannabis use and symptoms. 

Another limiting factor is the use of retrospective measures of cannabis use and symptoms. Such assessments are vulnerable to the influence of memory difficulties, affective states at assessment time, and cognitive biases and reframing. Even when prospective designs are used (eg, conducting assessments prospectively every 3 months for up to 2 years), these assessments are still based on the participants’ retrospective recollection of cannabis use and symptoms from the past week, from the past month, or since the previous assessment. These difficulties are particularly critical given the substantial memory deficits experienced by many individuals at high risk for psychosis,24,25 making the use of retrospective assessments potentially problematic in this population. This view is echoed in the preliminary assessment guidelines for the pharmaceutical industry published by the United States Food and Drug Administration.26 Accordingly, Patient-Reported Outcome (PRO) instruments that:

…require patients to rely on memory, especially if they must recall over a period of time, or to average their response over a period of time may threaten the accuracy of the PRO data. It is usually better to construct items that ask patients to describe their current state than to ask them to compare their current state with an earlier period or to attempt to average their experiences over a period of time.26 (p. 11)

A third limiting factor is rooted in the relatively brief impact period (minutes to hours) of Delta 9-tetrahydrocannabinol, the active ingredient of Cannabis sativa.27 Retrospective assessments that are completed days, weeks, or even months after the actual cannabis use are limited in their ability to provide information about the co-evolution of mood, symptoms, and drug use over the brief periods before and after the actual cannabis use. As a result, the determination of the temporal link between mood, symptoms, and cannabis use remains unclear.

Finally, the use of retrospective assessments may provide only limited information about the social and environmental context associated with cannabis use, as well as motivation for use. Thus, the current literature based on retrospective assessments of cannabis use and symptoms may have limited ecological validity to determine the temporal relationship between cannabis use and development of psychotic symptoms.

Diary Methods

To overcome some of these difficulties, researchers have employed daily diary methods to study cannabis use and symptoms during daily functioning in “real world” environments. Diary methods such as ESM is an ecologically valid time sampling of self-reports developed to study the dynamic process of person-environment interactions.28 Subjects in ESM studies are typically supplied with a digital wristwatch and booklets containing questionnaires about current mood, symptoms, activities, and social context. The subjects are instructed to complete a questionnaire upon hearing beeps from the wristwatches, which are typically preprogrammed to beep randomly numerous times a day to elicit experience samples. ESM offers numerous advantages over retrospective assessments including: the ability to record experiences, behavior, and context using high time-resolution measurement (over minutes to hours) that permits time-lag analyses; assessment of current experiences with limited need of episodic memory input; the potential for inclusion of minor/transient experiences that may not be recalled later, but may still have an impact on mood and behavior; the ability to assess motivation in vivo; and the possibility to analyze in high time-resolution the daily fluctuations and patterns of change across activities, social contexts, and time of day.

Spearheaded by researchers from the Maastricht group,28-31 ESM has been used extensively to study psychosis during the flow of daily functioning in individuals with schizophrenia spectrum disorders. More recently, the authors of this study demonstrated the feasibility and validity of using ESM with Palm computers in hospitalized individuals with schizophrenia32 and in young people identified as at heightened clinical risk for psychosis,33 allowing researchers to link these data to concurrent ambulatory physiologic measures.

A handful of attempts have been made to apply ESM to study cannabis use and psychosis. The Table lists peer-reviewed publications of studies using daily diary methods (such as ESM) to investigate cannabis use and psychosis.20,21,34,35 Among individuals with established psychosis, ESM has been used to investigate the link between psychosis, cannabis use, and the functional polymorphism in the catechol-O-methyltransferase gene (COMT Val(158)Met).20,21 Only two studies34,35 to date have used ESM to elucidate the link between cannabis use and psychotic symptoms in individuals with psychosis proneness. Verdoux and colleagues34 and Tournier and colleagues35 investigated this link in undergraduate university students. They reported that subjects with high vulnerability for psychosis were more likely to report unusual perceptions, as well as feelings of thought influence compared to subjects with low vulnerability.34 In contrast, cannabis use did not increase subsequent occurrences of psychotic experiences. Similarly, individuals with a diagnosis of agoraphobia were significantly more likely to use cannabis (regardless of state anxiety; however, overall, there was no evidence for anxiolytic or anxiogenic effect of cannabis use in this agoraphobia sample.35 These findings were interpreted as inconsistent with the self-medication model.34

 

 

While these findings35 shed light as to the temporal link between cannabis use and psychosis, the study included a nonclinical sample of college students. No study to date has used ESM to characterize prospectively in high time-resolution the temporal link between cannabis use and positive symptoms during the flow of daily functioning among individuals at clinical high risk for psychosis. Such a study may offer unique and vital information that may not be possible to collect using retrospective assessments. Such a study will permit the conduct of time-lag analyses that will shed light about the directionality of the cannabis use—positive symptom link, informing causality; will allow the collection of data as to motivation for use within close temporal proximity to time of use; and will provide information about the social and environmental context of cannabis use in the flow of daily functioning in this population. Understanding the motivation for and context in which individuals at clinical high risk for psychosis use cannabis could inform the development of preventive interventions to reduce exposure, and delay or possibly prevent psychosis onset. Numerous investigators, notably Barrowclough and colleagues,36 have demonstrated the safety and efficacy of psychological treatments aimed at reducing the use of cannabis and other drugs in patients with schizophrenia, including first-episode patients.37,38 Treatments include motivational models,39 cognitive-behavioral therapy (CBT), family intervention,36 and antipsychotics.9 With an understanding of motives for use, these programs for first-episode dual-diagnosis patients could be piloted in substance-using prodromal patients. Miller and colleagues40 is currently developing a study using ESM with Palm computers in a sample of urban, help-seeking adolescents and young adults who have been determined to be at clinical high-risk for psychosis using the Structured Interview for Prodromal Syndromes and Scale of Prodromal Symptoms–the diagnostic “gold standard” in psychosis high-risk research. Figure 1 presents screen shots of questions to be presented on the Palm computers as part of this study.

 

 

Daily diary methods such as ESM may also be used as a tool to identify in treatment the clinical correlates of psychosis, including cannabis use, during the flow of daily functioning in individuals at high risk of psychosis. Kimhy and colleagues32 has used ESM with Palm computers to collect information about stress and psychotic symptoms in hospitalized psychotic patients as part of their daily functioning. For example, Figure 2 presents the mean ratings of subjective stress and suspiciousness across time of day in this population. Such information may allow identifying associations between stress, symptoms, and specific activities or social context (in this example, lunch and dinner time on the unit). In this case, lunch and dinner times on the inpatient unit are temporally linked with lower ratings stress and suspiciousness by patients. In particular, use of ESM may elucidate the link between cannabis use and exacerbation of attenuated psychotic symptoms that may not be recognized or recalled retrospectively by patients during treatment session. As such, they may allow clinicians to identify individuals in whom the use of cannabis may increase psychotic symptoms. Kimhy and Corcoran33 recently published a case report in which ESM with a Palm computer was incorporated into CBT with an individual at clinical high risk of psychosis. The authors of this article are currently developing software for mobile devices that will allow data collection and homework completion as part of CBT treatment.

 

Conclusion

The use of daily diary methods offers a novel and unique way to gather information on the temporal link between cannabis use and psychosis; motivation for use; and the clinical, social and environmental correlates of psychosis. As such, they may inform the discussion about the putative causal role of cannabis use on the initial development of psychosis and schizophrenia. PP

References

1.    Ferdinand RF, van der Ende J, Bongers I, Selten JP, Huizink A, Verhulst FC. Cannabis-psychosis pathway independent of other types of psychopathology. Schizophr Res. 2005;79(2-3):289-295.
2.    Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systemic review. Lancet. 2007;370(9584):319-328.
3.    Murray RM, Morrison PD, Henquet C, Di Forti M. Cannabis, the mind and society: the hash realities. Nat Rev Neurosci. 2007;8(11):885-895.
4.    Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330(7481):11.
5.    Arseneault L, Cannon M, Witton J, Murray RM. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry. 2004;184:110-117.
6.    Pencer A, Addington J. Substance use and cognition in early psychosis. J Psychiatry Neurosci. 2003;28(1):48-54.
7.    Van Mastrigt S, Addington J, Addington D. Substance misuse at presentation to an early psychosis program. Soc Psychiatry Psychiatr Epidemiol. 2004;39(1):69-72.
8.    Sevy S, Robinson DG, Holloway S, et al. Correlates of substance misuse in patients with first-episode schizophrenia and schizoaffective disorder. Acta Psychiatr Scand. 2001;104(5):367-374.
9.    Phillips LJ, Curry C, Yung AR, Yuen HP, Adlard S, McGorry PD. Cannabis use is not associated with the development of psychosis in an ‘ultra’ high-risk group. Aust N Z J Psychiatry. 2002;36(6):800-806.
10.    Rosen JL, Miller TJ, D’Andrea JT, McGlashan TH, Woods SW. Comorbid diagnoses in patients meeting criteria for the schizophrenia prodrome. Schizophr Res. 2006;85(1-3):124-131.
11.    Haroun N, Dunn L, Haroun A, Cadenhead KS. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophr Bull. 2006;32(1):166-178.
12.    Corcoran CM, Kimhy D, Stanford A, et al. Temporal association of cannabis use with symptoms in individuals at clinical high risk for psychosis. Schizophr Res. 2008;106(2-3):286-293.
13.    Miller P, Lawrie SM, Hodges A, Clafferty R, Cosway R, Johnstone EC. Genetic liability, illicit drug use, life stress and psychotic symptoms: preliminary findings from the Edinburgh study of people at high risk for schizophrenia. Soc Psychiatry Psychiatr Epidemiol. 2001;36(7):338-342.
14.    Miller PM, Johnstone EC, Lawrie SM, Owens DGC. Substance use, psychiatric symptoms and the onset of schizophrenic illness. J Subst Use. 2006;11(2):101-113.
15.    Barkus EJ, Stirling J, Hopkins RS, Lewis S. Cannabis-induced psychosis-like experiences are associated with high schizotypy. Psychopathology. 2006;39(4):175-178.
16.    Kristensen K, Cadenhead KS. Cannabis abuse and risk for psychosis in a prodromal sample. Psychiatry Res. 2007;151(1-2):151-154.
17.    D’Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004;29(8):1558-1572.
18.    Koethe D, Gerth CW, Neatby MA, et al. Disturbances of visual information processing in early states of psychosis and experimental delta-9-tetrahydrocannabinol altered states of consciousness. Schizophr Res. 2006;88(1-3):142-150.
19.    Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005;57(10):1117-1127.
20.    Henquet C, Di Forti M, Morrison P, Kuepper R, Murray RM. Gene-environment interplay between cannabis and psychosis. Schizophr Bull. 2008;34(6):1111-1121.
21.    Van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull. 2008;34(6):1095-1105.
22.    Thomas H. A community survey of adverse effects of cannabis use. Drug Alcohol Depend. 1996;42(3):201-207.
23.    Degenhardt L, Hall W, Lynskey L. Exploring the association between cannabis use and depression. Addiction. 2003;98(11):1493-1504.
24.    Brewer WJ, Francey SM, Wood SJ, et al. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry. 2005;162(1):71-78.
25.    Lencz T, Smith CW, McLaughlin D, et al. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry. 2006;59(9):863-871.
26.    Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Rockville, MD; 2006.
27.    Curran HV, Brignell C, Fletcher S, Middleton P, Henry J. Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology. 2002;164(1):61-70.
28.    Delespaul P. Assessing Schizophrenia in Daily Life. Maastricht, The Netherlands: The International Institute for Psycho-Social and Socio-Ecological Research; 1995.
29.    Delespaul P, deVries M, van Os J. Determinants of occurrence and recovery from hallucinations in daily life. Soc Psychiatry Psychiatr Epidemiol. 2002;37(3):97-104.
30.    Myin-Germeys I, Nicolson NA, Delespaul PA. The context of delusional experiences in the daily life of patients with schizophrenia. Psychol Med. 2001;31(3):489-498.
31.    Myin-Germeys I, Delespaul P, van Os J. Behavioural sensitization to daily life stress in psychosis. Psychol Med. 2005;35(5):733-741.
32.    Kimhy D, Delespaul P, Corcoran C, Ahn H, Yale S, Malaspina D. Computerized experience sampling method (ESMc): assessing feasibility and validity among individuals with schizophrenia. J Psychiatr Res. 2006;40(3):221-230.
33.    Kimhy D, Corcoran CM. Use of palm computer as an adjunct to cognitive behavior therapy with an ultra high risk patient-a case report. Early Interv Psychiatry. 2008;2:234-241.
34.    Verdoux H, Gindre C, Sorbara F, Tournier M, Swendsen JD. Effects of cannabis and psychosis vulnerability in daily life: an experience sampling test study. Psychol Med. 2003;33(1):23-32.
35.    Tournier M, Sorbara F, Gindre C, Swendsen JD, Verdoux H. Cannabis use and anxiety in daily life: a naturalistic investigation in a non-clinical population. Psychiatry Res. 2003;118(1):1-8.
36.    Barrowclough C, Haddock G, Tarrier N, et al. Randomized controlled trial of motivational interviewing, cognitive behavior therapy, and family intervention for patients with comorbid schizophrenia and substance use disorders. Am J Psychiatry. 2001;158(10):1706-1713.
37.    Edwards J, Maude D, McGorry PD, Harrigan SM, Cocks JT. Prolonged recovery in first-episode psychosis. Br J Psychiatry Suppl. 1998;172(33):107-116.
38.    Addington J, Addington D. Impact of an early psychosis program on substance use. Psychiatr Rehabil J. 2001;25(1):60-67.
39.    Spencer C, Castle D, Michie PT. Motivations that maintain substance use among individuals with psychotic disorders. Schizophr Bull. 2002;28(2):233-247.
40.    Miller TJ, McGlashan TH, Rosen JL, et al. Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull. 2003;29(4):703-715.

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Dr. Haridas is a final year resident, Dr. Oluwabusi is a Child Fellow, and Dr. Gurmu is Chief resident in the Psychiatry Program at Drexel University College of Medicine in Philadelphia. Dr. Kushon is Clinical Associate Professor of Psychiatry at Drexel University College of Medicine and Medical Director of the Psychiatric-Medical Care Unit at Hahnemann University Hospital in Philadelphia, Pennsylvania.

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

Off-label disclosure: This article includes discussion of investigational treatments for major depression.

Please direct all correspondence to: Arun Haridas, MD, MRCPsych, Drexel University College of Medicine, Department of Psychiatry, 1427 Vine St, 8th Floor, Philadelphia, PA 19107; Tel: 215-762-6660; Fax: 215-762-6673; E-mail: aharidas@drexelmed.edu.


Focus Points

• Several case reports point to quetiapine’s abuse potential on the black market.
• Oral, intravenous, and intranasal routes of abuse have been reported.
• The inhalational method of quetiapine abuse is novel and counter-intuitive.
• Polysubstance abuse history may bring combinations of abuse, eg, quetiapine with cocaine-“Q” ball, quetiapine with marijuana “Maq ball.”

 

Abstract

Quetiapine abuse has been a cause for increased concern among clinicians. Several reports have highlighted this in the past. Reports of quetiapine abuse have varied in their routes of administration. The authors have had experience in managing several patients who have admitted to the use of quetiapine outside of prescription settings. This article examines the case of a recent patient on the authors’ inpatient unit who admitted to a novel route of abuse. While quetiapine’s abuse potential in the black market is well known, motivations for the abuse of quetiapine have varied in the past. Anxiety and insomnia has been amongst the reported motivations. Combination abuse of quetiapine with cocaine, called “Q ball,” have been reported previously. Quetiapine serves as a substitute for heroin when used in this combination. This article highlights a previously unreported combination of quetiapine with marijuana used in the inhalational route in what is termed a “Maq ball.”

Introduction

Quetiapine has been cited in several recent reports of being abused, especially in prison settings under the name “baby heroin” and “quell.”1,2  Reports of quetiapine abuse have varied in their routes of administration from the intravenous,1 intranasal,3,4 and oral.5 The authors have had experience in managing numerous patients in the in-patient unit who have admitted to obtaining and using quetiapine outside of prescription settings. A recent patient in an in-patient unit is highlighted below, illustrating this worrisome trend.

Case Report

A 27-year-old Hispanic male was admitted to the in-patient unit with a history of worsening depressed mood with suicidal ideation. He described polysubstance abuse involving marijuana, crack cocaine, alprazolam, and quetiapine; his preferred drug of choice was marijuana. He described smoking 1 oz. of marijuana daily. Approximately 1–2 times per week, he smoked crushed quetiapine tablets mixed with one ounce of marijuana. In addition, he smoked crack cocaine 3 times/week and alprazolam 5–10 mg/day orally up to 5 times/week.

Efforts to stop his quetiapine on this admission were unsuccessful on the unit, though he agreed to a tapered discharge dosage of quetiapine 100 mg/day. He requested to be discharged to a local drug and alcohol recovery house. Examination of prior admission records revealed that 5 months earlier, he had admitted to using quetiapine from the black market. At the time, he abused quetiapine orally, taking ~2–3 pills of quetiapine 100 mg/day, in addition to being prescribed quetiapine 100 mg BID by his primary care physician for his mood symptoms.

Discussion

Quetiapine is a drug of known value on the black market of antipsychotics.6 Its use is motivated by anxiety and insomnia.4 Quetiapine, amongst olanzapine, anticholinergics, and tricyclic antidepressants, have been a favored method to “zone out” or “take the edge off” amongst buyers in the black market.6 This may be related to the fact that quetiapine is associated with a better subjective response than its conventional antipsychotic counterparts.7

Quetiapine, crushed and mixed with cocaine and water, and taken intravenously, has been previously recorded in the literature as a “Q ball.”8 The strategy aims to mitigate the dysphoria associated with cocaine withdrawal through the sedative and anxiolytic effects of quetiapine. Quetiapine in the described case served as a substitute for heroin and the more classic cocaine and heroin “speed ball” combination.8

Conclusion

There have been no reports of quetiapine  combined with marijuana and serving as what we term a “Maq ball.” Unlike combining cocaine and quetiapine, which carries the risk for QT prolongation,8 lethal side effects are unlikely with this combination. However, it once again draws attention to this worrying trend of quetiapine becoming an increasing favorite for novel and hitherto unknown methods of abuse. Clinicians would do well to keep this fact in mind when deciding on an appropriate antipsychotic for individuals with comorbid substance use disorders. PP

References

1.    Hussain MZ, Waheed W, Hussain S. Intravenous quetiapine abuse. Am J Psychiatry. 2005;162(9):1755-1756.
2.    Del Paggio D. Psychotropic medication abuse in correctional facilities. The Bay Area Psychopharmacology Newsletter. 2005;8(1):5.
3.    Morin AK. Possible intranasal quetiapine misuse. Am J Health Syst Pharm. 2007;64(7):723-725.
4.    Pierre JM, Shnayder I, Wirshing DA, Wirshing WC. Intranasal quetiapine abuse. Am J Psychiatry. 2004;161(9):1718.
5.    Reeves RR, Brister JC. Additional evidence for the abuse potential of quetiapine. South Med J. 2007;100(8):834-836.
6.    Tarasoff G, Osti K. Black market value of antipsychotics, antidepressants and hypnotics in Las Vegas, Nevada. Am J Psychiatry. 2007;164(2):350.
7.    Voruganti L, Cortese L, Oyewumi L, Cernovsky Z, Zirul S, Award A. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side effects profile and impact on quality of life. Schizophr Res. 2000;43(2-3):135-145.
8.    Waters BM, Joshi KG. Intravenous Quetiapine-Cocaine Use (“Q- Ball”). Am J Psychiatry. 2007;164(1):173-174.

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Dr. IsHak is Director of Psychiatry Residency Training and Medical Student Education in Psychiatry at Cedars-Sinai Medical Center (CSMC) and Associate Clinical Professor of Psychiatry at the University of California, Los Angeles (UCLA), the University of Southern California, and CSMC, all in Los Angeles, California. Dr. Rasyidi is the CSMC Psychiatry Chief Resident. Dr. Saah is former research physician volunteer at CSMC and current psychiatry resident at Emory University in Atlanta, Georgia. Dr. Vasa is on medical staff at CSMC. Dr. Ettekal is Research Psychiatrist at California Clinical Trials in Glendale, California. Dr. Fan is Associate Director of Inpatient Psychiatry at CSMC and Assistant Clinical Professor of Psychiatry at UCLA and CSMC.

Disclosures: Dr. IsHak receives grant support from the National Alliance for Research on Schizophrenia and Depression and Pfizer. Drs. Saah, Rasyidi, Vasa, Ettekal, and Fan report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Waguih William IsHak, MD, FAPA, Cedars-Sinai Medical Center, Department of Psychiatry and Behavioral Neurosciences, 8730 Alden Dr, Thalians W-157, Los Angeles, CA 90048; Tel: 310-423-3515; Fax: 310-423-3947; E-mail: Waguih.IsHak@cshs.org.


Focus Points

• Factitious disorder is the intentional production of symptoms to assume the sick role in the absence of secondary gain.
• Factitious disorder could present with physical, psychological, or combined symptoms.
• Factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering.
• Medical records from previous hospitalizations and healthcare providers are essential.
• Factitious disorder needs to be suspected in frequent acute care utilizers with atypical presentations and negative results.

 

Abstract

In the clinical setting, factitious disorder is often mistaken for malingering or somatoform disorders. Three cases of factitious disorder with physical, psychological, and combined symptoms are reported. Comparing these patients may help facilitate identification of factitious disorder, especially with improving recognition in patients who are high utilizers of acute medical and psychiatric services. A high level of suspicion regarding the diagnosis of factitious disorder is needed, especially in cases with frequent utilizers of emergency room and inpatient services, atypical presentations, and negative diagnostic results.

Introduction

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision,1 refined the diagnosis for factitious disorder by providing three diagnostic criteria (Table 1).2 Studies indicate a .5% to .8% prevalence of factitious disorders in hospital patients, with a prevalence of up to 6% to 8% on psychiatric units.2-5 However, patients with factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering. Due to diagnostic difficulties, only the most severe cases of factitious disorder are diagnosed correctly. In other cases, factitious disorder may be suspected but not diagnosed. The following three cases of factitious disorder with disparate presentations are based on the subtypes described in the DSM-IV-TR (Table 2).1 Patient A presented with mainly physical symptoms. Patient B presented with physical and psychological symptoms. Patient C presented with mainly psychological symptoms. The patients presented depict the wide spectrum of severity and presentations in factitious disorders that contribute to the difficulty of accurate diagnosis. The management of these cases also demonstrates the diagnostic strategy needed for improving diagnosis of factitious disorder.

 

Factitious Disorder Case Reports

Patient A: Factitious Disorder with Predominantly Physical Signs and Symptoms

Patient A, a 27-year-old female, would often present to the emergency department with vague complaints of abdominal pain and bright red blood per rectum, which she stated was typical for her Crohn’s disease. The patient also freely reported a psychiatric history with multiple diagnoses, including bipolar disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, a history of anorexia nervosa, and Asperger’s syndrome, as well as a history of suicide attempts and self-injurious behaviors. The patient had a stable income through state disability and lived in a comfortable home with her parents in an affluent neighborhood. Psychiatric consultation was requested on her third admission to the medical center and after 13 previous presentations to the emergency department. At that point she had undergone extensive diagnostic testing, including computed tomography scans, upper gastrointestinal (GI) endoscopy with small bowel follow through, colonoscopy, and biopsies, all of which had been unsuccessful in finding the cause of GI bleeding. She was transferred to the inpatient psychiatric hospital for complaints of depressed mood and her diagnosis was refined to PTSD and borderline personality disorder. During hospitalization, a nurse found the patient in the bathroom one night inserting a toothbrush into her rectum, producing the bloody stools that she had been complaining of for the past several days. When confronted, the patient articulated that she desired the attention that came with her medical work-ups and that it instilled a sense of control over her environment. This behavior was different from previous suicide attempts in that there was no intent to die. It was also distinct from her self-injurious behaviors which were performed openly and freely admitted to. As for the discrepancy between reported psychiatric diagnoses and those at time of discharge, this was due to diagnostic errors on the part of previous treatment teams, not due to misrepresentation by the patient. The patient thus met criteria for factitious disorder with predominantly physical symptoms.

Patient B: Factitious Disorder with Combined Psychological and Physical Signs and Symptoms

Patient B, a 52-year-old female with bipolar depression, was admitted to the inpatient unit for the fifth time in 6 months after presenting with suicidality and depressed mood. The patient stated that she had been diagnosed with OCD, PTSD, and attention-deficit/hyperactivity disorder. She also stated that she was blind and had a guide dog. During hospitalization, she consistently reported that her depression and suicidality were worsening. However, observations showed that the patient joked, laughed, and regaled others with far-fetched stories. She ate and slept well, and ambulated without difficulty. It also became increasingly obvious that Patient B was not blind. She was observed reading, looking in the mirror, and dialing numbers from her phone book. In daily sessions, inconsistencies were noted in her elaborate recollections of traumas. The management plan consisted of performing a diagnostic work-up including medical, neurologic, and neuropsychological evaluations, in addition to a trial of citalopram 40 mg PO and lamotrigine 200 mg PO, both at bedtime, as well as psychotherapy. Ophthalmology and neurology consults did not reveal any visual loss. The psychological and neuropsychological testing confirmed suspicions about the presence of significant antisocial, narcissistic, and borderline personality traits, and showed intact neuro-cognitive functioning. Additional information confirmed the patient’s tendency to move from hospital to hospital, leave against medical advice, and express inconsistent medical and psychiatric complaints, which gave evidence to the diagnosis of a factitious disorder. The most important two differential diagnoses were conversion disorder and malingering. Conversion disorder was ruled out because the patient was shown to have intact vision on medical consultations. Regarding malingering, there were no specific secondary gains as she had a stable housing and financial situation. It became clear that Patient B was intentionally producing both physical (blindness) and psychological (worsening of depression) symptoms in order to assume the sick role. She was informed of the diagnostic possibility of factitious disorder with combined psychological and physical signs and symptoms, and was recommended for continuation of both psychotherapy and pharmacotherapy.

Patient C: Factitious Disorder with Predominantly Psychological Signs and Symptoms

Patient C, a 38-year-old male, presented complaining of a 3–4-month history of depressed mood, poor energy, difficulty sleeping, poor appetite, psychomotor retardation, increasing hopelessness, and suicidal ideation with a plan to walk into traffic. Once on the inpatient wards, the patient remained compliant with his medications; however, no change in mood was seen. Throughout his stay, Patient C demonstrated, on a consistent basis, a discrepancy between what he stated to staff and what was observed on the wards. The patient consistently reported depressed mood and suicidality, but was observed to be euthymic, in good spirits, and carousing with the other patients. The patient’s stay was also significant for two suicide attempts both with low lethality and high possibility of rescue. Elaborate stories regarding the death of his best friend, as well as his previous married life, employment status, and relations with his family, were for the most part later repudiated by the patient’s father. Eventually, the patient was so disruptive to the inpatient milieu that he was placed in seclusion. Within a few hours he arranged to be picked up by a friend and was successful in finding a place to stay. Before being discharged, the patient admitted to never being suicidal and that the two suicide attempts had both been feigned. The treatment team noticed that the patient had traits of antisocial, narcissistic, borderline, and histrionic personality disorders. The likelihood of malingering was low because the patient had stable income and was offered numerous housing options, which he refused. The treatment team concluded that this patient was willing to assume the sick role, by intentionally manifesting psychological symptoms, to gain the social interaction of being in a psychiatric unit.

Discussion

Although factitious disorders have been formally recognized for >30 years, diagnostic criteria have evolved significantly since the recognition of the disorder. From the DSM-II6 through the DSM-III7 and DSM-III-R,8 factitious disorders had no clear inclusion or exclusion criteria for diagnosis.9 The advent of the DSM-IV10 and DSM-IV-TR11 advanced the diagnosis of factitious disorder by defining three diagnostic criteria: A) intentional production of physical or psychological signs or symptoms, B) motivation to assume the sick role, and C) absence of external incentives or secondary gain.1,12-14 Criterion A differentiates factitious disorder from somatoform disorders by requiring the intentional production of signs or symptoms. Criterion C differentiates factitious disorder from malingering by eliminating the presence of secondary gains for the patient.15 It is also important to note that while patient cases B and C were also clear examples of pseudologia fantastica, where embellished truth and colorful fantasies are presented as fact in order to gain the interest of the listener, this phenomenon is neither pathognomonic nor necessary under our current nosology for the diagnosis of factitious disorder.14

The three cases presented elucidate several effective diagnostic strategies. With Patient A, psychiatric consultation led to psychiatric hospitalization and a careful review of the medical and psychiatric history. The treating psychiatrist had thoughtful discussions with the patient’s other doctors, which confirmed her history of high health services, utilization, and a lack of evidence for a medical etiology. The close observation of the psychiatric nursing staff then caught the patient in an act of self-injury. With Patient B, the treating psychiatrist also had a thorough diagnostic plan, which included consultation with the neurology, medicine, ophthalmology, and neuropsychological testing services. Nursing observations on the inpatient psychiatric unit revealed that the patient did not have the visual or depressive symptoms that she claimed to have. The treating psychiatrist was also able to obtain valuable medical and psychiatric history from collateral sources to confirm a pattern of multiple hospitalizations, inconsistent medical and psychiatric presentations, and hospital discharges against medical advice. With Patient C, nursing observations also found that the patient’s behavior on the psychiatric unit were inconsistent with his reported symptoms. The treating psychiatrist was able to obtain collateral history from the patient’s father, which confirmed that the patient had falsified his symptoms and psychiatric history to gain admission to the psychiatric unit.

The growing literature on factitious disorder indicates that patients have certain common traits. Understanding these traits may help in accurate diagnosis and management. Some studies have found that factitious disorder patients often have work experience in healthcare fields. They can use their medical knowledge to deceive and confuse the treatment team in their search for an accurate diagnosis. Factitious disorder patients are fearful of abandonment and highly sensitive to rejection.16 They usually have comorbid Axis I and II diagnoses. They use the hospital setting to find support, safety, and social relationships that they cannot obtain otherwise. Confronted with their falsification of history and intentional production of symptoms, factitious disorder patients have increased risk of self-harm and exacerbation of psychiatric disorders. They become extremely difficult to manage as the therapeutic rapport is broken.

From the three patients presented and a review of the literature, several recommendations to facilitate the accurate diagnosis and proper management of factitious disorder patients have been provided. In cases in which factitious disorder is suspected, always ask the patient for permission to obtain medical records from previous hospitalizations and healthcare providers. After Patient A had been caught in the act of producing her physical symptoms, she conceded consent. However, even in situations where patients are caught “red-handed,” there may be an impressive level of denial with patients going so far as to assert that events never actually took place. With Patients B and C, consent was obtained by explaining to the patients that access to sufficient information was necessary in providing appropriate treatment. Again, there may be scenarios where patients balk at this proposal. Refusal by the patient of a well-presented, reasonable request should make the treating physician suspicious of a non-medical diagnosis. Similarly, the treating physician should also ask the patient for permission to collect history from collateral sources such as family members, spouses, and friends. A refusal by the patient may indicate a fear of discovering a falsification. In a hospital, the treating physician should ask the nursing staff to closely monitor a patient suspected of factitious disorder. Close observation can reveal a patient’s surreptitious production of clinical signs. The treating physician should also seek consultations from specialists in other fields to exclude a medical etiology for the patient’s signs and symptoms. In a psychiatric unit, the treatment team, including nurses and therapists, needs to be reminded to set appropriate limits and boundaries for suspected factitious disorder patients. These limits and boundaries may decrease the social and psychological gains that a patient may want from a hospitalization.

Conclusion

The dearth of information available on factitious disorder and the difficulty in obtaining epidemiologic and diagnostic information should not preclude the possibility of more accurate diagnosis and better management. Large descriptive and longitudinal studies with adequate diagnostic work-ups, including medical, neurologic, neuropsychological, and personality testing evaluations, are needed in order to develop a clear understanding of factitious disorders. Unfortunately, such studies are very difficult to undertake in a patient population that is adverse to discovery. Nonetheless, factitious disorder should be considered in patients with atypical presentations and negative diagnostic results who are high utilizers of acute care facilities such as the emergency room and inpatient services. PP

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:513-516.
2. Hamilton JC, Feldman MD, Janata JW. The A, B, C’s of factitious disorder: a 220 response to Turner. Medscape J Med. 2009;11(1):27.
3. Catalina ML, Gómez Macias V, de Cos A. Prevalence of factitious disorder with psychological symptoms in hospitalized patients. Actas Esp Psiquiatr. 2008;36(6):345-349.
4. Sutherland AJ, Rodin GM. Factitious disorders in a general hospital setting: clinical features and a review of the literature. Psychosomatics. 1990;31(4):392-399.
5. Gregory RJ, Jindal S. Factitious disorder on an inpatient psychiatry ward. Am J Orthopsychiatry. 2006;76(1):31-36.
6. Diagnostic and Statistical Manual of Mental Disorders. 2nd ed. Washington, DC: American Psychiatric Association; 1968.
7. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
8. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.
9. Rogers R, Bagby RM, Rector N. Diagnostic legitimacy of factitious disorder with psychological symptoms. Am J Psychiatry. 1989;146(10):1312-1314.
10. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
11. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
12. Krahn LE, Li H, O’Connor MK. Patients who strive to be ill: factitious disorder with physical symptoms. Am J Psychiatry. 2003;160(6):1163-1168.
13. Dike CC, Baranoski M, Griffith EE. Pathological lying revisited. J Am Acad Psychiatry Law. 2005;33(3):342-349.
14. Turner MA. Factitious disorders: reformulating the DSM-IV criteria. Psychosomatics. 2006;47(1):23-32.
15. Drob SL, Meehan KB, Waxman SE. Clinical and conceptual problems in the attribution of malingering in forensic evaluations. J Am Acad Psychiatry Law. 2009;37(1):98-106.
16. Feldman MD. Playing Sick? Untangling the Web of Munchausen Syndrome, Munchausen by Proxy, Malingering, and Factitious Disorder. New York, NY: Brunner–Routledge; 2004.

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Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

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

Please e-mail questions or comments for Dr. Sussman to ns@mblcommunications.com.


It is a point I have made before, but the content of this month’s Primary Psychiatry reminds me of how important it is for those who diagnose and treat patients with mental disorders know those disorders and their treatments well. As primary care physicians (PCPs) increasingly treat psychiatric disorders, it is important to remember that many conditions and their treatment require full knowledge of differential diagnoses, even of rarely occurring disorders, as well as infrequent but potentially serious side effects of treatment.

Four years ago, a case report1 in our sister publication, CNS Spectrums, described a case of tardive dyskinesia (TD) associated with the long-term use of adjuvant aripiprazole in a patient with refractory depression. The authors wrote:

“Prior to the case of Mrs. C, there were no reports of aripiprazole-associated TD. In this report, however, we described the case of a woman who developed TD after 18 months of treatment with aripiprazole, and suggest that use of aripiprazole may be associated with this adverse effect. Clinicians who choose to prescribe aripiprazole as a primary antipsychotic agent or as an adjuvant treatment should be aware of the risk of TD.”

Shortly after the publication of this case report, aripiprazole became the first drug of any kind to be approved by the Food and Drug Administration as an addition to antidepressants for adults with major depressive disorder. Even though aripiprazole is an atypical antipsychotic, and there is a known risk of TD associated with these agents, published data have suggested that this risk is significantly lower than the risk of TD associated with older antipsychotics. This has made may clinicians comfortable using atypical antipsychotics as adjuncts in place of other add-on strategies. In fact, some early reports2,3 indicated that aripiprazole could cause improvement of TD.

In a Web-exclusive Letter to the Editor, Joseph H. Friedman, MD, and Daniel Tarsy, MD, express concern that increased use of aripiprazole by PCPs—a consequence of its FDA-approved indication for depression—increases the incidence of TD cases because, unlike psychiatrists, PCPs are not adequately accustomed to monitoring their patients for early signs of TD and do not counsel their patients about this risk.

They note that TD may occur in patients never treated with another dopamine antagonist, and even at the low doses recommended for treating depression. Although aripiprazole-associated TD may be reversible in some cases, in other cases the movement disorder may be permanent. They emphatically conclude that aripiprazole should only be used for refractory cases by doctors knowledgeable about antipsychotics. The dose should be as low as possible, and once the patient has achieved a stable improvement attempts should be made to wean off the drug. Alternatives include switching to other antidepressants, including the tricyclics, combined therapy with drugs of different chemical families, adjunctive exercise, and psychotherapy. They further note that psychiatrists should consider other alternatives, such as lithium or thyroid augmentation and that TD should be specifically evaluated and commented upon at each office visit so that the drug may be stopped if TD begins. It is worth noting that there are no data that compare either the safety or efficacy of long-term adjunctive atypical antipsychotic therapy with alternative combinations mentioned above.

In this issue, Waguih William IsHak, MD, and colleagues, in a case series on factitious disorder, describe three cases in which there is the intentional production of symptoms to assume the sick role in the absence of secondary gain. The disorder can present with physical, psychological, or combined symptoms. Like panic disorder, factitious disorders are commonly misdiagnosed with medical conditions or diagnosed as somatoform disorders or malingering. The authors note a .5% to .8% prevalence of factitious disorders in hospital patients, and a prevalence of up to 6% to 8% on psychiatric units. However, patients with factitious disorders are commonly misdiagnosed with medical conditions, somatoform disorders, or malingering. They nevertheless feel that only the most severe cases of factitious disorder are diagnosed correctly. They report on three cases of factitious disorder subtypes, each with a unique disparate presentation, but yet sharing some common clinical features. They also provide several recommendations to facilitate the accurate diagnosis and proper management of factitious disorder in patients. Most importantly, in cases in which factitious disorder is suspected, always ask the patient for permission to obtain medical records from previous hospitalizations and healthcare providers. The authors conclude that factitious disorder should be considered in patients with atypical presentations and negative diagnostic results who are high utilizers of acute care facilities such as the emergency room and inpatient services.

Raymond A. Lorenz, PharmD, and colleagues review the safety of varenicline in patients with mental illness. Varenicline is the most recently FDA-approved smoking cessation aid. However, it carries a boxed warning on its package labeling detailing the increased risk of psychiatric adverse events. Although the risk of developing psychiatric adverse events in the general population is relatively rare, the data presented in this article suggest that the risk for developing psychiatric adverse events is greater for those with pre-existing mental illness. This may not have been evident immediately after the drug came to market because patients with psychiatric conditions were excluded from the phase III clinical trials. Recognition of these rare adverse drug events are thus a result of post-marketing experiences. Thus, the authors caution that while varenicline is effective for facilitating smoking cessation, it may carry some serious risks, particularly for patients with preexisting mental illness. In the absence of clinical trials involving psychiatric patients, they conclude, the data reviewed in this article should lead to cautious use of varenicline in patients with mental illness, especially when the drug is used for extended periods of time.

A different type of smoking-related problem is discussed by Arun Haridas, MD, and colleagues. Quetiapine has been cited in several reports as being abused. This case report highlights a patient with a unique method of abusing quetiapine. The drug is relatively unique among antipsychotics in that it has value in the black market. It is used illicitly mainly as an anxiolytic or hypnotic, or to “take the edge off” amongst buyers in the black market. Quetiapine crushed and mixed with cocaine and water and taken intravenously has been termed a “Q ball,” and is used to mitigate the dysphoria associated with cocaine withdrawal. The authors describe quetiapine combined with marijuana, serving as what they term a “Maq ball.” They note that unlike the cocaine and quetiapine combination, which carries the risk for QT prolongation, lethal side effects are unlikely with this combination. However, they caution that clinicians would do well to keep the street use of quetiapine in mind when selecting antipsychotics for individuals with comorbid substance use disorders.

Robert Lasser, MD, and colleagues, all employees of Shire Development Inc., as disclosed in their conflict of interest disclosure, present an analysis of data—not the results of prospective and quantitative comparison studies—that suggests that lisdexamfetamine dimesylate may offer advantages over mixed amphetamine salts-extended release for the treatment of adults with attention-deficit/hyperactivity disorder.

I also encourage you to read the exchange of letters between Roger Z. Samuel, MD, and Kiki Chang, MD, regarding my recent interview with Dr. Chang on the topic of bipolar disorder in youths. PP

References

1. Maytal M, Michael Ostacher M, Stern TA. Aripiprazole-Related Tardive Dyskinesia. CNS Spectr. 2006;11(6)435-439.
2. Witschy JK, Winter AS. Improvement in tardive dyskinesia with aripiprazole use. Can J Psychiatry. 2005;50(3):188.
3. Duggal HS. Aripiprazole-induced improvement in tardive dyskinesia. Can J Psychiatry. 2003;48(11):771-772.

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Contents

Focus Points
Abstract
Introduction
Methods
       • Study Designs
       • Subjects
       • Efficacy Measures
       • Safety Measures
       • Statistical Analysis
Results
       • Subject Demographics
       • Efficacy
       • Safety
Discussion
Conclusion
References

 

Dr. Lasser is Senior Director, Dr. Dirks is Associate Director, and Dr. Babcock is Associate Director of Scientific Publications, all in the Clinical Development and Medical Affairs Department at Shire Development Inc. in Wayne, Pennsylvania. Mr. Adeyi is Associate Director of Global Biostatistics in the Biostatistics and Statistical Programming Department at Shire Development Inc.

Disclosures: Dr. Lasser, Mr. Adeyi, and Dr. Babcock are Shire employees and own stocks and/or stock options from Shire. Dr. Dirks is a Shire employee and owns stocks and/or stock options from Johnson & Johnson and Shire.

Acknowledgments: Clinical research was funded by Shire Development Inc. Authors directed writing assistance from Huda Ismail Abdullah, PhD, and Michael Pucci, PhD, employees of Health Learning Systems. Editorial assistance in the form of proofreading, copy editing, and fact checking was also provided by Health Learning Systems, part of CommonHealth. Health Learning Systems was funded by Shire Development Inc. for support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, ultimate interpretation, and decision to submit it for publication in Primary Psychiatry were made by the authors independently.

Please direct all correspondence to: Robert Lasser, MD, Senior Director, Clinical Development and Medical Affairs, Shire Development Inc., 725 Chesterbrook Blvd, Wayne, PA 10987; Tel: 484-595-8383; Fax: 484-595-8679; E-mail: rlasser@shire.com.


Focus Points

• This post hoc, matched group analysis using data from two similar short-term trials examined the efficacy and safety of lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts extended release (MAS XR) compared with their respective placebo groups for the treatment of adults with attention-deficit/hyperactivity disorder (ADHD).
• LDX and MAS XR were effective in the treatment of ADHD in adults and provided significantly greater control of ADHD symptoms than placebo. In this matched group qualitative comparison, LDX demonstrated better efficacy than MAS XR, as indicated by greater improvements in ADHD Rating Scale IV total scores and Clinical Global Impressions ratings.
• Both LDX and MAS XR demonstrated safety profiles consistent with stimulant use.
• LDX may offer efficacy advantages and a safety profile comparable with MAS XR for adult ADHD; however, this should be confirmed with appropriate comparative trials.

 

Abstract

Objective: To qualitatively compare the efficacy and safety of lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts extended release (MAS XR) using data from two similar trials.
Methods: Two randomized, 4-week, forced-dose escalation, double-blind trials in adults with attention-deficit/hyperactivity disorder (ADHD) were analyzed. This post hoc analysis examined active treatment groups and placebo with approximately equivalent amphetamine base quantities (50 and 70 mg/day LDX; 20 and 40 mg/day MAS XR). Efficacy measures included the ADHD Rating Scale IV (ADHD-RS-IV). Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms.
Results: Placebo-adjusted difference in least squares mean change from baseline with LDX for ADHD-RS-IV total score was -9.16
(50 mg/day) and -10.42 (70 mg/day) ( P<.0001); MAS XR was -5.56 (20 mg/day) and -8.80 (40 mg/day) ( P≤.047). Common TEAEs with these stimulants included dry mouth, decreased appetite, and insomnia. TEAE percent differences (all doses minus placebo) rates for either study were similar (slightly more with MAS XR).
Discussion: LDX had numerically larger ADHD-RS-IV score improvements than MAS XR. Both stimulants appeared similar in safety and tolerability.
Conclusion: LDX may offer efficacy advantages and a safety profile comparable with MAS XR for adult ADHD; but this should be confirmed with appropriate comparative trials.

Introduction

Psychostimulants are pharmacotherapeutic mainstays for children and adults with attention-deficit/hyperactivity disorder (ADHD).1,2 Efficacy and safety of both methylphenidate-(MPH) and d-amphetamine-based stimulants were demonstrated in controlled clinical trials.2-4 Although efficacy and tolerability profiles of both preparations share a high degree of similarity,2 subtle differences exist.5 Their putative mechanisms of action differ and individuals may exhibit different responses to both stimulants,2,5,6 suggesting an alternative formulation could be prescribed for subjects responding inadequately to one.1

Long-acting formulations generally have similar efficacy and tolerability versus multidose immediate-release (IR) stimulants.2,4,7,8 Once-daily dosing with long-acting formulations may enhance convenience and adherence2,4 as well as decrease potential abuse and diversion.4,9-12 Comparative data evaluating long-acting formulations for ADHD treatment are limited, especially in adults. Pelham and colleagues6 evaluated relative efficacies of four formulations in children, including sustained-release MPH and d-amphetamine formulations. Another pediatric ADHD study compared efficacy and safety of lisdexamfetamine dimesylate (LDX) versus placebo with mixed amphetamine salts extended release (MAS XR) as a reference arm (eg, no direct comparison with LDX).13 Several clinical trials14-19 compared efficacy of different long-acting MPH formulations in children, but the authors of this article are unaware of comparative efficacy trials of stimulants in adults. Direct head-to-head trials are required for clinicians to comprehensively compare long-acting formulations, but in their absence, we can only rely on indirect, qualitative comparisons.

LDX is a long-acting, amphetamine-based stimulant approved for ADHD in adults. LDX is the first prodrug stimulant. After oral ingestion, therapeutically inactive LDX is converted to l-lysine and active d-amphetamine, which is responsible for the therapeutic effect. The conversion of LDX into active d-amphetamine occurs primarily in the blood. The combination of l-lysine and d-amphetamine created a new chemical entity with a prodrug technology of delivery of d-amphetamine.20 In adults, LDX demonstrated significant efficacy versus placebo in a 4-week pivotal trial,21 and from 2–14 hours post dose in a randomized, controlled, simulated workplace environment trial.22

MAS XR is also a long-acting, amphetamine-based stimulant approved for ADHD in adults.23 MAS XR is a once-daily, extended-release, single-entity amphetamine product that contains equal proportions of IR and enteric-coated delayed-release beads.24 The capsule contains two types of drug-containing beads that were designed to give double-pulsed delivery of amphetamine to prolong release.23 MAS XR has demonstrated efficacy with various doses versus placebo in a 4-week, randomized trial25 and in a laboratory school study26 in children from 1.5–12 hours post dose. A classroom, crossover children’s study indicated that the percent coefficient of variance for Tmax, Cmax, and area under the curve-last for LDX-treated subjects was lower than those for MAS XR-treated subjects, suggesting lower intersubject variability with LDX and potentially more consistent drug delivery among subjects.13 Both treatments demonstrated a safety profile consistent with long-acting stimulant use.4,21,27,28

LDX and MAS XR are controlled substances and carry warnings for potential abuse. Head-to-head abuse liability studies have not been conducted between the products. Oral LDX capsules contain no free d-amphetamine and are not likely affected by simple mechanical manipulation (eg, crushing and simple extraction).29 In contrast, mechanical manipulation may be possible with beaded technology, such as MAS XR, in which active d- and l-amphetamine are contained in the capsule and can be made accessible. Oral and intravenous (IV) abuse liability studies have been conducted with LDX only,29,30 and not with MAS XR; therefore, no definitive conclusions can be made regarding comparative abuse-related drug-liking effect between these two treatments. However, unlike IR d-amphetamine, IV LDX did not produce significant subjective abuse-related liking in adult substance abusers compared with placebo.30 LDX (50 and 100 mg) taken orally had reduced abuse-related liking effects compared with IR d-amphetamine (40 mg equivalent amphetamine-base dose to LDX 100 mg). At higher doses of LDX (150 mg), subject abuse-related liking scores were similar between LDX and IR d-amphetamine (40 mg).29

Absence of direct head-to-head data motivated the present post hoc analysis of matched groups that qualitatively explores the safety and efficacy of both stimulants using data from two separate clinical trials in adults.21,25 This qualitative assessment was designed to compare the efficacy and safety profiles of LDX and MAS XR in a short-term, randomized, placebo-controlled clinical trial setting.

Methods

Study Designs

The study designs of both clinical trials in the present analysis have been described previously.21,25 Briefly, both were multicenter, randomized, double-blind, placebo-controlled, parallel-group, forced-dose escalation clinical trials. At baseline, subjects were randomized to receive stimulant (one of three dosages of LDX or MAS XR) or placebo and began a 4-week treatment period. In the LDX trial, subjects randomized to receive active treatment (LDX 30, 50, or 70 mg/day) initiated therapy at 30 mg/day with weekly adjustment to randomized dose. In the MAS XR clinical trial, subjects randomized to receive active treatment (MAS XR 20, 40, or 60 mg/day) initiated therapy at 20 mg/day with weekly adjustment to their randomized dose.

Subjects

Each clinical trial enrolled adults who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,31 criteria for a primary diagnosis of ADHD. In the LDX trial, subjects were required to be 18–55 years of age, whereas in the MAS XR trial only a lower age limit of 18 years was specified. Exclusion criteria in both trials included comorbid psychiatric conditions with significant symptoms, pregnancy, seizures, tic disorders, Tourette’s syndrome, hypertension, cardiac conditions, a positive drug screen, history of substance abuse, or use of any prescription/investigational medication (except that used to treat ADHD within 30 days of screening). Each study relied on clinical diagnosis of ADHD based on a structured diagnostic interview. The LDX study had the additional requirement that a baseline severity in clinician-rated ADHD Rating Scale IV (ADHD-RS-IV) be met for entry. The present analyses included only data from a subgroup of enrolled subjects in each trial who were matched for baseline ADHD severity and randomized to approximately equivalent doses of delivered amphetamine base content. Subjects in the MAS XR study with baseline ADHD-RS-IV total scores <28 were excluded from the analysis (see “Statistical Analysis” section).

Efficacy Measures

The primary efficacy measure in both studies was the total score of the ADHD-RS-IV.32 This is a validated rating instrument as used in the MAS XR study,33 but in the LDX trial, a newer version of the scale with adult prompts was administered.34 In both trials, the ADHD-RS-IV was administered at baseline and all postbaseline study weeks by trained and qualified clinical investigators. Originally designed to assess ADHD symptomatology in children, the ADHD-RS-IV for adults consists of 18 items based on DSM-IV-TR ADHD criteria. Each item is scored on a 4-point Likert scale from 0 (no symptoms) to 3 (severe symptoms), with total scores ranging from 0 to 54.

A secondary efficacy measure common to both trials were two of the Clinical Global Impressions (CGI) scales.35 The CGI scales provide clinician-rated assessment of global symptom severity and improvements over time. In both trials, the CGI-Severity (CGI-S) assessed baseline symptom severity on a scale from 1 (no symptoms) to 7 (very severe symptoms). As a measure of symptom improvement over time relative to baseline, clinicians completed the CGI-Improvement (CGI-I; LDX trial) or the CGI-Change (CGI-C; MAS XR trial) at all postbaseline weeks. For both scales, clinicians rated changes over time from 1 (very much improved) to 7 (very much worse). Although they are named differently, the CGI-I and CGI-C were identically worded instruments.

Safety Measures

In both trials, safety was assessed via the recording of adverse events (AEs) from baseline to the end of the trial. If the AEs occurred postrandomization, they were considered treatment-emergent AEs (TEAEs). Coding terminology for AEs in the LDX trial was based on Medical Dictionary for Regulatory Activities (MedDRA), Version 9.1,36 while Coding Symbols for the Thesaurus of Adverse Reaction Terms (COSTART) dictionary (Version 5.0),37 was used for the MAS XR trial. Both MedDRA and COSTART are standardized dictionaries that facilitate classification of AEs. Compared with COSTART, the newer MedDRA dictionary is more hierarchical, contains more terms, and is multiaxial in nature. Other safety measures in the trials included assessments of systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse, and electrocardiograms.

Statistical Analysis

This is a qualitative matched-group assessment of subjects who exceeded similar thresholds on the ADHD-RS-IV and were exposed to approximately equivalent doses of amphetamine base for a similar length of time. As an inclusion criterion, subjects in the LDX clinical trial were required to have a baseline ADHD-RS-IV total score ≥28. Although no such entry requirement existed in the MAS XR trial, for the purposes of this analysis, subjects with baseline ADHD-RS-IV total scores <28 were excluded. While 50 and 70 mg of LDX contained ~14.8 and 20.8 mg of d-amphetamine, respectively (data on file, Shire Development Inc.), 20 and 40 mg of MAS XR contained ~12.5 and 25 mg of total amphetamine base equivalence, respectively.23 Given that the amounts of amphetamine base in 50 and 70 mg/day LDX are approximately equivalent to those in 20 and 40 mg/day MAS XR, respectively, data from subjects in these treatment groups were included in the present analysis. In contrast, data from subjects randomized to treatment with 30 mg/day LDX and 60 mg/day MAS XR were excluded, since no similar dose groups were available for assessment. Although the amounts of amphetamine base were comparable, it should be noted that they were not exactly equal. For the first equivalency dose match, the amount of amphetamine base difference was 2.3 mg with LDX versus MAS XR; for the second equivalency dose match, the amphetamine base difference was 4.2 mg for MAS XR versus LDX.

LDX and MAS XR treatment groups were compared directly with their respective placebo groups. No direct quantitative comparisons between the LDX and MAS XR studies were performed because these post hoc analyses were an exploratory effort. Dunnett test was used to compare ADHD-RS-IV total scores between each active treatment dosage group and the placebo group in the same clinical trial. CGI scores were also compared between active treatment and placebo groups using Dunnett test. To further enable indirect comparisons across studies, effect sizes were calculated for each stimulant dose. The effect sizes provide a standardized assessment of treatment effect, and the calculations followed the method described by Curtin and colleagues.38 For presentation of TEAE data, when multiple MedDRA terms mapped to a single COSTART term, the COSTART terminology from the TEAEs of the MAS XR study were harmonized with the LDX study. The harmonization was conducted by recoding the MAS XR verbatim terminology, using the MedDRA dictionary (Version 9.1) and reporting all TEAEs with a subject incidence ≥5%, using MedDRA preferred terminology. Vital signs were summarized by treatment group. Categorical analysis using outlier criteria was performed for SBP (≥150 mm Hg), DBP (≥95 mm Hg), pulse (change to ≥ mean+2 SD), QT interval (>480 msec), and QT interval corrected using Fridericia’s formula (QTcF; >480 msec).

Results

Subject Demographics

Using the above selection criteria, the LDX trial comprised 301 subjects, including 239 randomized to receive LDX. In the MAS XR trial data set, 128 subjects were included, with 83 randomized to receive MAS XR. All subjects enrolled and randomized for this subgroup analysis were included in the safety analysis. Within each trial, the demographic characteristics of the subjects were similar (Table 1). The mean age of subjects in the LDX clinical trial was slightly younger than those in the MAS XR trial. The proportion of men in each treatment group in the LDX trial (51.6%–56.4%) was slightly less than that observed in the MAS XR trial (59.5%–70.7%).
 

Efficacy

Within each study, active treatment groups and placebo exhibited similar mean baseline ADHD-RS-IV total scores, although baseline scores in the LDX clinical trial were slightly higher than those in the MAS XR trial and endpoint scores were decreased versus baseline in both trials (Figure 1). In each clinical trial, active treatment was associated with significantly greater improvements from baseline in ADHD-RS-IV total score at endpoint (last valid postbaseline assessment) than placebo (Figure 2). Moreover, within these subgroups, the placebo-adjusted least squares mean (SE) ADHD-RS-IV total score change from baseline at endpoint for the placebo cohorts was -8.1 (1.40) and -7.4 (1.89) in the LDX and MAS XR trials, respectively. The ADHD-RS-IV treatment effect size was larger for both LDX doses when compared with approximately equivalent doses of MAS XR (Table 2); however, no statistical comparisons were performed.

In the LDX trial, subjects randomized to the placebo group had a mean (SD) baseline CGI-S score of 4.7 (.73) and in the MAS XR trial a score of 4.6 (.62). On the CGI-S scale, a score of 4 represents “moderately ill” while a score of 5 represents “markedly ill.”35 In the LDX trial at endpoint, Dunnett test determined that the mean (SD) CGI-I scores were significantly lower (indicating greater improvement) for both LDX dose groups compared with 3.2 (1.19) in the placebo group (P<.0001; Table 2). A CGI-I score of 3 indicates “minimally improved” while a score of 2 corresponds to “much improved.”35 At endpoint, the mean (SD) CGI-C scores were significantly lower in both MAS XR groups compared with 3.4 (1.00) in the placebo group (P≤.0027; Table 2). Effect sizes for treatment with LDX and MAS XR as assessed by the global improvement scales are presented in Table 2.

In the LDX trial, a post hoc analysis of dichotomized CGI-I difference in improved (very much improved [CGI-I=1] and much improved [CGI-I=2]) versus placebo was significant for both doses of LDX, at all weeks and at endpoint (P≤.0005 for each). The percentage of subjects for 50 and 70 mg/day LDX, respectively, at week 1 was 24.7% and 27.9%; at week 2 was 32.5% and 34.2%; at week 3 was 35.1% and 38.9%; at week 4 was 32.9% and 33.3%; and at endpoint was 32.5% and 31.8%. For the MAS XR trial, the analysis indicated that the categorical CGI-I difference in improved versus placebo was not significant for the 20 mg/day dose of MAS XR at all weeks and at endpoint. With the 40 mg/day dose of MAS XR, the percentage of subjects that had a difference in improved versus placebo was significant only at weeks 2 and 4, and at endpoint (P≤.0210 for each). The CGI-I difference for the 40 mg/day dose of MAS XR at week 2 was 27.3%; at week 4 was 29.2%; and at endpoint was 29.1%.

Safety

The harmonization of AE terminology resulted in the reclassification of the verbatim item mapping to the COSTART “anorexia” to the MedDRA “decreased appetite” or “anorexia.” The verbatim terms mapping to the COSTART “insomnia” was reclassified to the MedDRA “initial insomnia” or “insomnia.” In the LDX clinical trial, 80.3% of subjects in the active treatment groups experienced at least one TEAE compared with 58.1% of those receiving placebo (Table 3). The most common (≥10%) TEAEs reported by subjects receiving LDX were dry mouth (28%), decreased appetite (25.5%), headache (21.3%), and insomnia (19.2%). In the MAS XR clinical trial, 80.7% of subjects experienced at least one TEAE compared with 53.3% of those receiving placebo. After harmonization, the most common (≥10%) TEAEs reported by subjects receiving MAS XR were dry mouth (33.7%), decreased appetite (26.5%), insomnia (21.7%), headache (20.5%), and weight loss (14.5%; Table 4). The difference in percent incidence of all active treatment doses for either trial minus placebo TEAEs for both stimulants were dry mouth, decreased appetite, and insomnia; MAS XR all doses included headache and weight loss. In the LDX trial 22.2% of subjects and in the MAS XR trial 27.4% of subjects experienced at least one difference in percent incidence of all active treatment doses minus placebo TEAEs. In both trials, most TEAEs were mild or moderate in severity. Severe TEAEs were reported by 4.2% (n=10) of subjects receiving LDX, with only severe fatigue (n=2; 0.8%) and severe insomnia (n=6; 2.5%) reported by more than one subject. Among subjects receiving MAS XR, 8.4% (n=7) experienced severe TEAEs, with only severe insomnia reported by more than one subject (n=3; 3.6%).

Both stimulants were associated with small mean increases from baseline in SBP at endpoint (Table 5). LDX-treated subjects had a mean (SD) SBP increase from baseline at endpoint of 0.7 (9.2) mm Hg. At endpoint, subjects treated with MAS XR demonstrated a mean (SD) change in SBP from baseline of 2.1 (12.9) mm Hg. The maximum mean (SD) changes from baseline in SBP for the active treatment groups occurred at week 3 for LDX (1.5 [9.7] mm Hg) and at week 4 for MAS XR (2.2 [13.1] mm Hg). In their respective trials, both LDX and MAS XR were also associated with small mean increases from baseline in DBP at endpoint (Table 5). At endpoint, subjects treated with LDX exhibited a mean (SD) increase in DBP of 1.3 (7.5) mm Hg compared with 3.6 (9.9) mm Hg exhibited by MAS XR-treated subjects. The maximum mean (SD) change from baseline in DBP occurred at week 2 for LDX-treated subjects (1.9 [7.0] mm Hg) and at week 4 for MAS XR-treated subjects (3.6 [10.0] mm Hg). The lower dose of LDX (ie, 50 mg) was actually associated with a mean (SD) 0.3 (9.1) mm Hg decrease in SBP, while both doses of MAS XR were associated with increases in SBP at endpoint. Similarly, while both stimulants resulted in minimal increases in DBP at endpoint, the mean (SD) elevations associated with 70 mg/day LDX were ~2.5 times less than observed in subjects receiving 40 mg/day MAS XR (1.7 [6.9] mm Hg versus 4.3 [8.7] mm Hg).

In both trials, stimulant treatment was associated with mean increases in pulse (Table 5). The placebo-treated cohorts demonstrated virtually no mean (SD) change in pulse from baseline at endpoint: 0 (9.2) beats per minute (bpm) and 0.4 (11.3) bpm for placebo cohorts in the LDX and MAS XR trials, respectively. At endpoint, LDX and MAS XR were associated with mean (SD) increases in pulse of 4.6 (10.7) bpm and 4.9 (11.4) bpm, respectively. For the combined active treatment groups, the maximal mean (SD) increases in pulse were observed at week 3: 5.7 (10.4) bpm for LDX and 6.0 (13.5) bpm for MAS XR.

Overall, participants rarely met outlier criteria (Table 6). Blood pressure (BP) outlier criteria were not met at endpoint by any subject receiving LDX. Moreover, no subject in the present analysis had a QT or QTcF interval >480 msec at any LDX or MAS XR treatment week, nor did any subject demonstrate a prolongation of QTcF of 60 msec or more from baseline at any study week.

Consistent with the short-term safety profile of stimulants, in the present analysis both LDX and MAS XR were associated with dose-dependent decreases in weight. In the LDX trial, subjects receiving placebo exhibited a mean (SD) increase in weight from baseline of 0.4 (2.9) lb at endpoint. In contrast, subjects receiving 50 and 70 mg LDX exhibited mean (SD) changes in weight of -3.1 (6.5) lb and -4.3 (4.5) lb, respectively. At endpoint of the MAS XR trial, the mean (SD) change in weight from baseline was -2.1 (4.0) lb and -6.4 (4.9) lb in the 20 and 40 mg/day dose groups, respectively, compared with 0.4 (4.9) lb increase in the placebo group.

Discussion

This study is the first to qualitatively assess two long-acting, amphetamine-based stimulants, LDX and MAS XR, in adults. Using groups derived from registration trials that were matched on baseline severity of ADHD symptoms, duration of treatment, and approximately comparable amphetamine doses, a post hoc matched-group assessment was conducted. In these clinical trials, LDX and MAS XR had similar TEAEs. Common TEAEs ≥10% in the present analysis of both studies included dry mouth, decreased appetite, insomnia, and headache. The common differences of the percent incidence of all active treatment doses minus placebo TEAEs in both trials were decreased appetite, insomnia, and dry mouth. These are consistent with TEAEs observed with other long-acting stimulants in adults.39,40 Although most TEAEs in both clinical trials were mild or moderate in severity, the incidence of severe TEAEs was twice as low in LDX-treated subjects than in MAS XR-treated subjects. As expected for stimulant therapies, LDX and MAS XR were associated with weight loss over a 4-week treatment period. The degree of weight loss was lower in LDX treatment groups versus MAS XR treatment groups when assessing groups with approximately equivalent amounts of amphetamine base. Within each trial, the degree of weight loss appeared to demonstrate a dose response.

Although LDX and MAS XR were associated with increases in BP parameters and pulse, such changes were modest and not clinically meaningful. Given that the doses of LDX and MAS XR included in the present analysis have approximately equivalent amounts of amphetamine base, the mechanisms underlying the observed differences in cardiovascular effects are unclear. Subgroup post hoc analysis results for vital signs (SBP, DBP, and pulse) from the LDX and MAS XR analysis were consistent with what has been observed in their respective studies; the mean (SD) change from baseline at endpoint for both LDX and MAS XR were consistent with their respective primary study (data not shown). Another possibility for the difference was that this post hoc analysis of the selected groups may introduce some bias. A difference between these agents is the absence of l-amphetamine from LDX and its presence in MAS XR (both d- and l- isoforms), which may play an essential role in this slight cardiovascular difference between treatments.41-43 Studies comparing the cardiovascular effects of d- and l-amphetamine have not yielded clear answers; however, many sources suggest that l-amphetamine may have greater peripheral and cardiovascular effects and that d-amphetamine is more potent as a central stimulant.41,44 In a small clinical trial in children with ADHD, Arnold and colleagues44 found no significant differences in effects on BP and heart rate, but it was also assessed at the third week of treatment. Unlike changes in BP parameters, increases in pulse were very similar between equivalent (ie, similar total amphetamine base) doses of LDX and MAS XR with only minimally higher rates observed with MAS XR. In neither study did treatment result in clinically significant changes in QT interval.

Both LDX and MAS XR were associated with significant reductions (versus placebo) in ADHD core symptoms as assessed by ADHD-RS-IV total scores. Significant improvements were also observed on clinician ratings of global improvement as assessed by CGI score. At approximately equivalent amphetamine doses, LDX resulted in numerically greater improvements in ADHD-RS-IV and CGI than MAS XR. The ADHD-RS-IV treatment effect size and CGI-I/CGI-C was larger for both LDX doses when compared qualitatively with approximately equivalent doses of MAS XR. The ADHD-RS-IV total score effect sizes suggest that both LDX doses demonstrated effect sizes that are considered large; effects sizes for MAS XR were medium. The CGI effect sizes for LDX were medium and large for both LDX doses (50 and 70 mg/day), respectively, and medium for both doses of MAS XR (20 and 40 mg/day). These differences in effect sizes may be due to the relative sample sizes of LDX groups that were almost twice as large as the MAS XR group as well as relative placebo responses across both studies. When comparing placebo-adjusted comparisons (eg, effect size) for each stimulant, the reader is reminded that the placebo cohort used for comparison differed in each study. While no direct comparisons of these placebo groups were performed, the placebo effect appears greater in the LDX trial. This was indicated by the greater decrease in ADHD-RS-IV total score change from baseline at endpoint for the placebo cohort in the LDX trial. Overall, a qualitative assessment would imply a slightly better improvement with LDX versus MAS XR when compared with placebo.

The present analysis suggests that, at approximately comparable doses, LDX was more efficacious than MAS XR and had lower incidence of the differences (all active treatment doses [for either trial] minus placebo) in the percent of AEs and any percent differences of AEs versus MAS XR, although prospective and quantitative comparison studies are required to confirm these results. The results of this analysis are consistent with short-term controlled clinical trials evaluating the safety and efficacy of LDX and MAS XR in children and adolescents with ADHD that also demonstrated significant improvements versus placebo in both ADHD-RS-IV total score and CGI ratings.28,45 Furthermore, although the present analysis used data from a pair of short-term trials, the effectiveness of both LDX and MAS XR for the treatment of ADHD in adults has been demonstrated in long-term trials.46,47

Other considerations in terms of assessing potential differences between both treatment regimens should be noted. The mode of therapeutic action for amphetamines in the treatment of ADHD is thought to be due to the block of reuptake of norepinephrine and dopamine into the presynaptic neuron and their increased release into the extraneuronal space. LDX, the parent drug, does not bind to the sites responsible for the reuptake of the neurotransmitters.48 Thus, although there are similarities between LDX and MAS XR, they are different in terms of mechanism of action (prodrug versus mechanical release) and their pharmacokinetic profiles (LDX has a more predictable pharmacokinetic profile).

Although pharmacokinetic studies of MAS XR in adults indicated consistency in terms of bioavailability,49-51 the prodrug mechanism of LDX may provide a more consistent pharmacokinetic profile. In a clinical trial in healthy adults, LDX demonstrated low inter- and intrasubject variability, offering consistent time to maximum d-amphetamine concentration.52 With prodrug LDX administration, d-amphetamine plasma concentrations increased linearly and in a dose-dependent manner, with no indication of enzyme saturation in healthy adults and showed reliable delivery over a wide range of doses.52 The prodrug mechanism requires intrinsic enzymatic cleavage of intact LDX to active d-amphetamine and is independent of exogenous formulation/drug-release delivery systems such as MAS XR.53 Mechanically formulated delayed-release beads can be crushed, so they are more easily susceptible to abuse9; enteric-coated beads can be affected by gastric pH, since they have a pH-sensitive, release-delaying polymer layer and overcoating.54 Variations in pH did not affect the solubility profile of LDX, and increases in pH beyond this range only slightly reduced solubility.55 Hence, the absorption of LDX versus MAS XR is not readily altered or converted by enzymes that simulated conditions of the gastrointestinal tract and is consistent with intact LDX absorption.20 It has also been suggested that LDX is absorbed intact by active transport in the small intestine.20 Although, changes in urinary pH alter the elimination of either drug, with urinary alkalinization decreasing excretion and acidification increasing excretion,23,48 d-amphetamine is not available until after metabolism of LDX. Prescribing information for LDX, unlike that for MAS XR, does not warn about the effects of alterations in gastric pH on d-amphetamine absorption.23,48

The findings of this matched group qualitative assessment of two clinical trials must be viewed in light of several limitations. To develop matched comparison groups, the data set from the MAS XR trial was reduced in size and was smaller than the LDX data set (n=128 vs. n=301), potentially allowing for variability as a result of differences in sample size, although the original number of participants in the MAS XR trial was ~250.25 The nature of effect sizes is to estimate the apparent magnitude of relationships among data sets between treatment and placebo groups. As such, effect sizes facilitate comparisons between studies of various population sizes, limited study design differences, and with similar or different outcome measures.56 Nonetheless, since the assessed population of the LDX trial was ~2-fold higher, comparisons of study effect sizes and the differences between TEAE frequencies should be considered as qualitative in nature. Additionally, while the demographics of the groups analyzed are intended to be comparable, the participants were not matched by age, sex, or disease severity, which resulted in slight dissimilarities among cohorts (eg, greater mean age of subjects in the MAS XR trial). Differences in the inclusion/exclusion criteria and the AE classification/coding systems of the trials should also be recognized. Both studies largely excluded adults with coexisting conditions including comorbid psychiatric disorders and cardiovascular disease. As such, the populations studied may not fully represent patients encountered in clinical practice. The 30 mg/day LDX and 60 mg/day MAS XR treatment groups were excluded from this analysis because dose equivalents of amphetamine base were not available across trials. Finally, precise equivalent dosage strengths of different extended-release stimulants remain unknown due to differences in their pharmacokinetic profiles and mechanisms of delivery, and hence may not be entirely comparable.

Conclusion

The efficacy and relative safety of long-acting amphetamine- and MPH-based psychostimulants for the treatment of ADHD are well documented. Although early research focused on stimulant treatment for ADHD in children, recent studies have demonstrated similar benefits in adults. The virtual nonexistence of prospective head-to-head trials in this population makes direct comparisons of long-acting stimulants impossible. In lieu of such trials, clinicians are left to rely on indirect comparisons such as the post hoc analysis presented here. In these short-term clinical trials, both long-acting amphetamine-based stimulants, LDX and MAS XR, were effective in the treatment of ADHD in adults and provided significantly greater control of ADHD symptoms than placebo. In this matched group qualitative comparison, LDX demonstrated better efficacy than MAS XR, as indicated by greater improvements in ADHD-RS-IV total scores and CGI ratings. Both LDX and MAS XR demonstrated safety profiles consistent with stimulant use, although marginally smaller changes in cardiovascular parameters and the incidence of severe TEAEs were observed with LDX. Although not a substitute for prospective and quantitative comparison studies, this analysis suggests LDX may offer advantages over MAS XR for the treatment of adults with ADHD. PP

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50. Ermer JC, Shojaei A, Pennick M, Anderson CS, Silverberg A, Youcha SH. Bioavailability of triple-bead mixed amphetamine salts compared with a dose-augmentation strategy of mixed amphetamine salts extended release plus mixed amphetamine salts immediate release. Curr Med Res Opin. 2007;23(5):1067-1075.
51. Clausen SB, Read SC, Tulloch SJ. Single- and multiple-dose pharmacokinetics of an oral mixed amphetamine salts extended-release formulation in adults. CNS Spectr. 2005;10(12 suppl 20):6-15.
52. Ermer J, Homolka R, Martin P, Buckwalter M, Purkayastha J, Roesch B. Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers. J Clin Pharmacol. Feb 19, 2010 [Epub ahead of print].
53. Ermer JC, Shojaei AH, Biederman J, Krishnan S. Improved interpatient pharmacokinetic variability of lisdexamfetamine dimesylate compared with mixed amphetamine salts extended release in children aged 6 to 12 years with attention-deficit/hyperactivity disorder. Poster presented at: the 160th Annual Meeting of the American Psychiatric Association; May 19-24, 2007; San Diego, CA.
54. Sallee FR, Smirnoff AV. Adderall XR: long acting stimulant for single daily dosing. Expert Rev Neurother. 2004;4(6):927-934.
55. Shojaei A, Ermer JC, Krishnan S. Lisdexamfetamine dimesylate as a treatment for ADHD: dosage formulation and pH effects. Poster presented at: the 160th Annual Meeting of the American Psychiatric Association; May 19-24, 2007; San Diego, CA.
56. Faraone SV, Biederman J, Spencer TJ, Aleardi M. Comparing the efficacy of medications for ADHD using meta-analysis. MedGenMed. 2006;8(4):4.

Return

 

 

Dr. Lorenz is assistant clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy in Auburn, Alabama and adjunct assistant professor in the Department of Psychiatry at the University of South Alabama College of Medicine in Mobile. Dr. Whitley is assistant clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy and in the Department of Community and Rural Medicine at the University of Alabama School of Medicine in Tuscaloosa. Dr. McCoy is assistant clinical professor in the Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy.

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

Off-label disclosure: This article includes discussion of the unapproved use of varenicline for the adjunct treatment of depression and cognitive enhancement in depressed patients.

Acknowledgments: The authors thank Cory Wiggins, PharmD, a fourth-year student pharmacist during the writing of this article, for helping in preparing the article.

Please direct all correspondence to: Raymond Lorenz, PharmD, BCPP, University of South Alabama, Technology & Research Park Bldg. 3 Suite 2100, Mobile, AL 36688; Tel: 251-445-9316; Fax: 251-445-9341; E-mail: lorenz@auburn.edu.


 

Focus Points

• This article reviews literature regarding the safety of smoking-cessation aid varenicline for patients with mental illness.
• Although the relationship between varenicline and psychiatric adverse events (AEs) is not clear, there appears to be a greater likelihood of event development in those with baseline mental illness.
• Many confounding factors may contribute to psychiatric AEs in mentally ill patients who receive varenicline.
• Caution should be exercised when considering prescribing varenicline in patients with mental illness.
• Any patient receiving varenicline who develops new or exacerbated psychiatric symptoms should discontinue therapy immediately.

 

Abstract

This article reviews literature regarding safety of smoking-cessation aid varenicline for patients with mental illness. Although clinical trials with varenicline showed improved efficacy for smoking cessation and relatively low adverse events (AE) rates, many case reports suggest an increased risk of psychiatric AEs, particularly in patients with baseline mental illness. The Institute for Safe Medication Practices (ISMP) published a review of the serious AEs associated with varenicline obtained from Food and Drug Administration-submitted reports. The ISMP report specifically mentions psychiatric AEs in patients with preexisting psychiatric conditions. While varenicline use among patients without mental illness is likely safe, appropriate use in mentally ill patients is controversial; the paucity of data currently precludes drawing definite conclusions. While further prospective trials evaluating the use of varenicline in mental illness may be inappropriate, the information currently available does little to fully elucidate the effects of varenicline in patients with mental illness. As such, cautious use in this population is warranted. Varenicline discontinuation is recommended in any patient reporting new-onset psychiatric symptoms.

Introduction

Approximately 440,000 of the 45 million American smokers die annually from the leading preventable cause of death: tobacco use. This percentage accounts for 20% of deaths in the United States.1-2 Patients with mental illness are more likely to smoke cigarettes than patients without mental illness (59.0% vs. 39.1%).3 These data highlight the need for safe and effective smoking cessation aids, especially in patients with mental illness. Tobacco users are more likely to initiate a smoking cessation plan when encouraged by a healthcare professional and are more successful when aided by a pharmaceutical agent.1,4-8 Varenicline, the most recent Food and Drug Administration-approved smoking cessation aid, and the first in a class of α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists, came to market in 2006.

Since FDA approval, varenicline has been cited by mainstream media reports as an impetus for several suicides and suicide attempts. Case reports, an Institute for Safe Medication Practices (ISMP) report, and new FDA warnings have been published regarding the safety of varenicline. This new information may cause concern for its use in patients with a history of mental illness despite its improved efficacy and cost benefits over previous therapies. This article analyzes these newly reported risks of varenicline therapy and provides specific recommendations regarding the role of varenicline in smoking cessation among patients with mental illness.

Efficacy of Varenicline

Clinical trials that brought varenicline to market demonstrate greater benefit compared to placebo and bupropion sustained release (SR) in terms of patients achieving smoke-free status.4-8 In addition, a meta-analysis comparing abstinence rates for six first-line pharmacotherapies and placebo over 6 months demonstrated varenicline to have the highest estimated abstinence rate (33.2% for varenicline vs. 19.0% to 26.7% for other active treatments vs. 13.8% for placebo).9 Due to the documented efficacy of varenicline, the Health and Human Services guidelines on Treating Tobacco Use and Dependence has recommended the product as a first-line treatment option.9

Although data support varenicline as the most effective smoking cessation aid on the US market, some may argue that the cost of therapy is prohibitive and outweighs its benefits when considering use of generic alternatives.10 A recent pharmacoeconomic analysis considered this financial aspect and demonstrated varenicline as the most cost-effective smoking cessation option.11 The analysis used a hypothetical cohort of US adult smokers who make one attempt at smoking cessation. For the purposes of the analysis, efficacy was estimated using two head-to-head trials of varenicline, bupropion SR, and placebo, along with a meta-analysis of nicotine replacement therapy. Costs analyzed included the lifetime direct (medication cost plus smoking-related morbidity) but not indirect costs. Varenicline decreased direct costs compared to unaided smoking cessation, traditional nicotine replacement therapy, and bupropion SR by $4.7 billion, $4.1 billion, and $2.4 billion respectively.11 These cost savings were a direct result of the increased efficacy of varenicline in the models used. Additionally, if 25% of smokers initiated a quit attempt with the use of varenicline, 144,000 more smoking-related deaths would be prevented compared with unaided smoking cessation. Further, having a quit attempt with varenicline over unaided smoking cessation would produce 261,000 fewer incidences of asthma exacerbations, chronic obstructive pulmonary disease, coronary heart disease, stroke, and lung cancer. A follow-up cost-effectiveness study using an additional 12 weeks of varenicline after the initial 12-week treatment period (for a total of 24 weeks of treatment) showed similar results, even with the increased expenditure of obtaining varenicline.12

Safety of Varenicline

Pre-Marketing Safety Data

Phase II and III clinical trials showed varenicline to have a mild side-effect profile. Nausea (30%) was the most commonly reported adverse drug reaction (ADR), although it was generally mild to moderate and resolved over time. A lower incidence of nausea is seen when varenicline is initiated at a low dose (0.5 mg/day) and titrated slowly to the target dose (1 mg BID), as recommended in the product information.13 Headache (15%), insomnia (18%), and abnormal dreams (13%) were the next most commonly reported ADRs. Discontinuation rates due to ADRs were similar between varenicline (11.2% to 14.3%) bupropion SR (15.9%), and placebo (9.8%) in the phase III trials, with the main cause for discontinuation of varenicline being nausea. One episode of atrial fibrillation in one patient8 and one episode of worsening vertigo, increased blood pressure, and chest pain in a second patient4 were attributed to varenicline during the trials. Although weight gain was observed in two clinical trials,3,7 patients taking placebo averaged more weight gain (2.92 kg) compared to varenicline (2.37 kg); therefore, this event is considered a common effect of smoking cessation. Laboratory parameters, electrocardiogram recordings, incidence of seizures, and vital signs showed no clinically significant differences between placebo and varenicline.14 No neuropsychiatric adverse events (AEs) or deaths were reported in these clinical trials.

Clinical trials are not always able to identify rare, serious ADRs, defined as occurring once out of every 3,000 exposures, due to inclusion of relatively small sample sizes. In order to detect such events, studies must include a minimum of 3,000 patients per treatment arm. Phase III varenicline studies exposed >4,500 patients to varenicline,13 thus making detection of such events unlikely. Therefore, the FDA must rely on post-marketing reports, such as those reported to the ISMP to evaluate the true overall safety of any new medication. The ISMP is a nonprofit organization that monitors medication safety and recommends ways to prevent medication errors. This organization plays a major role in documenting and reporting AEs from medications once they are approved by the FDA. Reporting AEs to the ISMP is voluntary and information collected about AEs is limited.

Post-Marketing Safety Reports

Approximately 3.5 million people have taken varenicline since its FDA-approval in May 2006.15 Since that time, 6,363 cases of AEs have been submitted to the FDA; 3,063 were deemed as serious. The ISMP has compiled these cases into a single report to better collectively document risks of varenicline therapy (Table 1).15 According to the ISMP, risks of varenicline use have been underestimated. Neuropsychiatric AEs, such as agitation, mood and behavioral changes, and suicidal ideation, are most concerning.15 Also included in the ISMP report are 78 deaths in which varenicline was the principal suspect drug. Suicide contributed to 28 of these deaths and the majority of the other deaths were due to cardiovascular, arrhythmic, or thrombotic events. The report also specifically mentioned the increased rate of accidental injuries such as traffic accidents in users of varenicline, which was attributed to loss of consciousness, muscle spasms, dizziness, and mental confusion.15 As a result, the Federal Aviation Administration banned varenicline use in pilots.16

Furthermore, determining the strength of the relationship between varenicline and the proposed associated events noted in the ISMP report is complicated by confounding factors inherent in an analysis of this type. Certain facets of information, such as previous medications, medical history, and patient demographics, are lacking in the report. In fact, the ISMP states that “these reports do not establish causality; almost two-thirds of patients were taking multiple drugs; the event classification tool is limited to identifying potential cases and is not definitive. Reporting is voluntary for consumers and health professionals and little is known about reporting rates.”15

While the FDA acknowledges that there are many confounding factors affecting the development of neuropsychiatric symptoms,17 subsequent to the ISMP report, the FDA published early communication warnings in November 2007 about isolated reports of neuropsychiatric events including suicidal ideation as well as aggressive and erratic behavior following treatment with varenicline.18 The FDA alert notes that some of these events could be caused by withdrawal symptoms from nicotine, but in some cases the patients had yet to discontinue smoking.18 Later, in February 2008, the FDA requested the manufacturer of varenicline, Pfizer Inc., to develop a public health advisory and add warnings to the package labeling educating users about the possible risk of neuropsychiatric events.19 Pfizer heeded these requests in May 2008. The FDA released a second public health advisory in July 2009 which highlighted the addition of a boxed warning to the package labeling of varenicline. The advisory required this new boxed warning because of “…the risk of serious neuropsychiatric symptoms in patients receiving [varenicline].”17 The advisory included that the same black box warning be added to bupropion SR (Zyban) as well; other forms of bupropion SR (Wellbutrin SR), used for depression, already carried a similar warning.

Psychiatric Safety of Varenicline Compared to Other Smoking Cessation Aids

Because patients with mental illness were excluded from the initial clinical trials of varenicline,4-8 it is important to seriously consider the information detailed in the ISMP report. Although the ISMP does not specify details regarding the patients reporting these neuropsychiatric AEs, it documents the time course between varenicline initiation and development of the precipitating events. While some patients began exhibiting hostility, aggression, psychosis, or suicidal ideation, or performing self injury, only days after initiation of varenicline therapy, others did not develop these side effects until weeks after initiation. Furthermore, other patients did not develop psychiatric AEs until after varenicline was discontinued. As such, the time to development of psychiatric AEs from varenicline initiation or discontinuation remains unclear. Unfortunately, the ISMP did not specify any underlying medical or psychiatric conditions in these patients. This information may have elucidated causes or risk factors for developing psychiatric AEs from varenicline. In addition to the ISMP, one case report20 has documented the onset of psychiatric symptoms in a patient without a preexisting mental illness, and a second case report21 describes the onset of hallucinations upon varenicline withdrawal.

The United Kingdom (UK) also released results from similar AE surveillance data. This retrospective cohort study22 included 2,682 varenicline users in the interim analysis. Psychiatric AEs, which developed in <2% of the study population, included sleep disturbances, depression, anxiety, abnormal dreams, and changes in mood. In patients who experienced the psychiatric AEs (n=142), ~65% had no prior history of mental illness; however, 31% did have a preexisting mental illness. There were six episodes of suicidal ideation or attempts in five patients. Of these five patients, four had preexisting depression. The remaining patient had no history of mental illness.

Since the release of the FDA warnings, several studies have been conducted to examine the event rate of these psychiatric AEs comparing varenicline to other smoking cessation aids. One large cohort study (n=80,660)23 conducted in the UK examined the risk of suicide and suicidal behavior between patients using varenicline (n=10,973), nicotine replacement therapy (NRT; n=63,265), and bupropion SR (n=6,422). Approximately 48.5% of patients who received varenicline were current or past users of antidepressants. Other medications such as hypnotics and antipsychotics (37.8% and 17.6%, respectively) were less common, as was a past suicide event (9.5%). While varenicline was associated with a 43% increased risk of suicidal thoughts compared with NRT, it was not significant (95% CI –47%-285%). Hazard ratios comparing varenicline to NRT [1.12(0.68–0.88)] and bupropion to NRT for self harm were similar [1.17 (0.59-2.32)]. The authors23 concluded that varenicline had no increased risk of psychiatric AEs compared to other first-line cessation aids.

Impact of Pre-existing Mental Illness

Although psychiatric AEs may be uncommon in the general population, patients with preexisting mental illness or who use psychoactive medications might be at an increased risk of developing psychiatric AEs when taking varenicline. In fact, the ISMP report stated that many patients experiencing psychiatric AEs were concomitantly taking varenicline along with other psychoactive agents such as antidepressants, benzodiazepines, and antipsychotics.15 To date, there have been no reports of drug interactions between varenicline and antidepressants, benzodiazepines, and antipsychotics. These medications treat common mental illnesses, such as depression, anxiety, and schizophrenia, which may be exacerbated by varenicline.

Ten case reports (Table 2)20,21,24-33 have been published linking psychiatric AEs to varenicline use in patients with various mental illnesses including depression,24-27 bipolar disorder,28-31 schizoaffective disorder,32 and schizophrenia.33

A 2007 retrospective chart review34 evaluated 50 veterans who received varenicline for smoking cessation. Patients in this study had a high prevalence of preexisting mental illness (48%), including four patients who discontinued varenicline for worsening mood and behavioral changes. Interestingly, those subjects achieving a smoke-free status was significantly lower (P<.001) in mentally ill patients (27%) versus those without mental illness (57%). The small sample size precludes extrapolation to a larger population, but these results lay a foundation for further study.

In contrast, some post-marketing studies have not found varenicline to cause an exacerbation of psychiatric symptoms in patients with mental illness. A small (n=53) retrospective study35 conducted in the UK showed presence of mental illness had no impact on development of psychiatric AEs with varenicline use. In another case series,36 none of 19 patients with schizophrenia developed psychiatric AEs during a course of varenicline use. Two separate case reports also showed no development of psychiatric AEs with varenicline in a patient with schizophrenia37 and a patient with bipolar disorder.38 Although the data suggest preexisting mental illness has no impact on the likelihood of experiencing a psychiatric AE caused by varenicline, the small sample size within each of these publications prevents a definitive conclusion from being made regarding the safety of varenicline in patients with mental illness.

Another study (n=1,117)39 compared differences in psychiatric AE rates between patients with and without a history of depression taking varenicline. No differences in smoking cessation rates or overall AE rates were found between the two groups. However, those previously diagnosed with depression were more likely to experience a psychiatric AE (P<.01), including depression, anxiety, and irritability. Although statistically significant, the authors considered the difference to have no clinical significance.

An open-label study40 evaluated the addition of varenicline (up to 1 mg BID) to depressed tobacco users’ (n=18) current antidepressant to determine effects on depression rating scale scores. After 8 weeks, depression rating scale scores improved significantly (P<.001) and 44% of patients achieved abstinence. One patient discontinued treatment due to worsening mood; others experienced various common psychiatric AEs (eg, irritability, nightmares, insomnia).

The effect of varenicline therapy on improving cognitive functioning in the face of nicotine withdrawal was also examined through a prospective trial.41 In this study (n=67), varenicline showed positive results for improving mood, cognitive performance, and withdrawal symptoms compared to placebo. Insomnia, abnormal dreams, and fatigue were common AEs within both treatment arms; no other psychiatric AEs were reported.

Discussion

Varenicline has shown improved efficacy over other smoking cessation aids, but since the time of its approval it has also been associated with an increased risk of serious AEs. The FDA now requires a boxed warning in the package labeling and a patient medication guide dispensed with varenicline detailing the increased risk of psychiatric AEs.17 Studies22,23 have found that, for the general population, the risk of developing psychiatric AEs, while serious, is relatively rare. According to the data presented here, it appears that the risk for developing psychiatric AEs is greater for those with pre-existing mental illness. Patients with psychiatric conditions were excluded from the phase III clinical trials, which forced discovery of these rare ADRs into the post-marketing period. Since a large proportion of smokers may also have a mental illness,3 this seems to be a glaring oversight in the conduction of these trials.

One possible explanation for these increased risks could be the drug’s unique mechanism of action. Nicotinic receptors are selectively distributed throughout the central nervous system (CNS). While there are many subtypes of nicotinic receptors in the CNS, nicotine displays the highest affinity for the α4β2 nAChR subtype which causes dopamine release within the nucleus accumbens. The surge of dopamine release caused by α4β2 nAChR activation is responsible for the pleasurable feelings caused by nicotine. A selective partial agonist for this receptor, such as varenicline, decreases withdrawal symptoms and cravings without causing dependence. Combining this property with a long half-life (24 hours), varenicline blocks nicotine from binding to the receptor and prevents nicotine-induced dopamine release.12 This partial agonistic activity at nicotinic receptors, which increases dopamine transmission throughout the cortex, could cause the increased incidence of psychiatric AEs.42 Dopamine is hypothesized to be involved in the development and continuation of various psychiatric illnesses such as schizophrenia,43 bipolar disorder,44 and depression.45 Varenicline also binds to serotonin (5-HT)3 receptors, which may contribute to the high incidence of nausea experienced by patients when initiating therapy.13 Preclinical studies46 in mice using models of depression have shown that affinity at 5-HT3 receptors may help augment traditional antidepressant therapy. Therefore, this 5-HT3 agonistic activity of varenicline may also contribute to psychiatric AEs by disrupting the brain’s serotonin homeostasis.

Nicotine withdrawal alone may contribute to psychiatric AEs as well. Agitation, irritability, and decreased concentration are all possible withdrawal symptoms that may mimic certain aspects of psychiatric illnesses. The causal mechanism behind these psychiatric symptoms remains unclear, but may be the result of a lack of stimulation of the nAchR leading to decreased activation of dopamine receptors in the nucleus accumbens, ventral tegmental area, and prefrontal cortex. It is this decreased activation of the dopamine receptors in the prefrontal cortex that may lead to psychiatric AEs. Although the mechanism of varenicline’s action mutes the intensity of nicotine withdrawal symptoms, one study47 reported an increased incidence of depression after smoking cessation. Concomitant use of psychiatric medication may also heighten these AEs. One case report48 demonstrated amphetamine, commonly used for the treatment of attention-deficit/hyperactivity disorder, blocks the effects of varenicline, thus increasing the severity of nicotine withdrawal symptoms. Furthermore, patients with an underlying mental illness (diagnosed or undiagnosed) often exhibit neuropsychiatric symptoms, identical to those reported by the ISMP, as a result of their illness. In addition, patients who are noncompliant with their psychiatric medications may have symptoms similar to those seen with varenicline use. Collectively, these aspects of stress induced through the challenge of smoking cessation, including nicotine withdrawal, concomitant use of psychiatric medications, underlying mental illness, potential noncompliance with medication, and other unidentified factors, confound and complicate identifying the cause of psychiatric AEs in patients with mental illness.

The ISMP does not adequately evaluate the role these various factors may play in the development of psychiatric AEs. Additional factors such as comcomitant medications, previous psychiatric history including suicidality, and previous quit attempt methods need to be investigated further. The authors agree with the ISMP which states that some risks with varenicline may have been underestimated, specifically in patients with mental illness. However, while the number of AEs identified by the ISMP is striking, they constitute a very low percentage of the total number of patients who have received varenicline (3,063 out of 3.5 million exposures, ~.08%). In addition, the ISMP reports 78 deaths in which the principle suspect drug was varenicline. This number equates to a .002% death rate in the varenicline-exposed population, and when compared to the annual age-adjusted death rate in the general population (776.4 per 100,000), gives some perspective to the deaths attributed to varenicline.49 Further, the percentage of deaths due to suicide in the general and depressed populations are 1.3%49 and between 2% and 9%,50 respectively. Comparing these suicide rates with that of the varenicline-exposed population (.0008%) places the low incidence of suicide caused by varenicline into perspective. At first glance, comparison of these percentages may make it appear that varenicline actually prevents patients from committing suicide; however, the suicide rates for varenicline cannot be extrapolated to the general population as the amount of patients who have taken varenicline is low compared to the total US population. The calculation of suicide rates with varenicline is for illustrative purposes only and serves to frame the deaths due to varenicline in light of the recent ISMP and mass media reports. Still, it is unknown whether varenicline increases the risk of suicide further in patients with mental illness. Although the rates of death for varenicline presented here may be skewed due to under-reporting of AEs to the FDA, the difference in rates is noteworthy.

It is exceedingly difficult, given the relatively weak body of evidence, to come to a firm conclusion about the role varenicline plays in causing psychiatric AEs. Many of the articles incorporated in this review are case reports, case series, and retrospective chart reviews which include a small number of patients. This limits the ability to extrapolate results to the population at large. Further, four publications35-38 do not support an increased incidence of psychiatric AEs among varenicline users. However, a large prospective trial39 did show an increased risk of psychiatric AEs in patients with depression. While the absolute numbers of psychiatric AEs may be small and a large body of literature is lacking, their seriousness belies any lackadaisical approach, especially in patients with mental illness.

Patients desiring a pharmacotherapy smoking cessation aid have many available options. Selection of smoking cessation aids should be individualized to each patient’s needs.9 Presence of psychiatric conditions should be included in this decision-making process and may steer selection away from varenicline. Patients without a history of mental illness using varenicline should be monitored closely for psychiatric AEs, although the likelihood appears infrequent. Caution should be exercised and close monitoring implemented when varenicline is used by patients with preexisting psychiatric conditions to enable discovery of serious AEs. The authors echo the FDA’s statement from a recent Public Health Advisory:

“Healthcare providers should monitor all patients taking [varenicline] for symptoms of serious neuropsychiatric symptoms….Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder, may experience worsening of their pre-existing psychiatric illness while taking [varenicline].”51
 

It is prudent to engage patients in the product selection and discussion about common adverse reactions, serious AEs, and how to manage these occurrences. Discontinuation of varenicline is recommended in all patients reporting new-onset psychiatric symptoms or exacerbations of underlying psychiatric diseases.51 Practitioners should reevaluate the risks, benefits, and smoking cessation strategy when varenicline is used for extended periods of time.

Conclusion

Varenicline has proven efficacy for aiding in smoking cessation, but appears to carry some serious risks, particularly for patients with preexisting mental illness. While further prospective trials on the use of varenicline in mental illness may be inappropriate, the information currently available does little to fully elucidate the effects of varenicline in patients with mental illness. At a minimum, the data reviewed here validate cautious use of varenicline in patients with mental illness. PP

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27.    Raidoo BM and Kutscher EC. Visual hallucinations associated with varenicline: a case report. J Med Case Reports. 2009;3:7560.
28.    Morstad AE, Kutscher EC, Kennedy WK, Carnahan RM. Hypomania with agitation associated with varenicline use in bipolar II disorder. Ann Pharmacother. 2008;42(2):288-289.
29.    Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry. 2007;164(8):1269-1270.
30.    DiPaula BA, Thomas MD. Worsening psychosis induced by varenicline in a hospitalized psychiatric patient. Pharmacotherapy. 2009;29(7):852-857.
31.    Alhatem F, Black JE. Varenicline-induced mania in a bipolar patient. Clin Neuropharmacol. 2009;32(2):117-118.
32.    Liu ME, Tsai SJ, Yang ST. Varenicline-induced mixed mood and psychotic episode in a patient with schizoaffective disorder. CNS Spectr. 2009;14(7):346.
33.    Freedman R. Exacerbation of schizophrenia by varenicline. Am J Psychiatry. 2007;164(8):1269.
34.    Purvis TL, Mambourg SE, Balvanz TM, Magallon HE, Pham RH. Safety and effectiveness of varenicline in a veteran population with a high prevalence of mental illness. Ann Pharmacother. 2009;43(5):862-867.
35.    Stapleton JA, Watson L, Spirling LI, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction. 2008;103(1):146-154.
36.    Evins AE, Goff DC. Varenicline treatment for smokers with schizophrenia: a case series. J Clin Psychiatry. 2008;69(6):1016.
37.    Fatemi SH. Varenicline efficacy and safety in a subject with schizophrenia. Schizophrenia Res. 2008;103(1-3):328-329.
38.    Ochoa EL. Varenicline reduced smoking behavior in a mentally ill person. J Psychopharmacol. 2009;23(3):340-341.
39.    McClure JB, Swan GE, Jack L, et al. Mood, side effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. J Gen Intern Med. 2009;24(5):563-569.
40.    Phillip NS, Carpenter LL, Tyrka AR, Whiteley LB, Price LH. Varenicline augmentation in depressed smokers: an 8 week, open label study. J Clin Psychiatry. 2009;70(7):1026-1031.
41.    Patterson F, Jepson C, Strasser AA, et al. Varenicline improves mood and cognition during smoking abstinence. Biol Psychiatry. 2009;65(2):144-149.
42.    Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors. Mol Pharmacol. 2006;70(3):801-805.
43.    van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635-645.
44.    Cousins DA, Butts K, Young AH. The role of dopamine in bipolar disorder. Bipolar Disord. 2009;11(8):787-806.
45.    aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ. 2009;180(3):305-313.
46.    Rollema H, Guanowsky V, Mineur YS, et al. Varenicline has antidepressant-like activity in the forced swim test and augments sertraline’s effect. Eur J Pharmacol. 2009;605(1-3):114-116.
47.    Tsoh JY, Humfleet GL, Munoz RF, ReusVI, Hartz DT, Hall SM. Development of major depression after treatment for smoking cessation. Am J Psychiatry. 2000;157(3):368-374.
48.    Whitley HP, Moorman KL. Interference with smoking cessation effects of varenicline after administration of immediate release amphetamine-dextroamphetamine. Pharmacotherapy. 2007;27(10):1440-1445.
49.    Heron MP, Hoyert DL, Xu JQ, Scott C, Tejada-Vera B. Deaths: preliminary data for 2006. Natl Vital Stat Rep. 2008;56(16). Available at: www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_16.pdf. Accessed July 28, 2010.
50.    Centers for Disease Control and Prevention. Suicide. Facts at a Glance. Summer 2009. Available at: www.cdc.gov/violenceprevention/pdf/Suicide-DataSheet-a.pdf. Accessed August 4, 2010.
51.    U.S. Food and Drug Administration. Information for healthcare professionals: varenicline (marketed as chantix). Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124818.htm. Accessed July 28, 2010.

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Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and president of Pacific Sleep Medicine Services.

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

 


 

 

“Sleep is that golden chain that ties health and our bodies together.” — Thomas Dekker, English dramatist (1572-1632)

 

Insomnia can be a symptomatic complaint or a disorder. When insomnia presents as an uncomplicated symptomatic complaint, ie, transient insomnia associated with travel or stress, the use of a hypnotic medication as a “solo therapy” may not only be appropriate but advisable. However, when patients suffer from the disorder of insomnia, it is a gross disservice for clinicians to simply provide a medication with no effort made to help patients change perceptions and behaviors that will otherwise play a role in promoting a persistent insomnia condition.

 

Stimulus Control

Various cognitive and behavioral therapies have been tainted for the treatment of insomnia (Table 1). Most physicians are familiar with the elements of stimulus control, a form of treatment originally developed by Richard R. Bootzin, PhD, director of the Insomnia Program at the Arizona Sleep Disorders Center at the University of Arizona in Tucson. The aim of stimulus-control therapy is to break the negative associations of being in bed unable to sleep. It is especially helpful for patients with sleep-onset insomnia and prolonged awakenings. This approach utilizes specific techniques such as not remaining in bed if unable to sleep, avoiding naps, and getting up from bed if one is unable to sleep. It can be very effective as a treatment approach; however, although it was designed as a global approach to the treatment of insomnia it is often used in a piecemeal approach, with practitioners electing to use certain elements of this technique but ignoring others. It also does not incorporate any efforts at changing cognitive perceptions with regard to insomnia and sleep needs.

 

 

 

Sleep Restriction

Another strictly behavioral approach is sleep restriction, first codified as a formal therapy by Arthur J. Spielman, PhD, director of the Sleep Disorders Laboratory at the City College of New York in New York City. In this approach, patients completed questionnaires to determine the amount of sleep that they report obtaining per night on a regular basis. They are then restricted to this amount of sleep and asked to stay up to a late bedtime hour in order to obtain this amount of sleep in a single consolidated period of sleep. For example, a patient who reports sleeping only 5 hours per night may be asked to stay up until 2:15am, and then allowed to sleep until 7:15am. If the patient has demonstrated success at obtaining these 5 hours of sleep per night on a regular basis, the amount of time that they are allowed to spend in bed is increased. This model is based on several assumptions, including that patients typically underestimate the amount of sleep that they obtained, and that the sleep restriction that they obtain when they are restricted to a limited time in bed will promote sleepiness and sleep consolidation during their bedtime hours.

Several practical factors limit the utility of this approach. Patients must first agree to a model of treatment that may not conform to their perception of how sleeplessness affects them, ie, that no matter how little sleep they obtain on a given night, they will not sleep the next night. If their sleep deprivation does cause them to feel sleepy, they must still restrict their sleep to their allowed nighttime hours. They are not allowed to take naps in the daytime, or to “sleep in” (ie, extend the number of hours of sleep they obtain beyond their specified, restricted amount). Patients must be motivated enough to be willing to spend numerous weeks recording their perceptions of the amount of sleep that they have been obtaining, reviewing data with trained office personnel, and implementing the changes in hours of sleep dictated by their progress.

 

Progressive Muscular Relaxation

Various types of relaxation therapies have been utilized in the treatment of insomnia, although few of these have been formally tested. Simple approaches such as progressive muscular relaxation may be helpful for patients as part of a regimen intended to reduce arousal immediately before bedtime and can generally be taught to patients with the aid of “relaxation tapes” or compact disks. Although many patients may benefit from such an approach, others become concerned about technique, ie, doing the relaxation correctly, and may experience a paradoxical increase in alertness in association with their efforts to relax. Other relaxation techniques that may be beneficial to some individuals include self-hypnosis, yoga, meditation, and focused imagery.

 

Cognitive-Behavioral Therapy

Research studies have demonstrated that the most effective treatment for insomnia is cognitive-behavioral therapy (CBT), which, as the name implies, comprises elements with both a cognitive and a behavioral component (Table 2).1,2 The cognitive component of this therapy is designed to reduce autonomic and cognitive arousal, facilitating the capacity to fall asleep at the start of the night and to return to sleep if patients wait during the night. Elements of cognitive therapy also target maladaptive coping, recognizing that patients develop inappropriate responses to their difficulties with sleep (eg, going to bed at an early hour to make up for poor sleep the night before despite the fact that circadian rhythms may prevent sleepiness from being present at such an hour).

 

This approach challenges dysfunctional beliefs about sleep held by insomnia patients (eg, “I must sleep 8 hours or I will not be able to function the following day”), corrects unrealistic expectations (eg, “I should never wake up at night as good sleepers do not do so”), helps insomniacs to develop more appropriate perceptions about the expected consequences of a night of poor sleep (eg, “If I do not get 8 hours of sleep I will not be able to work, my boss will notice, and I will get fired”), and recognizes that maladaptive thoughts and associated catastrophic ideas promote and sustain chronic insomnia.

As a part of this therapeutic approach, patients begin to appreciate that their worries and catastrophic thoughts our irrational and destructive. They begin to appreciate that on previous nights when they slept poorly, they still were able to function at work, were not criticized by their boss or coworkers, and were not fired. Despite their poor sleep they were not divorced by their spouse or abandoned by their children, and did not get sick and die. Although they might have been certain that they appeared sick and unattractive, people did not appear to avoid wanting to be in their presence. CBT, specifically, challenges black and white thinking, such as words like “always” (eg, “I always sleep poorly”) or “never” (eg, “I never can get a good night of sleep”).

The behavioral component of CBT identifies patient-specific perpetuating factors of insomnia and eliminates them behaviorally (eg, use of alcohol to fall asleep, watching scary movies before going to bed). The patient is encouraged to create a relaxing pre-bedtime ritual to use on a nightly basis (eg, diary writing, hot bath, meditation) and to not try to compensate for a poor night’s sleep by extending time in bed in the morning or by napping in the daytime. The behavioral components target maladaptive coping (eg, staying in bed for 12 hours), works to promote good sleep hygiene, regularizes the sleep schedule, and educates patients about healthier sleep practices.

In most research studies, CBT is effective for 70% to 80% of insomnia patients.3 It significantly reduces several measures of insomnia, including sleep-onset latency and wake-after-sleep onset. Aside from the clinically measurable changes, CBT enables many patients to regain a feeling of control over their sleep, thereby reducing the emotional distress that sleep disturbances cause.

However, practical limitations also exist regarding the utility of CBT. Practitioners trained in the use of this technique are scarce and are most likely to be associated with university psychology departments or university-based sleep disorders centers. Although some research studies have demonstrated benefit from very short-term CBT approaches, most CBT programs expect patients to be involved for at least 6 weeks of outpatient therapy if positive results are to be seen. Insurance plans often will not pay for CBT, requiring patients to make a financial commitment in order to obtain this form of therapy.

A greater obstacle for many patients is the need to discontinue use of medications prior to initiating a CBT treatment program. It is easy to understand that some patients will develop a psychological dependency on medications used along a nightly basis for extended periods of time; further, some medications, particularly the benzodiazepines, may promote a degree of physical dependence associated with withdrawal effects when they are discontinued. It may thus be impractical, or impossible, for some patients to discontinue use of medications prior to entry into a CBT program.

Finally, patients must have a belief system that this therapy will be of benefit for them and a strong motivation to succeed in order to forego the “easy” choice of medication therapy as a treatment for their insomnia.

 

Sleep Hygiene

All patients can benefit from education about sleep hygiene, and sleep hygiene should be a component of all therapy for insomnia whether medications are utilized or not. The notion of sleep hygiene may seem alien to patients and physicians alike (eg, shouldn’t sleep come naturally? Why can’t we choose when we want to fall asleep? Why can’t we stay up later on weekends if we want?). In understanding how and why sleep hygiene is important, it may be helpful to draw analogies to how acceptance of hygiene and cleanliness in medicine and public health were dependant on some understanding of the germ theory of disease. Until research findings of medical pioneers such as Ignaz Semmelweis, Robert Koch, Sir Joseph Lister, and Louis Pasteur was publicized and accepted, it may have seemed perfectly acceptable to move from the dissection table to the delivery room, to drink water contaminated by sewage, or to use medical instruments “cleaned” as we might clean our tableware. Recognition of the germ theory of disease, of need for hygiene in public health, and of new standards for sterility allowed great advances in public health and medical care that have not had their full influence felt in some quarters of the world to this day.

The more we understand and can educate patients about sleep physiology, the more logical and obvious the elements of sleep hygiene become. Sleep and wake habits are regulated by circadian rhythms controlled by the light-dark cycle; it should be readily apparent that we cannot choose to sleep and be awake while ignoring the circadian sleep-wake cycle any more than we can avoid jet lag or the effects of shift work by choosing to be alert when we want or choosing to go to sleep despite the fact that our brains and bodies are in alert phases, ready for daytime activities.

Why should our bedrooms be dark, quiet, and secure? No matter how tired we are, we would not be able to fall asleep on a highway median or adjacent to an active airport runway. The noise, light, and activity would cause us to be in an alert, vigilant state. Our bedrooms should be designed to promote sleep, not to facilitate wakefulness.

Basic elements of sleep hygiene are listed in Table 3. It is often helpful to identify one or two elements that could be improved for specific patients, helping him or her to understand why these changes would be expected to improve sleep. For example, patients should be advised to avoid looking at the clock if they wake up during the night. It is impossible to make sense of the display of the digits or hands on the clock without being fully awake; the now fully alert patient must also deal with the frustration and upset associated with the inability to return to sleep.

 

 

Using computers in bed or in the bedroom should also be avoided. Although patients may believe that using the Internet or playing computer games will help them to relax if they are unable to sleep, the motor activity, mental stimulation, and exposure to light associated with computer use in bed will promote greater levels of alertness, interfering with the capacity to fall off to sleep.

 

Conclusion

Treatment of insomnia is complicated, complex, and usually multifactorial. If generalizations can be made, they are that no patients should be given the message that a medication alone is the solution to their insomnia problem. A clinician’s goal with all patients should be to emphasize the role that cognitive and behavioral strategies may play in promoting better sleep habits and sleep hygiene, whether or not medications are utilized. Ideally, patients will be able to reduce their reliance on the use of medications over time, relying on them on an as-needed basis but utilizing cognitive and behavioral techniques to promote good sleep and prevent a recurrence of insomnia symptoms. PP

References

1. Chesson AL Jr,  Anderson WM, Littner M, et al. Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22(8):1128-1133.
2. National Institutes of Health. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28(9):1049-1057.
3. Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry. 1994;151(8):1172-1180.

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To the Editor:              

It is with dismay that I read Kiki Chang, MD’s1 response to the argument that the increase in diagnosis of bipolar disorder in children and adolescents is because there are now drugs approved and promoted for that diagnosis. Chang minimizes this consideration, even going as close to describing it as “complete lunacy.”

The peril of accepting Dr. Chang’s dismissal at face value—since he was interviewed as an expert—is that it hinders an objective appraisal of presented information promoting the diagnosis and treatment of bipolar disorder in youths, eg, pharmaceutical company-sponsored dinners. This is especially salient for practitioners (primary care physicians and psychiatrists) who are not well versed in diagnosing and treating childhood conditions; they may not take the time or effort to review the relevant literature or use accepted criteria in diagnosing these serious conditions, thereby doing a disservice to patients.

There has been a debate in child psychiatry for many years now about the criteria used to diagnose mania and bipolar disorder. There are a large number of child psychiatrists who believe that it is not wise to relax the criteria delineated by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision.2 Though many psychiatrists, especially adult psychiatrists, loosely diagnose bipolar disorder or mania in children, this is not the standard of practice nor is it acceptable unless specific criteria are utilized in making such diagnoses.

In a well-written letter to the editor of the Journal of the American Academy of Child and Adolescent Psychiatry, Roberts and colleagues3 pointed out that long-term follow-up suggested that a 4% to 8% later diagnosis of bipolar disorder in previously identified children was prudent, ie, that the true incidence of bipolar disorder later in life was not as high as expected in children with symptoms that might be consistent with bipolar disorder. Carlson and colleagues4 pointed out that a diagnosis of mania or bipolar disorder was confirmed in only four out of 15 children admitted to an inpatient hospital setting with a preadmission diagnosis of bipolar disorder. Other sources of data suggest that ~50% of youngsters diagnosed with bipolar disorder do not persist into adulthood with that diagnosis.5 Stringaris and colleagues6 found that only 1.2% of children with “severe mood dysregulation” had hypomanic or manic episodes on follow-up compared to 62.4% with narrowly defined bipolar disorder.

In another letter to the editor, Holtmann and colleagues7 noted the United States trend in outpatient diagnosis of bipolar disorder8 in which there was a nearly 40-fold increase of bipolar disorder diagnosis from 1994–2003 in children and adolescents ≤19 years of age. Commenting from a European perspective, they noted that while there was an increase in hospitalization rates for bipolar disorder in youths in Europe, this rise was far more moderate than the 40-fold increase in the US, and the estimated underlying prevalence was much lower. Holtmann and colleagues7 pointed out that the prevalence rate in children using strict criteria for bipolar disorder was comparable with pediatric bipolar disorder rates in other countries, which was ~1% of an epidemiologic sample and ~7% in a child psychiatric clinical sample. US psychiatrists would have overdiagnosed that sample with bipolar disorder (~75% instead of 1% and 7%).

Similarly, Parry and Allison9 pointed out “the very marked rise” in bipolar disorder diagnosis in youths in the US, which appeared to be driven by reconceptualizing emotional and behavioral symptom clusters, which in turn was spearheaded by three regional academic departments; among the controversial features they noted was pharmaceutical company influence.

All these indicate that the rise in bipolar disorder rates reported in the US may be a local or regional trend, which is the “flavor of the day” that is magnified by lax diagnostic thinking and precision. One might consider what factors would promote such a fad.

I would suggest that it is more than coincidence that this increase in awareness and rates of diagnosis of bipolar disorder in youths corresponds with the increase in the more expensive pharmaceutical interventions promoted by the pharmaceutical industry. This mirrors the increase in awareness and rates of diagnosis of other conditions that have manifested in the US market in synchrony with greater marketing of branded commercial pharmaceutical agents, eg, social phobia in the 1990s and attention-deficit/hyperactivity disorder (ADHD) in children and adults.

We would be wise as clinicians in the US to be precise and conservative in the diagnosis of such a serious condition, as the lifelong or protracted use of psychotropic medications such as thymoleptics and antipsychotics exposes such children to significant long-term risks.10 It has been my clinical (anecdotal) experience that the judicious application of diagnostic criteria for bipolar disorder results in changes in diagnosis in youths from bipolar disorder to conditions such as ADHD comorbid with oppositional defiant disorder. When treated for the more benign conditions, those children had good long-term response to treatment for the new diagnosis, did not require thymoleptics, and did not manifest manic episodes with long-term follow up.

Sincerely,

Roger Z. Samuel, MD, FAPA

Dr. Samuel is medical director at the Boca Raton Psychiatric Group in Florida.

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

References

1.    Chang K, Sussman N. In session with Kiki Chang, MD: bipolar disorder in children and adolescents. Primary Psychiatry. 2010;17(4):23-26.
2.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
3.    Roberts N, Parker KC, Woogh C, Cripps L, Froese AP. Bipolar disorder and ADHD children growing up [letter]. J Am Acad Child Adolesc Psychiatry. 2000;39:6.
4.    Carlson GA, Potegal M, Margulies D, Gutkovich Z, Basile J. Rages – What are they and who has them? J Child Adolesc Psychopharmacol. 2009;19(3):281-288.
5.    Ruggero CJ, Carlson GA, Kotov R, Bromet EJ. Ten-year diagnostic consistency of bipolar disorder in first-admission sample. Bipolar Disord. 2010;12(1):21-31.
6.    Stringaris A, Baroni A, Haimm C, et al. Pediatric bipolar disorder versus severe mood dysregulation: risk for manic episodes on follow-up. J Am Acad Child Adolesc Psychiatry. 2010;49(4):397-405.
7.    Holtmann M, Bölte S, Poustka F. Rapid increase in rates of bipolar diagnosis in youth: “true” bipolarity or misdiagnosed severe disruptive behavior disorders? Arch Gen Psychiatry. 2008;65(4):477.
8.    Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039.
9.    Parry P, Allison S. Pre-pubertal paediatric bipolar disorder: a controversy from America. Australas Psychiatry. 2008;16(2):80-84.
10.    Samuel RZ. Letters to the editor. Side effects of atypical antipsychotics in children and adolescents. Primary Psychiatry. 2005:12(10):14-15.

Response
 

To the Editor:              

I agree with many if not most of the main points brought up by Roger Z. Samuel, MD, FAPA. The field clearly needs more education regarding the diagnosis of bipolar disorder in children and adolescents. In my clinical practice, I provide consultations on children who have presumable bipolar diagnoses, from the Bay Area in California, and beyond. Many of these children have been diagnosed with bipolar disorder (rarely classified further as I, II, or not otherwise specified [NOS]) in the community. Approximately 50% of those children I re-diagnose with another condition that better explains their symptoms (such as explosive irritability). Frequently, these diagnoses are depression (either major depressive episode, dysthymia, or depression NOS), anxiety (usually generalized anxiety disorder, or NOS), or pervasive developmental disorder (PDD; usually NOS, or Aspergers). That is, irritability is clearly a common presenting problem of children in general, and most children with irritability do not have bipolar disorder. However, the other 50% I do diagnose with a form of bipolar disorder. At Stanford, we have adopted criteria for bipolar disorder NOS, similar to that used by researchers at the University of Pittsburgh for their Course and Outcome of Bipolar Youth study.1 Thirty-eight percent of these children have been found to progress to bipolar I or II disorder within 4 years.2

However, it is easy to dismiss bipolar disorder as a “rare” disorder in children. It is not rare. However, the exact prevalence of bipolar spectrum disorders in children and adolescents is indeed unclear. One study of high schoolers in Oregon found the incidence of bipolar spectrum disorders to be .99%. Of the 18 adolescents with bipolar disorder, two had bipolar I disorder, 11 bipolar II disorder, and five cyclothymia.3 Ninety-seven were found to have a distinct period of elevated, expansive, or irritable mood, without meeting full criteria for a bipolar spectrum disorder. However, whereas a reliable semi-structured interview was used to interview adolescents, parents themselves were not interviewed. Furthermore, only adolescents in the regular public high school were assessed. Adolescents in alternate education programs (home school, special education schools, etc) were not included, which may have significantly skewed the sample away from including children with bipolar disorder, as many of them would likely have been in these alternate education placements.

A Midwest study4 indicated rates of <2% in the general population. One could also extrapolate from epidemiologic studies in adults to estimate the prevalence of bipolar disorder in children. The 2001–2003 National Comorbidity Survey Replication study5 found a prevalence of bipolar I or II disorder in the United States to be 4%. Studies6,7 assessing age of onset of bipolar disorder retrospectively in adults with bipolar disorder in the US have shown that between 15% and 28% had their onset before 13 years of age, and between 50% and 66% before 19 years of age. Thus, the prevalence of bipolar disorder (or early forms of bipolar disorder) in children <13 years of age could be as high as 1% and in children <19 years of age is 2% to 3%. Therefore, 420,000–2,072,000 US children alone could suffer from bipolar I or II disorder.8

Regarding Dr. Samuel’s concerns for my dismissal of the pharmaceutical industry’s role of increasing the diagnosis of bipolar disorder in children, I wish to clarify that I did not say it was complete lunacy, rather I stopped short of that and wrote that “Without just flat out saying that is complete lunacy… I think it is a little bit of an incorrect kind of accusation.”9 It is possible that industry-sponsored dinners, in which the diagnosis of bipolar disorder in children were discussed, may have led to community practitioners being more aware of this diagnosis in children and then feeling more comfortable to use this “label,” even in children who did not meet the criteria. There is no real way of knowing the level of impact these dinners may have had. However, to me, these practitioners would have gotten the information from any number of other sources, as they would for any condition, and would be free to distort or misinterpret the information regardless. Children with explosive irritability, who may or may not have bipolar disorder, are nonetheless very ill, and their doctors and parents are searching for solutions. Very often they are prescribed antipsychotics or mood stabilizers, whether they are diagnosed with bipolar disorder or not, often in desperation. The recent proposal from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,10 committee to include “Temper Dysregulation Disorder with Dysphoria”11 in the DSM-5 came from a desire to better categorize these types of children and take away their bipolar diagnoses. However, this may be another misguided attempt to solve the situation by creating another category, this one not studied at all, in which children will be lumped into and probably treated with the same psychotropic medications anyway. What we need are better studies parsing children with explosive and chronic irritability into different etiologies (eg, anxiety, depression, mood dysregulation, PDD, bipolar disorder) and examining response to varying treatments (including behavioral and psychosocial ones).

Regardless, Dr. Samuel does not present any actual data supporting his claim that industry is responsible for the growth in bipolar disorder diagnosis among youths. It is his opinion that this is the case, an opinion that is difficult to prove or refute given the absence of empirical data. However, my opinion is that the pharmaceutical industry influence on the rise of pediatric bipolar disorder diagnoses in the community has been small, and more a symptom of the problem than a cause. Such dinners, or other educational events, could be used to better educate practitioners regarding the subtleties of diagnosing bipolar disorder in children, leading to more accurate community-based diagnoses. However, as of 2010 in the US, there is little to no marketing of psychotropic medications to treat children <18 years of age with bipolar disorder. I believe this is due to fear of a media and public opinion backlash and fear of legal actions from consumer groups such as class action lawsuits. In this way, it is possible that children are actually losing out due to the pharmaceutical industry not supporting such dinners anymore.

I would also like to clarify some of the studies that Dr. Samuel references. Dr. Samuel states that “Other sources of data suggest that ~50% of youngsters diagnosed with bipolar disorder do not persist into adulthood with that diagnosis,” citing Ruggero and colleagues.12 This is an erroneous interpretation of the study, as the Ruggero and colleagues study consisted of subjects 15–60 years of age, who were diagnosed at some point over 10 years with bipolar disorder. Approximately half of all the subjects diagnosed at some point with bipolar disorder did not carry this diagnosis consistently. Examples included a college graduate with psychosis who was first diagnosed with bipolar disorder and then later felt to have schizophrenia, and a patient with ADHD and psychosis as a youth who was at some point diagnosed with bipolar disorder, but later felt to have schizoaffective disorder at follow-up. Clearly, these are important issues, but not relevant to Dr. Samuel’s assertion.

The Carlson and colleagues13 study cited by Dr. Samuel is not relevant either, as it simply supports the notion that many children are being diagnosed incorrectly with bipolar disorder in the community, and that when they are subject to more rigorous interviews in the hospital, many are re-diagnosed with a different condition. The other letters to the editors cited by Dr. Samuel also are not based on data, but simply continue to support this point. One letter14 is simply a review of the controversy in the US and briefly mentions that the media has had concerns of pharmaceutical company influence. There was not any stated link of pharma to three academic centers in the US. Regardless, many, but not all, academic researchers do have pharma ties—this in itself does not mean that pharma is responsible for the increase in pediatric bipolar disorder diagnoses!

I am not an apologist for pharmaceutical companies, although I do work with a few. I find it mostly a good situation, in which companies can benefit from the expertise of academic researchers to better design their studies and conduct studies they otherwise would not be required to do by the Food and Drug Administration. However, I do believe that the industry’s effect on psychiatry has been strong and not always positive. It is just my opinion that the current overdiagnosis of pediatric bipolar disorder in the US is not largely due to pharma’s influence—that is simply my opinion, and in the absence of any evidence to the contrary it appears reasonable to me that other forces have been at work to lead to this point. The answer is not blaming pharma, but educating community physicians better and supporting more research in the field to discover biological markers that will ultimately aid in better diagnosis and parsing this disorder to more meaningful subtypes.

Overall, Dr Samuel and I appear to agree that careful diagnosis is required to separate out children with bipolar disorder from children with other disorders, such as ADHD, anxiety, and depression. Better education to community practitioners may aid in this cause, but ultimately, better methods of diagnosis, using biological markers such as genetics or brain imaging, may eventually be brought from the research bench to clinical practice.

In the midst of this discussion, please let us not forget that there are real children out there with real bipolar disorder who are suffering and require thoughtful treatment to prevent lifelong morbidity and early mortality.

Sincerely,

Kiki Chang, MD

Dr. Chang is associate professor of Psychiatry and Behavioral Sciences in the Division of Child Psychiatry at the Stanford University School of Medicine in California.

Disclosures: Dr. Chang is consultant to Bristol-Myers Squibb, Eli Lilly, and GlaxoSmithKline; is on the speaker’s bureau Merck; and receives research support from GlaxoSmithKline, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health.

References

1.     Axelson D, Birmaher B, Strober M, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006;63(10):1139-1148.
2.     Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry. 2009;166(7):795-804.
3.     Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disord. 2000;2(3 pt 2):281-293.
4.     Carlson GA, Kashani JH. Manic symptoms in a non-referred adolescent population. J Affect Disord. 1988;15(3):219-226.
5.    Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.
6.     Leverich GS, Post RM, Keck PE Jr, et al. The poor prognosis of childhood-onset bipolar disorder. J Pediatr. 2007;150(5):485-490.
7.     Perlis RH, Miyahara S, Marangell LB, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004;55(9):875-881.
8.     Post RM, Kowatch RA. The health care crisis of childhood-onset bipolar illness: some recommendations for its amelioration. J Clin Psychiatry. 2006;67(1):115-125.
9.    Chang K, Sussman N. In session with Kiki Chang, MD: bipolar disorder in children and adolescents. Primary Psychiatry. 2010;17(4):23-26.
10.    Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association. In press.
11. American Psychiatric Association. DSM-5 Development. Temper Dysregulation Disorder with Dysphoria. Available at: www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=397. Accessed August 10, 2010.
12. Ruggero CJ, Carlson GA, Kotov R, Bromet EJ. Ten-year diagnostic consistency of bipolar disorder in first-admission sample. Bipolar Disord. 2010;12(1):21-31.
13. Carlson GA, Potegal M, Margulies D, Gutkovich Z, Basile J. Rages – What are they and who has them? J Child Adolesc Psychopharmacol. 2009;19(3):281-288.
14. Parry P, Allison S. Pre-pubertal paediatric bipolar disorder: a controversy from America. Australas Psychiatry. 2008;16(2):80-84.


Please send letters to the editor to Primary Psychiatry, c/o Norman Sussman, MD, 333 Hudson St., 7th Floor, New York, NY 10013; via the Web: http://mc.manuscriptcentral.com/primarypsy.

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Dr. Ginsberg is vice-chair of clinical affairs in the Department of Psychiatry at New York University Medical Center in New York City.


Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.

 


 

Add-On Aripiprazole to Treat Olanzapine-Induced Metabolic Syndrome

Aripiprazole is an atypical neuroleptic indicated for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder. A potent dopamine partial agonist, aripiprazole acts as an antagonist at dopamine (D)2 receptors under hyperdopaminergic conditions and as a D2 agonist under hypodopaminergic conditions. It has been theorized that dopamine partial agonists may be able to stabilize the dopaminergic system without inducing a hypodopaminergic state, thereby reducing the risk of side effects associated with pure blockade of dopamine receptors. In addition to these effects, aripiprazole also acts as a partial agonist at serotonin (5-HT)1A and as an antagonist at 5-HT2A receptors.1 Aripiprazole has a low incidence of clinically significant weight gain and hyperlipidemia.2,3

Olanzapine is one of the atypical antipsychotics associated with the highest incidence of body weight gain, hyperglycemia, and hyperlipidemia.4,5 The following is a report of two patients in whom addition of aripiprazole to ongoing treatment with olanzapine resulted in attenuation of obesity and metabolic disturbance.6

The first patient was a 41-year-old man with a 17-year history of schizophrenia. In the past, he had undergone unsuccessful trials of haloperidol, sulpiride, and trifluoperazine culminating in several psychiatric admissions due to agitation and prominent psychosis. Olanzapine 15 mg/day and fluvoxamine 50 mg/day were prescribed for psychotic depression. His symptoms improved; however, his body weight increased from 63 kg up to 68 kg (138.6 lb up to 149.6 lb). Moreover, after olanzapine treatment his fasting cholesterol increased from 162 mg/dL up to 200 mg/dL, his fasting glucose from 120 mg/dL to 132 mg/dL, and triglyceride from 289 mg/dL to 344 mg/dL. As the patient was reluctant to switch off of olanzapine, aripiprazole was added as an augmenting agent. The same doses of olanzapine and fluvoxamine were maintained throughout. During the first 2 weeks of aripiprazole 10 mg/day, the patient reported a decrease in appetite; however, his activity did not significantly change. By the end of 2 weeks of aripiprazole augmentation, his weight decreased from 68.5 kg down to 63.5 kg (150.7 lb to 139.7 lb). Moreover, fasting glucose, cholesterol, and triglyceride levels were 108, 162, and 110 mg/dL, respectively. Over the next 6 weeks, due to akathisia, the dosage of aripiprazole was decreased to 5 mg/day. At the end of 8-week combined treatment, the patient’s body weight gradually decreased to 61 kg (134.2 lb) while the fasting glucose, cholesterol, and triglyceride levels were 125, 163, and 164 mg/dL, respectively. At last follow up, his psychiatric symptoms remained stable without evidence of akathisia.

The second patient was a 35-year-old woman with a 10-year history of schizoaffective disorder, depressed type, with multiple prior psychiatric admissions. Treated unsuccessfully in the past with adequate trials of risperidone and haloperidol, this time she received olanzapine 10 mg/day and fluoxetine 20 mg/day for psychotic depression. Her symptoms improved but she gained significant weight: from 49.3 kg up to 58.5 kg (108.5 lb up to 128.7 lb) over the course of 6 months. Fasting glucose, cholesterol, and triglyceride levels were 180, 173, and 285 mg/dL, respectively. To address these metabolic disturbances, aripiprazole 10 mg/day was added as augmentation. The patient tolerated the olanzapine-aripiprazole-fluoxetine combination without any adverse effects. After 1 month of combined treatment, her weight declined from 58.5 kg down to 56.6 kg (128.7 lb down to 124.5 lb) without any significant lifestyle changes. Fasting glucose, cholesterol, and triglyceride levels were 117, 170, and 190 mg/dL, respectively. After 3 months of combined treatment, her body weight further decreased to 52.3 kg (115.1 lb). By this point, fasting glucose, cholesterol, and triglyceride levels were 109, 149, and 146 mg/dL, respectively.

This is the first report on the use of aripiprazole in olanzapine-treated schizophrenic patients to induce a favorable effect on body weight and metabolic profiles. There is an open-label study of adjuvant aripiprazole to clozapine which, without loss of efficacy, resulted in a significant decrease in weight, serum cholesterol, and triglycerides.7 While the mechanism of action underlying this effect is not precisely known, it is possible that aripiprazole’s partial agonist properties at 5-HT2C receptors may compete with antagonist activity by olanzapine at this receptor, thereby promoting weight loss. Agonism of 5-HT2C receptors has been associated with decreased appetite and weight loss.8 Additionally, 5-HT2C receptors might also play a role in the peripheral dysregulation of leptin and ghrelin pathways as well as impair neural processing of glucose and fat metabolism.9,10 As pointed out by the authors of this report,6 there are no reported clinically relevant interactions between olanzapine and aripiprazole. Whether adding aripiprazole to olanzapine results in long-term safety benefits requires further study. PP

 

References

1. Abilify [package insert]. San Francisco, CA: Otsuka Pharmaceutical Group; 2005.
2. McQuade RD, Stock E, Marcus R, et al. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry. 2004;65(suppl 18):47-56.
3. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60(7):681-690.
4. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696.
5. Nasrallah HA, Newcomer JW. Atypical antipsychotics and metabolic dysregulation: evaluating the risk/benefit equation and improving the standard of care. J Clin Psychopharmacol. 2004;24(suppl 1):7-14.
6. Chen CH, Huang MC, Lu ML. Aripiprazole improves metabolic adversity in olanzapine-treated schizophrenic patients. J Clin Psychopharmacol. 2007;27(5):516-517.
7. Henderson DC, Kunkel L, Nguyen DD, et al. An exploratory open-label of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand. 2006;113(2):142-147.
8. Bickerdike MJ. 5-HT2C receptor agonists as potential drugs for the treatment of obesity. Curr Top Med Chem. 2003;3(8):885-897.
9.  Nonogaki K. New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia. 2000;43(5):533-549.
10. Nonogaki K, Ohashi-Nozue K, Oka Y. A negative feedback system between brain serotonin systems and plasma active ghrelin levels in mice. Biochem Biophys Res Commun. 2006;341(3):703-707.

 

Add-On Aripiprazole to Treat Haloperidol-Induced Hyperprolactinemia

Dopamine acts to inhibit the release of prolactin, a hormone that initiates and sustains lactation. Neuroleptic-induced blockade of dopamine receptors in the tubero-infundibular tract releases prolactin from the tonic inhibitor control of dopamine, thereby allowing prolactin levels to rise. Prolactin elevation in women can cause amenorrhea, cessation of normal cyclic ovarian function, loss of libido, hirsutism, and increased long-term risk of osteoporosis and breast cancer; prolactin elevation in men can cause impotence, loss of libido, and hypospermatogenesis.1,2 Except for risperidone, atypical neuroleptics such as clozapine, olanzapine, quetiapine, and ziprasidone are generally viewed as elevating prolactin only transiently.1,3 Agents that do not elevate prolactin levels appear to be loosely or intermediately bound to dopamine (D)2 receptors, whereas agents that increase prolactin appear to be tightly bound to the D2 receptors.

Aripiprazole is an atypical neuroleptic indicated for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder. A potent dopamine partial agonist, aripiprazole acts as an antagonist at D2 receptors under hyperdopaminergic conditions and as a D2 agonist under hypodopaminergic conditions. It has been theorized that dopamine partial agonists may be able to stabilize the dopaminergic system without inducing a hypodopaminergic state, thereby reducing the risk of side effects associated with pure blockade of dopamine receptors. In addition to these effects, aripiprazole also acts as a partial agonist at serotonin (5-HT)1A and as an antagonist at 5-HT2A receptors. In short-term trials, the most common side effects reported with aripiprazole included headache, agitation, anxiety, insomnia, nausea, dyspepsia, somnolence, akathisia, lightheadedness, vomiting, and constipation.4

The following is a report of a patient in whom addition of aripiprazole to ongoing treatment with haloperidol decanoate resulted in resolution of haloperidol-induced hyperprolactinemia.5 A 29-year-old African American man with a 9-year history of bipolar I disorder, manic with psychotic features, was admitted to the acute care psychiatric unit at the Medical University of South Carolina. On the day of admission, he had received a haloperidol decanoate intramuscular (IM) injection at his outpatient psychiatrist’s office. Haloperidol decanoate had been initiated 1 year earlier due to noncompliance and to therapeutic failures with trials of olanzapine, quetiapine, and ziprasidone. Six months prior to admission, on haloperidol decanoate 150 mg every 4 weeks, he had developed gynecomastia. No prolactin levels were drawn at that time. After reducing the haloperidol decanoate to 100 mg IM every 4 weeks, the gynecomastia eventually resolved.

Three days after admission, an additional haloperidol decanoate 50 mg IM was administered. Oral haloperidol was tapered to 5 mg twice daily, then discontinued 3 days after the patient had received the additional haloperidol decanoate. Six days after admission, a prolactin level was drawn and found to be elevated at 35.2 ng/mL (normal 2.1–17.7 ng/mL). At this point, aripiprazole was initiated at 30 mg/day, then decreased to 15 mg/day after 3 days. Two additional prolactin levels were drawn 1 and 2 weeks after starting aripiprazole and were 2.1 and 2.6 ng/mL, respectively. All prolactin levels were obtained at 2pm. The patient maintained improvement of his psychotic symptoms with no adverse effects. At the time of discharge, the patient’s medication regimen consisted of aripiprazole 15 mg/day, valproic acid elixir 2,500 mg/day, clonazepam 2 mg at bedtime, and haloperidol decanoate 150 mg IM once monthly.

This appears to be the first published report of using concomitant aripiprazole to treat haloperidol-induced hyperprolactinemia. There is a similar report, however, of combining aripiprazole with risperidone to offset hyperprolactinemia.6 Parodoxically, there are also reports of aripiprazole causing galactorrhea.7,8 Perhaps these apparent inconsistencies may be reconciled by considering that aripiprazole is a partial agonist, thereby it may act as either an agonist or an antagonist depending upon the conditions. Similar to conclusions about the role of adding aripiprazole to atypical antipsychotics to offset metabolic syndrome,9,10 additional trials are indicated before recommending routine adoption of this strategy in clinical practice. PP

 

References

1. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res. 1999;35(suppl):S67-S73.
2. Wang PS, Walker AM, Tsuang MT, et al. Dopamine antagonists and the development of breast cancer. Arch Gen Psychiatry. 2002;59(12):1147-1154.
3. Maguire GA. Prolactin elevation with antipsychotic medication: mechanisms of action and clinical consequences. J Clin Psychiatry. 2002;63(suppl 4):56-62.
4. Abilify [package insert]. San Francisco, CA: Otsuka Pharmaceutical Group; 2005.
5. Lorenz RA, Weinstein B. Resolution of haloperidol-induced hyperprolactinemia with aripiprazole. J Clin Psychopharmacol. 2007;27(5):524-525.
6. Wahl R, Ostroff R. Reversal of symptomatic hyperprolactinemia by aripiprazole. Am J Psychiatry. 2005;162(8):1542-1543.
7. Mendhekar DN, Andrade C. Galactorrhea with aripiprazole. Can J Psychiatry. 2005;50(4):243.
8. Ruffatti A, Minervini L, Romano M, et al. Galactorrhea with aripiprazole. Psychother Psychosom. 2005;74(6):391-392.
9. Henderson DC, Kunkel L, Nguyen DD, et al. An exploratory open-label of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand. 2006;113(2):142-147.
10. Chen CH, Huang MC, Lu ML. Aripiprazole improves metabolic adversity in olanzapine-treated schizophrenic patients. J Clin Psychopharmacol. 2007;27(5):516-517.

 

Unfavorable Smell Associated with Citalopram

Citalopram is a widely used selective serotonin reuptake inhibitor. The most commonly reported side effects associated with citalopram include nausea, vomiting, excessive sweating, headache, tremor, insomnia, and decreased libido. The following is a report of an adolescent patient who developed an unpleasant smell in association with use of citalopram.1

A 17-year-old male student presented for psychiatric evaluation upon referral from his family physician. He was quite depressed, irritable, restless, and felt hopeless. In addition, he reported trouble sleeping and manifested impairments in educational and interpersonal functioning. He had no prior psychiatric history and was not taking any medication. His general physical and laboratory examinations were normal.

Diagnosed with major depressive disorder, citalopram 10 mg/day was initiated, then after 10 days increased to 20 mg/day. After 4 more weeks without any improvement, the dosage of citalopram was increased to 40 mg/day. By week 8 of treatment, significant subjective and clinical improvement were observed. However, the patient reported a sense of an unfavorable and intolerable smell that began at approximately 7 weeks into citalopram treatment. Physical examination, including neurologic and nose and throat consultations, was unremarkable. At week 9 of treatment, citalopram was tapered, eventually to discontinuation. Subsequently, 6 days after cessation of citalopram, the odor disappeared. No rechallenge was conducted.

Given the absence of findings of neurologic or nose and throat pathology, olfactory hallucinations ought to be considered in the differential diagnosis. However, as pointed out by the author of this report, there was no evidence of other psychotic symptoms. Regardless of the cause, given the widespread use of citalopram, it appears that this adverse event of an unpleasant odor occurs rather infrequently. PP

Reference

1. Ghanizadeh A. Unfavorable smell with citalopram? J Clin Psychopharmacol. 2007;27(5):528-529.

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e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.


 

Suicide is the ultimate act of a hopeless and suffering individual. Those who know the victim frequently describe the suicide as senseless. Yet, the person who takes his or her own life experiences and perceives the future as more unbearable than death. Feeling trapped, unbearably agitated, or shamed, the victim sees death as a friend. However, to families and acquaintances, or to the health professional that may have treated that person, the suicide is inevitably traumatic. Everyone who cared about the victim is somehow diminished by the act.

Most recent publicity surrounding suicide has come from analyses of clinical trials that have implicated antidepressants as triggers of suicide among children and adolescents. Starting in 2003, reports appeared of a possible link between antidepressant use in clinical trials among youths and the emergence of suicidality. In addition to making front-page news, these findings triggered Senate hearings as well as a precipitous decline in the number of antidepressant prescriptions given to youths. The number of cases of child and adolescent depression diagnosed by primary care physicians declined as well. Both the diagnostic and prescription trends no doubt were accelerated by a series of black box warnings added to the product information. As it turns out, as the number of prescriptions dispensed and cases diagnosed have declined, there has been a precipitous rise in youth suicides. These findings have been noted in both the United States and the Netherlands.1 Next year, data may confirm that the hysteria about antidepressants costing more lives than they save is unwarranted. As such, this entire episode will become part of the curriculum of every medical, public health, and governmental affairs school as examples of a dysfunctional political and regulatory sytem. I feel confident in saying that, ultimately, this misconceived action by the Food and Drug Administration will be shown to have cost lives. Antidepressants will be shown to save lives. Psychiatric interventions that carry small risks to some patients should be viewed the same way other medical treatments are regarded, with the benefits for most patients outweighing the adverse outcomes for the very few.

One lesson that can be drawn from this is that the variables involved in causing suicide, its prediction, and its prevention are complex. Accordingly, the November and December issues of Primary Psychiatry will focus on recent evidence that improves our understanding of factors that lead to suicides as well as on strategies that can help prevent these events. Two shared risk factors for suicide attempts are a diagnosis of depression and young age. Robert J. Valuck, PhD, RPh, and colleagues, present a study that examines annual suicide attempts among managed care enrollees. The article describes the demographics, diagnoses, and prior treatment history of these individuals.

The recent black box warnings against antidepressants, with the possible consequences described above, make it even more important that toxicology studies be conducted after every attempted or completed suicide. However, Dirk M. Dhossche, MD, PhD, argues that toxicologic analysis should be conducted in every suspected suicide and other types of unnatural death. The results of toxicologic procedures can be useful for reconstructing some events before a suicide, such as impaired mental functioning due to intoxication with alcohol or other drugs, or, if prescription medication is detected, recent contact with a physician. Dhossche observes that examination for prescribed psychoactive medications may also be useful to estimate the frequency and type of psychiatric treatment before a suicide. One of the more significant findings from the study was that the majority of depressed patients who committed suicide had sought professional help within the month prior to their deaths, yet the majority of these individuals were not being treated with antidepressants at the time of their death. This suggests that underrecognition and undertreatment of depression remain a problem.

Yogesh Dwivedi, PhD, and Ghanshyam N. Pandey, PhD, discuss the role of the signal transduction molecule protein kinase A (PKA) in the pathophysiology of suicide. The article explains how psychological, social, and environmental factors are weak predictors of suicide. They offer a neurobiologic approach to understanding risk factors associated with suicide. The authors review the potential role of PKA, one of the crucial signaling molecules whose activation and expression may be involved in the pathophysiology of suicide. They critically discuss findings in human postmortem brain and in pre-clinical models that link stress to suicide attempts.

Mao-Sheng Ran, MD, PhD, provides a systematic review of studies conducted on suicide in Micronesia. Ran notes that suicide among different islanders has not been extensively studied. As with any geographic area, a limited knowledge of suicidal behavior interferes with the development of suicide prevention. The number of suicides in Micronesia has risen sharply over the past 40 years, especially among youths. In fact, youth suicide rates are amongst the highest in the world. One of the more surprising statistics in this article is that in Micronesia, <40% of suicide victims were linked to an existing mental disorder.

On a separate but related topic, as many suicidal patients are seen in emergency rooms, Leslie S. Zun, MD, MBA, and LaVonne Downey, PhD, present a study involving the use of a medical clearance protocol that reduces the number and cost of testing for psychiatric patients. The authors note that while the American College of Emergency Physicians published numerous guidelines and protocols for use in the emergency department, recommendations take into consideration the need to reduce the costs of testing for many conditions such as seizures, acute mental status change, and headache. These guidelines have not been published for the medical evaluation of psychiatric patients. The protocol described in this study did not require testing of psychiatric patients but, rather, left the option of testing to the emergency physician. PP

Reference

1. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363.

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