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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 11, February 2013 — Guest Commentator: Ashwin A. Patkar, MD, MRCPsych, Duke University Medical Center, Durham, NC

Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

Krupitsky E, Zvartau E, Blokhina E, et al.

Arch Gen Psychiatry. 2012;69(9):973-981.

Objective: Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. This study compared outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment.

Methods: Six-month double-blind, double-dummy, randomized trial conducted in addiction treatment programs in St Petersburg, Russia. Participants included 306 opioid-addicted patients recently undergoing detoxification. Biweekly counseling and 1 of the following 3 treatments were given for 24 weeks: 1,000 mg naltrexone implant and oral placebo (NI+OP group; 102 patients); placebo implant and 50 mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or placebo implant and oral placebo (PI+OP group; 102 patients). Percentage of patients retained in treatment without relapse was utilized as the main outcome measure.

Results: By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and 11 of 102 patients in the PI+OP group (10.8%) (P<.001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P=.07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with anti-allergy medication treatment. Other non local-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found.

Conclusions: The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment.

Clinical Commentary
Naltrexone is a mu-opioid antagonist that reduces the positive reinforcing effects of opioids and is approved to treat opioid dependence in the U.S. and several countries. Unfortunately, adherence to oral naltrexone is poor and clinical use has been limited except in selected groups of motivated patients. This study was done in Russia, where use of prescription opioid agonists (eg, methadone) to treat opioid addiction is highly restricted. The results showed that a 1,000 mg subcutaneous biodegradable 2-month naltrexone implant was superior to placebo implant and oral naltrexone on the primary outcome measure of retention without relapse. The outcome differences were striking. Over the 6-month study period, approximately 53% of patients in the naltrexone implant group remained in treatment without relapse compared to 16% in the oral naltrexone and 11% in the placebo group. All participants received biweekly drug counseling. Those with an active implant had a higher rate of wound infections (~5%) compared to the placebo implant group (~1%), but the infections were minor and successfully treated with oral antibiotics. The clinical considerations worth noting are: (1) Delivery systems that ensure sustained administration of naltrexone are effective to treat opioid dependence when combined with counseling; (2) Compliance with oral naltrexone limits its clinical utility; (3) Given the potential for diversion, misuse, and overdose of opioid agonists, naltrexone, a non-abusable and effective drug, deserves attention. Although naltrexone implant is not available in the U.S., an extended release, once monthly formulation of naltrexone is FDA approved. Commercial considerations are likely to influence future availability of the implant in the US.


Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive 'Bath Salts' Products

Baumann MH, Partilla JS, Lehner Kr, et al

Neuropsychopharmacology. 2012;Oct 17. doi: 10.1038/npp.2012.204. [Epub ahead of print]

Objective: The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods.

Methods: In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats.

Results: We found that MDPV blocks uptake of [(3)H]dopamine (IC(50)=4.1 nM) and [(3)H]norepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of [(3)H]serotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats.

Conclusions: Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.

Clinical Commentary

MDPV is the primary ingredient in "bath salts," synthetic designer drugs that are labeled as such to avoid criminal prosecution. Bath salts have seen a tremendous increase in popularity in recent years as drugs of abuse and have only been classified recently as controlled substances in the United States and some other countries. Intoxications with bath salts can have serious adverse effects, including acute psychosis with delusions, hallucinations, and bizarre behavior such as self-mutilation and violence. Physical effects can include hypertension, arrhythmias, and seizures. There has been limited information on mechanism of action of MDPV and its addictive potential. This preclinical study clearly demonstrates that MDPV is more selective and potent than cocaine in inhibiting the monoamine uptake leading to acute increase in dopaminergic transmission. This mechanism can explain the reinforcing nature of bath salt use, and the potentially dangerous physical and psychiatric manifestations of toxicity. It is worth noting that MDPV was 10 times more potent than cocaine in producing adverse cardiovascular effects in this study. Intoxication with bath salts should be a differential diagnosis in acute psychotic episodes, especially in young adults or adolescents who have a history of substance abuse. MDPV is not detected by routine drug screens but overdose can be life-threatening. Hence, clinicians must be especially vigilant about assessment of bath salt use.


A Double-Blind Randomized Controlled Trial of N-acetylcysteine in Cannabis-Dependent Adolescents

Gray KM, Carpenter MJ, Baker NL, et al

Am J Psychiatry. 2012;169(8):805-812.

Objective: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy.

Methods: In an 8-week, double-blind, randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1,200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group.

Results: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4; 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events.

Conclusions: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Clinical Commentary

Cannabis is the most commonly used illicit drug among adolescents. Heavy use of cannabis has been associated with a variety of adverse effects. Existing behavioral treatments are associated with modest abstinence rates in adolescents. Furthermore, there is no medication that has demonstrated consistent efficacy in cannabis dependence. N-acetylcysteine (NAC) is an inexpensive, over-the-counter supplement that has been shown to upregulate the cysteine-glutamate exchanger and modulate glutaminergic neurotransmission. NAC also has anti-inflammatory properties that are linked to oxidative pathways. This is the first randomized controlled pharmacotherapy trial for cannabis dependence that showed a positive primary abstinence outcome as opposed to decreased use of cannabis in adolescents. About 41% of the NAC group were abstinent during the study compared to 27% of placebo-treated subjects.
At the dose employed (2.4 g per day), NAC did not have any significant side effects. While it is tempting to think of NAC as a daily supplement for cannabis dependence, more information is required. In this single-site study, NAC was effective when added to contingency management and brief cessation counseling. Will it be as effective in the absence of adjunctive psychosocial treatments? Are the effects of NAC sustained beyond the post-treatment period? Will it work for patients with dependence on other substances or high levels of psychopathology? It is hoped that we may have these answers in the near future. A large, federally funded, multi-site controlled trial of NAC for marijuana dependence in adolescents is underway.

Integrated Exposure-Based Therapy for Co-occurring Posttraumatic Stress Disorder and Substance Dependence: A Randomized Controlled Trial

Mills KL, Teesson M, Back SE, et al

JAMA. 2012;308(7):690-699.

Objective: There is concern that exposure therapy, an evidence-based cognitive-behavioral treatment for posttraumatic stress disorder (PTSD), may be inappropriate because of risk of relapse for patients with co-occurring substance dependence. This study aimed to determine whether an integrated treatment for PTSD and substance dependence, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), can achieve greater reductions in PTSD and substance dependence symptom severity compared with usual treatment for substance dependence.

Methods: Randomized controlled trial enrolling 103 participants who met DSM-IV-TR criteria for both PTSD and substance dependence. Participants were recruited from 2007-2009 in Sydney, Australia; outcomes were assessed at 9 months post baseline, with interim measures collected at 6 weeks and 3 months post baseline. Participants were randomized to receive COPE plus usual treatment (n=55) or usual treatment alone (control) (n=48). COPE consists of 13 individual 90-minute sessions (ie, 19.5 hours) with a clinical psychologist. The main outcome measures were change in PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS; scale range, 0-240) and change in severity of substance dependence as measured by the number of dependence criteria met according to the Composite International Diagnostic Interview version 3.0 (CIDI; range, 0-7), from baseline to 9-month follow-up. A change of 15 points on the CAPS scale and 1 dependence criterion on the CIDI were considered clinically significant.

Results: From baseline to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment group (mean difference, -38.24 [95% CI, -47.93 to -28.54]) and the control group (mean difference, -22.14 [95% CI, -30.33 to -13.95]); however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity (mean difference, -16.09 [95% CI, -29.00 to -3.19]). No significant between-group difference was found in relation to improvement in severity of substance dependence (0.43 vs 0.52; incidence rate ratio, 0.85 [95% CI, 0.60 to 1.21), nor were there any significant between-group differences in relation to changes in substance use, depression, or anxiety.

Conclusion: Among patients with PTSD and substance dependence, the combined use of COPE plus usual treatment, compared with usual treatment alone, resulted in improvement in PTSD symptom severity without an increase in severity of substance dependence.

Clinical Commentary

Exposure therapy, a cognitive-behavioral therapy involving exposure to memories and reminders of past trauma, has long been regarded as a gold standard treatment for PTSD. However, there has been a concern that exposure therapy may be inappropriate for patients with co-occurring substance dependence because it may activate unpleasant memories and trigger relapse. To date, there was an absence of evidence to support or refute this belief because most trials of PTSD treatment have excluded individuals with substance dependence. Mills and colleagues from Australia have published the first large, randomized controlled trial of an integrated treatment for PTSD and substance dependence that incorporated prolonged exposure therapy. The researchers found that from the beginning of the study to 9-month follow-up, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity compared with the control group. By 9 months, rates of substance dependence had decreased to 45.4% in the treatment group and 56.2% in the control group; however, the difference between groups was not statistically significant. There are two important take-home messages from the study. First, most patients continued to use substances throughout the study. This indicates that abstinence from substances is not required for exposure therapy to be effective for PTSD in patients with comorbid substance abuse. Second, it is important to integrate exposure therapy with evidence-based treatments for substance dependence because no significant benefits were observed for substance-related outcomes with exposure therapy. We await replication of these results in a US sample, especially in those with combat trauma.


Randomized Controlled Trial of Contingency Management for Stimulant Use in Community Mental Health Patients With Serious Mental Illness

McDonell MG, Srebnik D, Angelo F, et al

Am J Psychiatry. 2012 Nov 9. doi: 10.1176/appi.ajp.2012.11121831. [Epub ahead of print]

Objective: The primary objective of this study was to determine whether contingency management was associated with increased abstinence from stimulant drug use in stimulant-dependent patients with serious mental illness treated in a community mental health center. Secondary objectives were to determine whether contingency management was associated with reductions in use of other substances, psychiatric symptoms, HIV risk behavior, and inpatient service utilization.

Methods: A randomized controlled design was used to compare outcomes of 176 outpatients with serious mental illness and stimulant dependence. Participants were randomly assigned to receive 3 months of contingency management for stimulant abstinence plus treatment as usual or treatment as usual with reinforcement for study participation only. Urine drug tests and self-report, clinician-report, and service utilization outcomes were assessed during the 3-month treatment period and the 3-month follow-up period.

Results: Although participants in the contingency management condition were significantly less likely to complete the treatment period than those assigned to the control condition (42% compared with 65%), they were 2.4 times (95% CI=1.9-3.0) more likely to submit a stimulant-negative urine test during treatment. Compared with participants in the control condition, they had significantly lower levels of alcohol use, injection drug use, and psychiatric symptoms and were one-fifth as likely as those assigned to the control condition to be admitted for psychiatric hospitalization during treatment. They also reported significantly fewer days of stimulant drug use during the 3-month follow-up.

Conclusions: When added to treatment as usual, contingency management is associated with large reductions in stimulant, injection drug, and alcohol use. Reductions in psychiatric symptoms and hospitalizations are important secondary benefits.

Clinical Commentary

About 50% of patients with serious mental illness suffer from a substance use disorder at some point in their lives. Contingency management is an evidence-based intervention for substance dependence in which individuals are provided with reinforcers (eg, vouchers, prizes) based on abstinence from drugs. The present study is the first adequately powered randomized controlled trial conducted to evaluate the efficacy of 12-week, contingency management alone or as an adjunct to treatment as usual for cocaine and/or methamphetamine dependence in 176 patients with schizophrenia, bipolar disorder, or recurrent major depressive disorder. The results were impressive. Participants who received the contingency management intervention showed favorable effects on stimulant-negative urine samples during treatment (primary outcome) as well as several secondary outcomes such as alcohol use, HIV risk behavior, psychiatric symptoms, and inpatient care (138 fewer days of hospitalization in treatment group versus control group). Of note, the positive effects of contingency management on stimulant abstinence persisted after treatment was discontinued. The intervention was delivered at low cost. For example, the cost of urine testing and reinforcers was $256 per participant for the treatment group. The principal limitation was that 42% of subjects completed contingency management compared to 65% in the control group, suggesting that acceptability of the intervention among patients with serious mental illness is not universal. Unfortunately, despite empirical support and potential cost savings, it appears that contingency management will continue to be underutilized in clinical settings until payers provide funding for the costs of delivering this treatment.

The Role of the Asn40Asp Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

Ray LA, Barr CS, Blendy JA, et al

Alcohol Clin Exp Res. 2012;36(3):385-394.

The endogenous opioid system has been implicated in the pathophysiology of alcoholism, as it modulates the neurobehavioral effects of alcohol. A variant in the mu-opioid receptor gene (OPRM1), the Asn40Asp polymorphism has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: genetic association studies; behavioral studies of alcoholism; neuroimaging studies; pharmacogenetic studies and clinical trials; and preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response.

Clinical Commentary

The research enthusiasm for advancing our understanding of the genetic underpinnings of alcohol dependence has yet to be translated into clinical benefit. There is convergence of evidence that the mu-opioid receptor gene (OPRM1) may be a promising candidate gene in alcohol dependence. This review focuses on effects of the allelic variations in the OPRM1 gene, the Asn40Asp polymorphism in particular, on the etiopathology and treatment of alcohol dependence. Clinicians and researchers should take note of the rapidly accumulating evidence for the effect of the ORM1 Asn40Asp polymorphism on alcohol-related endophenotypes and response to opioid antagonist medications. Post hoc analyses of the COMBINE study, one of the largest controlled trial in alcohol dependence, showed that this polymorphism predicted response to naltrexone, an FDA-approved medication for alcohol dependence. If these findings are confirmed by a prospective randomized controlled pharmacogenetic clinical trial, it opens up the possibility for the OPRM1 receptor to be examined as a genetic biomarker for alcohol dependence and moreover for the FDA to consider pharmacogenetic indications in alcohol dependence. Although much work remains to be done, it appears that this line of research holds promise for increased understanding of pathways to risk and recovery from alcohol dependence and improving treatment outcomes.

GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


ISSUE 10, January 2013 — Guest Commentator: Rakesh Jain, MD, MPH, University of Texas Medical School, Houston, TX


State-Dependent Changes in Hippocampal Grey Matter in Depression

Arnone D, McKie S, Elliott R, et al
Mol Psychiatry. 2012; November 6. doi: 10.1038/mp.2012.150. [Epub ahead of print]

Objective: Reduced hippocampal volume has been reported in depression and may be involved in the etiology of depressive symptoms and vulnerability to depressive relapse. Neuroplasticity following antidepressant drug treatment in the hippocampus has been demonstrated in animal models but adaptive changes after such treatment have not been shown in humans. In this study, we determined whether grey matter loss in the hippocampus in depression (1) is present in medication-free depressed; (2) changes in response to antidepressant treatment; and (3) is present as a stable trait in medication-free remitted patients.

Methods: Sixty-four medication-free unipolar depressed patients (39 currently depressed and 25 in remission) and 66 healthy controls (HC) underwent structural magnetic resonance imaging in a cross-sectional and longitudinal design. Thirty-two currently depressed participants were then treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring plasma citalopram concentration. We measured regional variation in grey matter concentration by using voxel-based morphometry-Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra.

Results: Patients with current depression had bilaterally reduced grey matter in the hippocampus compared with HC and untreated patients in stable remission, with the latter groups not differing. An increase in grey matter was observed in the hippocampus following treatment with citalopram in currently depressed patients.

Conclusion: Grey matter reduction in the hippocampus appears specific to the depressed state and is a potential biomarker for a depressive episode.

Clinical Commentary
This article should make the list of “Top Ten” most interesting articles of 2012. Arnone and colleagues elegantly demonstrate the impact depression has on hippocampal volume. What makes this study so impressive is the prospective follow-up of three groups: medication-free, currently depressed individuals; non-depressed controls; and medication-free remitted patients. In addition, the depressed individuals were treated with citalopram (compliance to which was confirmed by measuring it in the serum) and their hippocampal volumetric changes were re-examined in just eight weeks. The findings are as follows: at baseline, currently depressed individuals had significantly decreased hippocampal volumes compared to both of the other groups. Treatment with citalopram, even for eight weeks, was associated with volumetric increases in hippocampal volume. This demonstrates that hippocampal volume changes are state dependent and that this change is responsive, even in a short amount of time, to treatment. This study therefore lends further support to the “neurotoxic” impact depressive symptoms have on the brain, and the positive impact of treatment. This study perhaps foretells the future potential use of volumetric brain studies by everyday treating clinicians as a means to assess treatment response. While its too early to tell if this will be the case, this study adds valuable information to our emerging understanding of the neurobiology of depression and its treatment.


Might Different Cytokine Trends in Depressed Patients Receiving Duloxetine Indicate Differential Biological Backgrounds

Fornaro M, Rocchi G, Escelsior A, et al
J Affect Disord. 2012; Sep 13.

Background: Correlational studies investigating neurohormonal-cytokine modulation by antidepressants suggest, among others, variations in cytokines balances as state markers of different biological subtypes of major depressive disorder (MDD) and response predictors to specific treatments. Objective of the study was to investigate cytokines modulation by duloxetine, a relatively newer SNRI with "clean" dual serotonin/norepinephrine mechanism.

Methods: 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for levels of IL-1β, IL-2, IL-4, IL-10, IL-12, IFN-γ and TNF-α, at baseline, week 6 and week 12 of duloxetine treatment (60mg/day) and at baseline, respectively.

Results: Early responders (ER: defined at week 6 by reduction >50% of baseline HAM-D score) and early non-responders (ENR) showed opposite trends in cytokine levels during duloxetine treatment: ENR were characterized by baseline Th2 shift compared to controls (lower IL-1β, IFN-γ and TNF-α) with increase in Th1 cytokines levels during treatment (increase of IL-1β, IL-12, IFN-γ, IL-1β/IL-10 and TNF-α/IL-10, decrease of IL-10), achieving clinical response at week 12; ER were characterized by baseline Th2-to-Th1 relative switch compared to ENR (higher IL-1β, IL-1β/IL-10 and TNF-α/IL-10) with reduction in Th1 cytokines levels during treatment (decrease of TNF-α and TNF-α/IL-10), achieving clinical response at week 6. Limitations: Small sample size.

Conclusions: In accordance to early clinical response, duloxetine treatment could divide depressed patients into at least 2 subgroups characterized by clinical and laboratory differentiated behavior, suggesting different neurobiological background within depressive syndrome differentially sensitive to different drug components: pro-serotonergic effect and increase in Th1 cytokines in ENR vs. pro-noradrenergic effect and decrease in Th1 cytokines in ER.

Clinical Commentary
The year 2012 marked the beginning of dramatically increased interest in the area of psychoneuroimmunology. It is now fairly well established that the immune system plays a significant role in the pathogenesis of major depression. However, much less is known about how treatment impacts the immune system, and whether or not cytokine changes (the foot soldiers in the immune system) are different in early responders to antidepressants versus late or nonresponders. This important study adds to our understanding of this issue by examining cytokine changes that occur during treatment with the SNRI duloxetine in two groups of patients: those who achieve early response (50% reduction of symptoms in 6 weeks) and those who did not. The study results reveal that no single cytokine clearly helped differentiate these two groups. However, when ratios of Th1 cytokines (cell-based immunity markers such as TNF-alpha, IL-12, etc) and Th2 cytokines (humoral-based immunity markers such as IL-4, IL-6, IL-10) were examined, these two groups showed opposite trends. This is an important finding as it sheds light on why some depressed individuals do not respond early to antidepressants. This study raises the possibility that we may soon be able to use a patient’s immune response patterns to individualize treatment and improve outcomes.


What Predicts Outcome, Response, and Drop-out in CBT of Depressive Adults? A Naturalistic Study

Schindler A, Hiller W, Witthoft M.
Behav Cogn Psychother. 2012; Dec 5:1-6.

Background: The efficacy of CBT for unipolar depressive disorders is well established, yet not all patients improve or tolerate treatment. The aim was to identify factors associated with symptomatic outcome, response, and drop-out in depressive patients under naturalistic CBT.

Method: 193 patients with major depression or dysthymia were tested. Sociodemographic and clinical variables were entered as predictors in hierarchical regression analyses. Results: A higher degree of pretreatment depression, early improvement, and completion of therapy were identified as predictors for symptomatic change and response. Drop-out was predicted by concurrent personality disorder, less positive outcome expectancies, and by failure to improve early in treatment.

Conclusions: Our results highlight the importance of early response to predict improvement in routine CBT. Attempts to refine the quality of treatment programs should focus on avoiding premature termination (drop-out) and consider motivational factors in more depth. Routinely administered standardized assessments would enhance symptom monitoring and help to identify persons at risk of not improving under therapy.

Clinical Commentary
The scientific approach of rigorous observation and analysis of data is beneficial to both biologically based studies and nonpharmacological treatment studies. This German CBT intervention study is a shining example of how data, when well analyzed, offer pearls of wisdom for clinicians. The study naturalistically followed 193 patients to identify who responds to CBT, who does not, and who is at risk for premature dropouts—all of which are incredibly important questions that deserve close scrutiny. Interestingly, three factors predicted a good response: higher degree of depression at treatment initiation; early response; and completion of prescribed CBT therapy sessions. As expected, dropouts were predicted by presence of a concurrent personality disorder, lower positive outcome expectations, and a failure to improve early. These findings, when examined in their totality, may help clinicians assign CBT to appropriate patient profiles. Those at risk for early dropouts may benefit from proactive measures such as open and frank early discussions regarding expectations, more frequent visits, and use of rating instruments to track symptom progress.

Treatment Resistant Adolescent Depression with Upper Airway Resistance Syndrome Treated with Rapid Palatal Expansion: A Case Report

Miller P, Iver M, Gold AR
J Med Case Rep. 2012 Dec 4;6(1):415.

Background: To the best of our knowledge this is the first report of a case of treatment-resistant depression in which the patient was evaluated for sleep disordered breathing as the cause and in which rapid palatal expansion to permanently treat the sleep disordered breathing produced a prolonged symptom-free period off medication.

Case Presentation: An 18-year-old Caucasian man presented to our sleep disorders center with chronic severe depression that was no longer responsive to medication but that had recently responded to electroconvulsive therapy. Ancillary, persistent symptoms included mild insomnia, moderate to severe fatigue, mild sleepiness, and severe anxiety treated with medication. Our patient had no history of snoring or witnessed apnea, but polysomnography was consistent with upper airway resistance syndrome. Although our patient did not have an orthodontic indication for rapid palatal expansion, rapid palatal expansion was performed as a treatment of his upper airway resistance syndrome. Following rapid palatal expansion, our patient experienced a marked improvement of his sleep quality, anxiety, fatigue and sleepiness. His improvement has been maintained off all psychotropic medication and his depression has remained in remission for approximately two years following his electroconvulsive therapy.

Conclusions: This case report introduces the possibility that unrecognized sleep disordered breathing may play a role in adolescent treatment-resistant depression. The symptoms of upper airway resistance syndrome are non-specific enough that every adolescent with depression, even those responding to medication, may have underlying sleep disordered breathing. In such patients, rapid palatal expansion, by widening the upper airway and improving airflow during sleep, may produce a prolonged improvement of symptoms and a tapering of medication. Psychiatrists treating adolescents may benefit from having another treatment option for treatment-resistant depression.

Clinical Commentary
Can depression be caused by breathing problems? Case reports inherently possess strengths and weaknesses. Despite the fact that a sample size of 1 is inadequate to fully examine any issue, our own experience in treating individual patients often forms the basis our treatment habits. This particularly dramatic case report deserves our attention. Here, a young man’s case of treatment-refractory depression is presented. After correction of obstructive airway disease, the patient remarkably went into sustained remission of depression, anxiety, fatigue, and sleepiness, even though he was off all psychotropic medications. This case report adds to the burgeoning literature on the importance of airway obstruction and how this can create symptoms that resemble major depression. The lessons learned from this case report and other literature on this topic are clear: when we encounter patients with symptoms of depression, we should take a full medical history, including a history of snoring or other symptoms that could indicate airway disease obstruction. If potential concerns are found, a referral to a sleep specialist is highly warranted.


The Nature of the Association Between Childhood ADHD and the Development of Bipolar Disorder: a Review of Prospective High-Risk Studies

Duffy A.
Am J Psychiatry. 2012 Dec 1;169(12):1247-55.

Objective: The author reviewed prospective longitudinal studies of the offspring of parents with bipolar disorder to inform our understanding of the nature of the association between childhood ADHD and the risk of developing bipolar disorder in adolescence and young adulthood.

Methods: A literature review of published prospective cohort studies of the offspring of bipolar parents since 1985 was undertaken using a comprehensive search strategy in several electronic databases. The author provides a qualitative synthesis of results focusing on ADHD and the association with bipolar disorder in prospectively assessed high-risk offspring. These results are discussed in light of findings from other prospective epidemiological and clinical cohort studies.

Results: From the reviewed high-risk studies, evidence suggests that the clinical diagnosis of childhood ADHD is not a reliable predictor of the development of bipolar disorder. However, the author found evidence that symptoms of inattention may be part of a mixed clinical presentation during the early stages of evolving bipolar disorder in high-risk offspring, appearing alongside anxiety and depressive symptoms. The author also found preliminary evidence that childhood ADHD may form part of a neurodevelopmental phenotype in offspring at risk for developing a subtype of bipolar disorder unresponsive to lithium stabilization.

Conclusions: While childhood ADHD does not appear to be part of the typical developmental illness trajectory of bipolar disorder, subjective problems with attention can form part of the early course, while neurodevelopmental abnormalities may be antecedents in a subgroup of high-risk children.

Clinical Commentary
It is doubtful one will find a more controversial topic in mental health than that of pediatric bipolar disorder and ADHD. Questions abound here: Which comes first? Are they reliably differentiable? Is inattentiveness solely a symptom of ADHD, or is it shared with pediatric bipolar disorder? Do parents with bipolar disorder only produce children with this disorder, or is risk for ADHD also elevated? This comprehensive literature review by Dr. Duffy bravely attempts to answer many of these questions by conducting a literature search of prospective cohort studies of the offspring of bipolar parents. The results are both surprising and clinically useful. Some of the findings include: the presence of pediatric ADHD does not reliably predict, even in children of bipolar parents, that these children will go on to develop bipolar disorder; early-onset ADHD followed by bipolar disorder may predict lack of responsiveness to lithium; and inattention in a high-risk child (ie, one with a parent with bipolar disorder) may predict development of mixed bipolar states. All of these findings are worrisome. Children of bipolar individuals should be closely monitored for both emergence of ADHD and bipolar symptoms. One should not assume bipolar disorder when only ADHD symptoms are present. If bipolar disorder does emerge in such children with ADHD, lithium has a lower likelihood of being beneficial. Finally, it appears that mixed states are common in these children. Judicious interventions can be based on these emerging findings.


A Randomized Controlled Trial of the Tumor Necrosis Factor Antagonist Infliximab for Treatment-Resistant Depression: The Role of Baseline Inflammatory Biomarkers

Raison CL, Rutherford RE, Woolwine BJ, et al
Arch Gen Psychiatry. 2012 Sep 3:1-11.

Background: Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants.

Objectives: To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response.

Methods: A double-blind, placebo-controlled, randomized clinical trial was conducted at the Outpatient infusion center at Emory University in Atlanta, Georgia. Participants included a total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n=37) or medication-free (n=23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Three infusions of the TNF antagonist infliximab (5 mg/kg) (n=30) or placebo (n=30) at baseline and weeks 2 and 6 of a 12-week trial. The 17-item Hamilton Scale for Depression (HAM-D) scores. Were the primary efficacy measure.

Results: No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P=.01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P=.19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P<.05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P<01). Dropouts and adverse events were limited and did not differ between groups.

Conclusions: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.

Clinical Commentary
Some proof-of-concept studies are so remarkable that you do a double take at first glance. This is one of those rare studies. We have known for a few years that elevated levels of inflammatory cytokines predict poor response to antidepressants. This study treated resistant depression patients with a TNF-alpha antagonist (infliximab), knowing fully well that this anti-inflammatory agent does not cross the blood brain barrier. Hence, it would only attack peripheral inflammation without any direct effects on the brain. Results showed that the use of the peripheral TNF-alpha produced a significant antidepressant effect, but only in those who had elevated peripheral inflammatory markers. Remarkably, even “attacking” the periphery with medications that do not cross the blood-brain barrier can have positive effects. This groundbreaking study furthers our understanding of personalized treatment of treatment-resistant patients and the mind-body treatment approach to major depression.

GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 9, December 2012—Guest Commentator: Antonio Y. Hardan, MD, Stanford University School of Medicine



Treatment with Paliperidone in Children with Behavior Disorders Previously Treated with Risperidone: An Open-label Trial

Fernández-Mayoralas DM, Fernández-Jaén A, Muñoz-Jareño N, et al
Clin Neuropharmacol. 2012;35(5):227-230.

Objectives: Paliperidone is the main active metabolite of risperidone, with certain pharmacokinetic and tolerability characteristics that suggest it may be used in special groups, such as children. Our purpose is to document the clinical experience with the use of paliperidone in children with severe behavior problems that were partially refractory to treatment with risperidone and psychological treatment.

Methods: This is a prospective 16-week open-label study of paliperidone in 18 patients (mean age, 13.4 years) with severe and excessive irritability in the context of generalized developmental disorders or attention-deficit/hyperactivity disorder. Patients who had exhibited an inadequate response to treatment with risperidone (1.5–2 mg/day) over a treatment period of 6 months were treated with paliperidone at 3 mg/day. Symptom severity at the beginning of the study and in response to paliperidone were rated with the Clinical Global Impression (CGI) scale and Overt Aggression Scale.

Results: A significant difference was documented between the mean score before treatment and the score after the drug intervention with paliperidone. There was a noticeable clinical improvement in 50% of the cases, as reflected in the CGI. Severity of aggressive behavior, as assessed by the Overt Aggression Scale, decreased significantly after paliperidone treatment: mean (SD), 2.7 (0.92) before treatment versus 1.5 (0.60) after treatment. This compound was safe and well tolerated.

Conclusion: Half of the patients clearly responded to paliperidone extended release. Tolerance to this treatment was distinctly better than to risperidone. These preliminary results lay the foundation for further research into the use of paliperidone to treat pediatric disruptive behavior disorders within the context of randomized, double-blind, controlled clinical trials.

Clinical Commentary
Disruptive behaviors commonly occur in a variety of childhood-onset neuropsychiatric disorders and can be very disabling. Currently, medications including risperidone and aripiprazole are used to target these disruptive behaviors commonly found in children and adolescents with behavioral disorders. However, they do have side effects including lethargy and weight gain. Paliperidone is the primary active metabolite of risperidone, and paliperidone ER had been shown to be effective in improving clinical symptoms of schizophrenia. The current open-label trial assessed the effectiveness and tolerability of paliperidone ER for disruptive behaviors in individuals with generalized developmental disorders or ADHD who did not respond to risperidone and psychoeducation. The small pilot study provides some evidence that paliperidone ER might be effective in improving aggression and disruptive behaviors with fewer side effects compared to risperidone 1.5 to 2 mg. However, findings from this study should be examined with caution in light of several methodological limitations including the open-label design and the heterogeneity of the sample included. Large, randomized, controlled trials are needed in well-characterized and homogenous clinical populations to determine the effectiveness of paliperidone ER.


Randomized Controlled Double-Blind Trial of Optimal Dose Methylphenidate in Children and Adolescents with Severe Attention-Deficit/Hyperactivity Disorder and Intellectual Disability

Simonoff E, Taylor E, Baird G, et al
J Child Psychol Psychiatry. 2012 Jun 7. doi: 10.1111/j.1469-7610.2012.02569.x. [Epub ahead of print]

Background: Attention-deficit/hyperactivity disorder (ADHD) is increased in children with intellectual disability. Previous research has suggested that stimulants are less effective than in typically developing children, but no studies have titrated medication for individual optimal dosing or tested the effects for longer than 4 weeks.

Methods: One hundred and twenty-two drug-free children 7–15 years of age with hyperkinetic disorder and IQ scores of 30–69 were recruited to a double-blind, placebo-controlled trial that randomized participants using minimization by probability. Patients were stratified by referral source and IQ level in a one-to-one ratio. Methylphenidate was compared with placebo. Dose titration comprised at least 1 week each of low (0.5 mg/kg/day), medium (1.0 mg/kg/day), and high dosages (1.5 mg/kg/day). Parent and teacher ADHD index of the Conners Rating Scale-Short Version at 16 weeks provided the primary outcome measures. Clinical response was determined with the Clinical Global Impressions-Improvement scale (CGI-I). Adverse effects were evaluated by a parent-rated questionnaire, weight, pulse, and blood pressure. Analyses were by intention to treat.

Results: Methylphenidate was superior to placebo with effect sizes of 0.39 [95% confidence intervals (CIs) 0.09, 0.70] and 0.52 (95% CIs 0.23, 0.82) for the parent and teacher Conners ADHD index. Four (7%) children on placebo versus 24 (40%) of those on methylphenidate were judged improved or much improved on the CGI. IQ and autistic symptoms did not affect treatment efficacy. Active medication was associated with sleep difficulty, loss of appetite, and weight loss, but there were no significant differences in pulse or blood pressure.

Conclusions: Optimal dosing of methylphenidate is practical and effective in some children with hyperkinetic disorder and intellectual disability.

Clinical Commentary
Inattention, hyperactivity, and impulsivity are commonly observed in individuals with intellectual disability (ID), but can often go unrecognized in this population. Previous studies of methylphenidate in children and adolescents with severe ADHD primarily excluded individuals with ID. The present double-blind, placebo-controlled trial randomized immediate-release methylphenidate and titrated it over at least 3 weeks in children with ID between the ages of 7 to 15 years. The results suggest that this medication is helpful in improving clinical symptoms. Although overall safety was noted to be good, adverse effects were observed. Findings suggest that individuals with ID should be monitored closely while using slow titration schedules. Finally, clinicians should pay particular attention to identifying and treating individuals with ID and comorbid ADHD, as this combination often goes unrecognized.

The Effects of Aripiprazole on Electrocardiography in Children with Pervasive Developmental Disorders

Ho JG, Caldwell RL, McDougle CJ, et al
J Child Adolesc Psychopharmacol. 2012; 22(4):277-83. doi: 10.1089/cap.2011.0129.

Objectives: Psychotropic medications, including atypical antipsychotics, have historically been scrutinized for cardiac effects and risk of sudden death. Aripiprazole is an atypical antipsychotic approved for pediatric use in schizophrenia, bipolar I disorder, and autistic disorder. Adult studies have evaluated the effects of aripiprazole on electrocardiograms, but no pediatric studies have been published to date.

Methods: Electrocardiographic data were collected from children and adolescents participating in a 14-week, prospective, open-label study (n=25) of aripiprazole for irritability in pervasive developmental disorder not otherwise specified and Asperger's disorder. A 12-lead electrocardiogram was obtained at the baseline and endpoint visits. The electrocardiograms were evaluated for abnormal findings, and the PR, QRS, QT(c), and RR intervals were recorded. The QT interval was corrected using Bazett's, United States FDA Pharmacology Division, and Frederica's formula.

Results: Twenty-four subjects received both baseline and posttreatment electrocardiograms. The mean age was 8.6 years (range 5–17 years). The average final aripiprazole dose was 7.8 mg/day (range 2.5–15 mg/day). There were no significant differences noted with the PR, QRS, RR, and QT(c) intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QT(c). No posttreatment QT(c) exceeded 440 ms.

Conclusions: To our knowledge, this is the first systematic evaluation of the cardiac effects of aripiprazole in children and adolescents. The results are consistent with previously published literature in adults indicating that aripiprazole has no significant cardiac effects and can be deemed a low risk for causing sudden death. It will be important to confirm these findings in a randomized controlled trial.

Clinical Commentary
Antipsychotic medications, such as thioridazine and clozapine, have historically been linked to possible cardiac effects. Aripiprazole, a second-generation antipsychotic, has been approved for use in adults with schizophrenia, bipolar I, and major depressive disorder, as well as for use in pediatric populations for schizophrenia, bipolar I, and irritability associated with autistic disorder. Changes in electrocardiograms, including prolongation of the QTc interval have been associated with abnormal arrhythmias and sudden death. Previous studies have found no prolongation of the QTc interval in adults after taking aripiprazole. The present open-label study is consistent with the adult literature, suggesting that there is little cardiac risk for pediatric patients with pervasive developmental disorder taking aripiprazole. These results should be taken with caution in light of the methodological limitations of the study, mainly its uncontrolled design. Large randomized and long-term trials are warranted to have final conclusions regarding the cardiovascular safety of aripiprazole in pediatric populations, including individuals with autism spectrum disorders.

Axis I and II Comorbidity and Psychosocial Functioning in Female Adolescents with Borderline Personality Disorder

Kaess M, von Ceumern-Lindenstjerna IA, Parzer P, et al
Psychopathology. 2012 Aug 7. [Epub ahead of print]

Background: Borderline personality disorder (BPD) is known to be associated with high rates of comorbidity and severe impairment of psychosocial functioning in adults. The aim of this study was to investigate Axis I and Axis II disorders, as well as psychosocial functioning, in a clinical sample of adolescents with BPD and to compare these with participants with mixed psychiatric diagnoses.

Methods: Female adolescent patients were consecutively recruited from the child and adolescent psychiatry department of a university hospital. Axis I and Axis II diagnoses were assessed by experienced clinicians using well-established semi-structured interviews, along with psychosocial functioning.

Results: The final sample (87 participants) comprised 31 participants with a diagnosis of BPD and 56 participants with mixed psychiatric diagnoses. The most common comorbid disorders in the adolescent BPD sample were mood, eating, dissociative, and substance use disorders in Axis I, and cluster C personality disorders in Axis II. The BPD group showed a significantly higher average number of comorbid Axis I and Axis II diagnoses and significantly lower psychosocial functioning compared with the clinical control group. Regression analyses revealed that psychosocial functioning was predicted by socioeconomic status and comorbid disorders, as well as the unique influence of BPD itself.

Conclusion: Adolescent BPD in females is accompanied by high rates of psychiatric comorbidity and poor psychosocial functioning. This underscores the need for diagnosis of BPD at its early stages, in order to facilitate appropriate interventions.

Clinical Commentary
Borderline personality disorder (BPD) is characterized by pervasive instability in emotion regulation, impulse control, interpersonal relationships, and self-image. Adults with BPD often have high rates of comorbid mood, anxiety, and substance use disorders. However, limited information is available on the comorbidity of youths affected with BPD. The present study examined comorbid conditions and psychosocial functioning in adolescent females with diagnosed BPD compared to a mixed diagnosis clinical sample. Similar to adult populations, the BPD group showed high rates of mood, eating, dissociative, and substance use disorders as well as cluster C personality disorders including avoidant, dependent, and obsessive-compulsive disorder. Due to the high rates of comorbidities and poor psychosocial functioning in adolescents with BPD, clinicians need to pay particular attention to and assess systematically for Axis I disorders in this population. Intervening early in the course of the disorder in youths with BPD is crucial to help improve long-term outcome as supported by previous investigations. Psychotherapeutic interventions as well as medications including antidepressants, mood stabilizers, and antipsychotics have been shown to treat some of the symptoms of BPD.


Developmental Pathways for Different Subtypes of Early-Onset Bipolarity in Youths

Masi G, Mucci M, Pfanner C, et al
J Clin Psychiatry. 2012 Sep 4. [Epub ahead of print]

Objective: Two main patterns of comorbidity have been described in bipolar disorder in children and adolescents: the first including preexisting attention-deficit/hyperactivity disorder (ADHD) and related disruptive behavior disorders and the second including anxiety disorders, namely, the association of co-occurring multiple anxiety disorders, usually predating the onset of bipolarity. This study was aimed at exploring whether ADHD and multiple anxiety disorders may exhibit different pathways to specific bipolar phenotypes.

Method: We compared 49 youths (7 to 18 years) with bipolar disorder + ADHD without anxiety, 76 youths with bipolar disorder + multiple anxiety disorders without ADHD, and 52 youths with bipolar disorder without ADHD or multiple anxiety disorders who were referred to a third-level hospital and diagnosed according to DSM-IV-TR in the period 2005-2011. Subjects were evaluated for current and lifetime Axis I psychiatric disorders by using a structured clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version) and followed up for at least 6 months.

Results: Compared to both patients with bipolar disorder + multiple anxiety disorders and patients with bipolar disorder without ADHD and multiple anxiety disorders, patients with bipolar disorder + ADHD without anxiety were more frequently male, were younger, had an earlier onset of bipolar disorder, had a prevalent chronic course and irritable mood, were more likely to present with a bipolar disorder not otherwise specified diagnosis, had a greater clinical severity and functional impairment, had a manic/mixed index episode, had a higher risk of conduct disorder, and were more resistant to treatments, according to the CGI-Improvement scores (P< .0001). Patients with bipolar disorder + multiple anxiety disorders were similar to those with bipolar disorder without ADHD or multiple anxiety disorders, except for a higher rate of diagnosis of bipolar II disorder, more use of antidepressants, and less use of atypical antipsychotics.

Conclusions: The presence of comorbid ADHD versus anxiety disorders is indicative of fundamental differences in the phenomenology of bipolar disorder in youth. While ADHD prior to bipolar disorder is associated with a specific bipolar phenotype, bipolar patients with multiple anxiety disorders are similar to "typical" bipolar patients.

Clinical Commentary
There is still debate about the clinical phenotypes of bipolar disorder in children and adolescents. This is due to differences in presentation of the early-onset form compared to adult onset as well as frequent comorbidities which can often blur diagnostic categories. The present study examined youths with bipolar disorder and either comorbid ADHD or multiple comorbid anxiety disorders including at least two of the following: separation anxiety disorder, panic disorder, generalized anxiety disorder, and specific phobias. Consistent with previous studies, this research suggests that bipolar disorder plus ADHD might represent a distinct early-onset phenotype with different course and worse prognosis. Clinicians should be particularly aware of the differential diagnosis and treatment for children and adolescents with these conditions.


An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Risperidone in Adolescents with Schizophrenia

Pandina G, Kushner S, Karcher K, Haas M.
Child Adolesc Psychiatry Ment Health. 2012;6(1):23. [Epub ahead of print]

Background: Data on the long-term efficacy, safety, and tolerability of risperidone in adolescents with schizophrenia are limited. The objective of this study was to evaluate the efficacy and safety of maintenance risperidone treatment in adolescents with schizophrenia.

Methods: This open-label study of adolescents aged 13 to 17 years with schizophrenia was a single extension study of two short-term double-blind risperidone studies and also enrolled subjects directly in open-label risperidone treatment. The risperidone dose was flexible and ranged from 2 to 6 mg/day. Most subjects enrolled for 6 months; a subset enrolled for 12 months. Assessment tools included the Positive and Negative Syndrome Scale total and factor scores, Clinical Global Impressions, Children's Global Assessment Scale, adverse event (AE) monitoring, vital signs, laboratory testing, and extrapyramidal symptom rating scales.

Results: A total of 390 subjects were enrolled; 48 subjects had received placebo in a previous double-blind study; 292 subjects had received risperidone as part of their participation in one of two previous controlled studies; and 50 subjects were enrolled directly for this study. A total of 279 subjects enrolled for 6 months of treatment, and 111 subjects enrolled for 12 months of treatment. Overall, 264 (67.7%) subjects completed this study: 209 of the 279 subjects (75%) in the 6-month group and 55 of the 111 subjects (50%) in the 12-month group. The median mode dose was 3.8 mg/day. At 6 months, all three groups experienced improvement from open-label baseline in symptoms of schizophrenia as well as general assessments of global functioning. Improvements were generally maintained for the duration of treatment. The most common AEs (greater than or equal to 10% of subjects) were somnolence, headache, weight increase, hypertonia, insomnia, tremor, and psychosis. Potentially prolactin-related AEs (PPAEs) were reported by 36 (9%) subjects. The AE profile in this study was qualitatively similar to those of other studies in adult subjects with schizophrenia and in other psychiatric studies of risperidone in pediatric populations.

Conclusions: Risperidone maintenance treatment in adolescents over 6 to 12 months was well tolerated, consistent with related studies in this clinical population, and associated with continued efficacy.

Clinical Commentary
Limited information is available on the long-term efficacy and safety of risperidone in youths, and previous trials of risperidone use for various disorders have focused primarily on adults. This is the first study to examine the effectiveness and side-effect profile of risperidone in adolescents with schizophrenia over 6–12 months. The open-label study provides evidence of efficacy in this population, with side effects similar to those experienced in other pediatric populations such as children with disruptive behavior. However, findings should be interpreted with caution in light of its open-label design. Note that this study also only examined the treatment course up to 1 year. Thus, when using risperidone to treat children and adolescents with schizophrenia, clinicians should take extra caution to assess potential risks and side effects, especially over longer periods of time.


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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 8, November 2012—Guest Commentator: Chi-Un Pae, MD, PhD, The Catholic University of Korea College of Medicine; Duke University Medical Center


Early Switch Strategy in Patients with Major Depressive Disorder: A Double-Blind, Randomized Study

Romera I, Pérez V, Menchón JM, et al.
J Clin Psychopharmacol. 2012;32(4):479-486.

Objective: Antidepressant switch is a commonly used strategy in the absence of an adequate response, but optimum timing is not well established. We compared the efficacy of an early and a conventional antidepressant switch strategy in patients with major depressive disorder.

Methods: Patients with no or minimal improvement (30 mm overall pain visual analog scale [VAS]). Patients not achieving 30% reduction in Hamilton Depression Rating Scale (HAM-D) after 4 weeks of escitalopram (10 mg/day) were randomized to duloxetine 60–120 mg/day (early switch) or continued on escitalopram (conventional switch), with non-responders at week 8 switching to duloxetine. Endpoints were time to confirmed response and remission, VAS pain severity, and Sheehan disability scale (SDS). Switch strategies were compared using Kaplan-Meier, logistic regression, and repeated measures analyses.

Results: No differences between early and conventional switching were found in time to confirmed response after randomization (3.9 vs. 4.1 weeks, P=0.511) or remission (6.0 vs. 8.0 weeks, P=0.238). Significantly lower VAS mean pain levels for overall pain, headache, back pain, shoulder pain, interference with daily activities, and time being awake in pain were found for patients in the early switching group. Time to achieving normal functioning (SDS total score <6) was shorter in the early switching group (P=0.042). Safety results were comparable between switch strategies.

Conclusions: In MDD patients with moderate to severe painful physical symptoms not improving after 4 weeks of treatment with escitalopram, an earlier switch to duloxetine may lead to better pain and functional outcomes.

Clinical Commentary
Although depressed mood and lack of interest are the key symptoms of MDD, it also has a number of somatic and psychological symptoms that negatively affect the clinical course. In fact, patients with residual symptoms showed greater chance of relapse and experienced a recurrence more than 3 times faster than those with full recovery. Painful physical symptoms are also highly associated with residual symptoms. Currently, existing data also suggest a negative impact of painful physical symptoms on various treatment outcome measures including antidepressant efficacy, medical cost, daily productivity, quality of life, and treatment compliance. Hence, timely and early control of painful physical symptoms should be considered an important target for MDD treatment. The study preliminarily proposes that early switch to a different antidepressant leads to better clinical outcomes in MDD patients with moderate to severe pain, when the initial antidepressant shows inadequate response within 4 weeks.


Antidepressant Combination for Major Depression in Incomplete Responders: A Systematic Review

Lopes Rocha F, Fuzikawa C, Riera R, et al
J Affect Disord. 2012. Jul 24. [Epub ahead of print]

Background: Antidepressant combination has been suggested as a strategy to increase treatment efficacy. The objective of this study was to perform a systematic review and meta-analysis of studies that assessed the effect of antidepressant combination for major depression in patients with incomplete response to an initial antidepressant.

Methods: Studies were retrieved from PubMed (1966-February 2012), Cochrane Library (February 2012), Embase (1980-February 2012), PsycINFO (1980-February 2012), Lilacs (1982-February 2012), clinical trials registry, thesis database (, and secondary references. Included studies had an open-label phase in which an initial antidepressant was used for the treatment of major depression and a double-blind phase for the incomplete responders that compared monotherapy with the first antidepressant versus the association of a second antidepressant to the first one.

Results: Out of the 4,884 studies retrieved, only five satisfied the inclusion criteria. The total number of patients included was 483. Only two small trials reported benefits of adding a second antidepressant to the initial antidepressant. Dropouts due to side effects were not reported in three studies. Meta-analysis was not performed due to the small number of studies, the inconsistency in the direction of effect, and the possible instability of effect size. Only limited kinds of combination, involving mianserin, mirtazapine, and desipramine were studied. Some properties of the first two drugs such as the anxiolytic, sedative, and orexigenic effects, can mimic depression improvement. Limitations: Publication bias cannot be ruled out. Only one study included a monotherapy arm with the antidepressant used for augmentation of the first antidepressant.

Conclusions: The practice of using a combination of antidepressants for major depression in incomplete responders is not warranted by the literature.

Clinical Commentary
According to a number of clinical trials and meta-analyses, approximately 30% of major depressive disorder (MDD) patients do not achieve remission after multiple treatment trials. For MDD patients with initial treatment failure, augmentation, combination, and switching strategies are available in clinical practice. Combination of different antidepressants may be beneficial for such patients, since this strategy may offer synergistic effects while counteracting existing tolerability issues from primary antidepressant. However, there are sparse data to support combination strategy due to small sample sizes and methodological pitfalls. The present meta-analysis by Lopes Rocha and colleagues confirms a lack of clear data supporting combination strategy as routine practice for MDD patients with initial treatment failure, and calls well-controlled, adequately-powered, short- and long-term studies to evaluate the efficacy and tolerability of antidepressant combinations.


Omega-3 Fatty Acids for the Treatment of Depression: Systematic Review and Meta-Analysis

Bloch MH, Hannestad J.
Mol Psychiatry. 2011; Sep 20. doi: 10.1038/mp.2011.100. [Epub ahead of print]

Objective: We conducted a meta-analysis of randomized, placebo-controlled trials of omega-3 fatty acid (FA) treatment of major depressive disorder (MDD) in order to determine efficacy and to examine sources of heterogeneity between trials.

Methods: PubMed (1965-May 2010) was searched for randomized, placebo-controlled trials of omega-3 FAs for MDD. Our primary outcome measure was standardized mean difference in a clinical measure of depression severity. In stratified meta-analysis, we examined the effects of trial duration, trial methodological quality, baseline depression severity, diagnostic indication, dose of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in omega-3 preparations, and whether omega-3 FA was given as monotherapy or augmentation.

Results: In 13 randomized, placebo-controlled trials examining the efficacy of omega-3 FAs involving 731 participants, meta-analysis demonstrated no significant benefit of omega-3 FA treatment compared with placebo (standard mean difference [SMD]=0.11, 95% confidence interval [CI]: -0.04, 0.26). Meta-analysis demonstrated significant heterogeneity and publication bias. Nearly all evidence of omega-3 benefit was removed after adjusting for publication bias using the trim-and-fill method (SMD=0.01, 95% CI: -0.13, 0.15). Secondary analyses suggested a trend toward increased efficacy of omega-3 FAs in trials of lower methodological quality, trials of shorter duration, trials which utilized completers rather than intention-to-treat analysis, and trials in which study participants had greater baseline depression severity.

Conclusion: Current published trials suggest a small, non-significant benefit of omega-3 FAs for major depression. Nearly all of the treatment efficacy observed in the published literature may be attributable to publication bias.

Clinical Commentary
The utility of omega-3 fatty acids for treating MDD is of considerable interest as one of promising complimentary medicines, particularly for MDD patients who have partial response or tolerability issues with modern antidepressants. Despite the fact that preexisting meta-analyses have reported positive outcomes for omega-3 fatty acid treatment for MDD, the meta-analysis by Bloch and Hannestad found no significant benefit of omega-3 fatty acids for MDD. However, caution must be undertaken when interpreting these findings. Omega-3 fatty acids have been found to demonstrate greater effects in patients with MDD diagnosed formally with proper diagnostic criteria than in those without formal diagnosis. Hence, a conclusive remark on the exact role of omega-3 fatty acids in the use of MDD treatment as adjunct or monotherapy should be delayed until clear and sufficient evidence from many adequately-powered and well-designed clinical trials are available.


A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy Among Depressed Outpatients with Inadequate Response to Prior Antidepressant Therapy (ADAPT-A Study)

Fava M, Mischoulon D, Iosifescu D, et al
Psychother Psychosom. 2012;81(2):87-97.

Background: We assessed the efficacy of low-dose aripiprazole added to antidepressant therapy (ADT) in major depressive disorder (MDD) patients with inadequate response to prior ADT.

Methods: As per the sequential parallel comparison design, 225 MDD subjects were randomized to adjunctive treatment with aripiprazole 2 mg/day or placebo across two 30-day phases, with a 2:3:3 randomization ratio to drug/drug (aripiprazole 2 mg/day in phase 1; 5 mg/day in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1; aripiprazole 2 mg/day in phase 2). Eligible subjects were patients whose MDD was independently deemed 'valid' with SAFER criteria. Subjects had been receiving ADT for ≥8 weeks, and had inadequate response to ≥1 and <4 adequate ADTs in the current episode, as defined by the Antidepressant Treatment Response Questionnaire.

Results: The pooled, weighted response difference between aripiprazole 2 mg/day and placebo in the two phases was 5.6% (P=0.18; NS). The aripiprazole 2 mg/day-placebo difference on the Montgomery-Asberg Depression Rating Scale pooled across the two phases was -1.51 (P=0.065; NS). Other secondary endpoint analyses showed nonsignificant pooled differences favoring aripiprazole over placebo. Of the 225 randomized subjects in phase 1, 2 dropped out in both arms; of the 138 phase 1 placebo nonresponders in phase 2, 9 dropped out on aripiprazole and 5 on placebo. There were only minimal differences in adverse event rates between treatments, except for constipation, weight gain, and dry mouth, more common on aripiprazole.

Conclusion: This study provides clear support for the tolerability of low-dose aripiprazole as an ADT-augmenting agent, with marginal efficacy.

Clinical Commentary
Aripiprazole, quetiapine XR, and olanzapine/fluoxetine (combination agent) have been approved and widely used for treating patients with MDD worldwide. Among such agents, aripiprazole has been approved first  and its use has dramatically increased in MDD treatment; however, selection of proper starting and target doses for the individual patient is challenging in clinical practice due to risk of developing akathisia and inadequate efficacy in the use of aripiprazole for MDD. The results herein offer clear support for the tolerability of aripiprazole 2 mg/day as an augmenting agent, with limited efficacy; clinicians may have to increase the dose of aripiprazole up to 5–15 mg/day based on the individual patient’s response and tolerability. Pharmacokinetic differences in different ethnicities should also be considered in selection of starting and target dose of aripiprazole; slight differences in dosing pattern of aripiprazole were observed in clinical trials conducted in Asian countries.


Effects of S-Adenosylmethionine Augmentation of Serotonin Reuptake Inhibitor Antidepressants on Cognitive Symptoms of Major Depressive Disorder

Levkovitz Y, Alpert JE, Brintz CE, et al
J Affect Disord. 2012;136(3):1174-1178.

Background: Major depressive disorder (MDD) is often accompanied by significant cognitive impairment, and there are limited interventions specific to this particular symptom. S-adenosyl methionine (SAMe), a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism, is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD.

Methods: This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD. Forty-six serotonin reuptake inhibitor (SRI) non-responders with MDD enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe were administered the self-rated cognitive and physical symptoms questionnaire (CPFQ), a validated measure of cognitive as well as physical symptoms of MDD, before and after treatment.

Results: There was a greater improvement in the ability to recall information (P=0.04) and a trend toward statistical significance for greater improvement in word-finding (P=0.09) for patients who received adjunctive SAMe than placebo. None of the remaining five items reached statistical significance.

Conclusion: These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients, and warrant replication.

Clinical Commentary
S-adenosylmethionine (SAMe) is a natural compound that is found in almost every tissue and fluid in the body. SAMe has a major role in the immune system and cell metabolism as well as involvement in the life cycles of major neurotransmitters (e.g., serotonin) which are implicated in the development of MDD. Existing data suggest that augmentation with SAMe is tolerable for MDD patients and may boost the antidepressant effect in treating these patients. The data herein present a potential utility of SAMe in the treatment of MDD-related cognitive decline without safety or tolerability issues, although more replication studies are needed to confirm such findings. In fact, cognitive impairment is common in MDD patients, especially in the geriatric population. Hence, SAMe may be another viable option for treating cognitive dysfunction in MDD patients. In addition, SAMe may be beneficial in the treatment of MDD patients with minimal cognitive impairment.

GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 7, October 2012 — Guest Commentator: W. Vaughn McCall, MD, MS, Georgia Health Sciences University


A Randomized Controlled Trial of Telephone-Delivered Cognitive-Behavioral Therapy for Late-Life Anxiety Disorders

Brenes GA, Miller ME, Williamson JD, et al
Am J Geriatr Psychiatry. 2012;20(8):707-716.

Objectives: Older adults face a number of barriers to receiving psychotherapy, such as a lack of transportation and access to providers. One way to overcome such barriers is to provide treatment by telephone. The purpose of this study was to examine the effects of cognitive behavioral therapy delivered by telephone (CBT-T) to older adults diagnosed with an anxiety disorder.

Methods: This randomized controlled trial included 60 participants age 60 and older with a diagnosis of generalized anxiety disorder, panic disorder, or anxiety disorder not otherwise specified. CBT-T versus information-only comparison was utilized in the homes of the participants. Co-primary outcomes included worry (Penn State Worry Questionnaire) and general anxiety (State Trait Anxiety Inventory). Secondary outcomes included clinician-rated anxiety (Hamilton Anxiety Rating Scale), anxiety sensitivity (Anxiety Sensitivity Index), depressive symptoms (Beck Depression Inventory), quality of life (SF-36), and sleep (Insomnia Severity Index). Assessments were completed prior to randomization, immediately upon completion of treatment, and 6 months after completing treatment.

Results: CBT-T was superior to information-only in reducing general anxiety (ES = 0.71), worry (ES = 0.61), anxiety sensitivity (ES = 0.85), and insomnia (ES = 0.82) at the posttreatment assessment; however, only the reductions in worry were maintained by the 6-month follow-up assessment (ES = 0.80).

Conclusions: These results suggest that CBT-T may be efficacious in reducing anxiety and worry in older adults, but additional sessions may be needed to maintain these effects.

Clinical Commentary
Anxiety is a potentially disabling problem in older adults which, left unaddressed, could lead to premature loss of independence. Delivery of adequate treatment for geriatric anxiety disorders is beset by several challenges including (1) a lack of adequate numbers of mental health providers with geriatric expertise; (2) barriers for older people in attending appointments in doctor’s offices, and (3) dangers in prescribed anxiolytics, including risk for falls and amnestic disturbance. These challenges may be offset by bringing the treatment to the older person’s home. This could be accomplished by self-help books, the Internet, house calls, or in the case of this report, telephone-assisted psychotherapy. The positive findings of this report may surprise those who assume that older persons do not do well without a face-to-face treatment component. Further development of telephone-assisted psychotherapy will require definition of means of provider reimbursement, which for Medicare recipients usually requires face-to-face interaction. Replication of this study will challenge the status quo regarding how mental health care is delivered to older people.


Electroconvulsive Therapy in China: Clinical Practice and Research on Efficacy

Tang YL, Jiang W, Ren YP, et al
J ECT. 2012 Jul 13.

Objective: Electroconvulsive therapy (ECT) was first introduced in China in the early 1950s and has evolved into a significant psychiatric treatment. Research from Chinese psychiatrists provides important clinical data for ECT practitioners. However, most of the research has only been published in Chinese language journals. This article summarizes data from publications in the Chinese scientific community related to the clinical practice of ECT and research on efficacy in the treatment of psychiatric disorders.

Methods: Descriptive study primarily based on Chinese language literature identified from searches of the China National Knowledge Infrastructure and the Medline databases (1979-2012).

Results: More than 900 journal papers on ECT have been published in the Chinese language between 1979 and 2012. Currently, modified ECT has replaced unmodified ECT, and treatments were performed both in inpatient and outpatient settings. Electroconvulsive therapy is primarily used for the treatment of schizophrenia and mood disorders and has been shown to be very effective in both. The primary use of ECT in China is in the treatment of schizophrenia. The Chinese literature provides a rich database on the efficacy of modified and unmodified ECT, with and without adjunctive antipsychotics, in the treatment of schizophrenia.

Conclusion: The Chinese medical literature provides an important database that will help advance the practice of ECT in both China and the international community.

Clinical Commentary
Electroconvulsive therapy (ECT) is used principally in the treatment of severe mood disorders in the USA, Western Europe, Australia, and the remainder of the developed world. Therefore, the research conducted by Tang et al may surprise Western readers. It claims that in China, the main indication of ECT is for schizophrenia and other primary psychotic disorders. This report is entirely consistent with the use of ECT in India, parts of Africa, and other developing worlds. The reasons for these differences are complicated, but at the very least this report challenges the notion that ECT has limited application in psychotic disorders. Practitioners of ECT in the developed world should take note that ECT may help some otherwise intractable cases of schizophrenia, or may accelerate symptom relief in conjunction with standard antipsychotic treatment of schizophrenia.


Naltrexone Implant for the Treatment of Poly-Drug Dependence: a Randomized Controlled Trial

Tiihonen J, Krupitsky E, Verbitskaya E, et al
Am J Psychiatry. 2012;169(5):531-536.

Objective: The majority of drug addicts are polydrug dependent, and no effective pharmacological treatment is currently available for them. The authors studied the overall real-world effectiveness of the naltrexone implant in this patient population.

Methods: The authors assessed the effectiveness of a naltrexone implant in the treatment of coexisting heroin and amphetamine polydrug dependence in 100 heroin- and amphetamine-dependent outpatients in a 10-week randomized, double-blind, placebo-controlled trial. The main outcome measures were retention in the study, proportion of drug-free urine samples, and improvement score on the Clinical Global Impressions Scale (CGI). Analyses were conducted in an intent-to-treat model.

Results: At week 10, the retention rate was 52% for patients who received a naltrexone implant and 28% for those who received a placebo implant; the proportions of drug-free urine samples were 38% and 16%, respectively, for the two groups. On the CGI improvement item, 56% of the patients in the naltrexone group showed much or very much improvement, compared with 14% of those in the placebo group (number needed to treat=3).

Conclusions: Naltrexone implants resulted in higher retention in the study, decreased heroin and amphetamine use, and improved clinical condition for patients, thus providing the first evidence of an effective pharmacological treatment for this type of polydrug dependence.

Clinical Commentary
Substance abuse treatment requires a multi-modal approach that necessarily includes a psychosocial component. However, a period of abstinence is often required before psychosocial approaches can provide protection against relapse. Detoxification and abstinence may rely upon substitution approaches (benzodiazepines for alcohol; methadone for heroin) or relief of craving and/or blunting of the euphoria from the substance. All of the oral medications used in detoxification are liable to failure if the substance abuser fails to take the medication; thus, the study by Tiihonen et al. represents an encouraging, novel approach to non-adherence. While the rates of drug-free urine samples at week 10 were significantly twice as high in the those receiving the naltrexone implant as compared with the placebo implant, the overall low rate of drug-free urine tests underscores both the difficulty in treating this population and the need to combine medication therapy with a variety of psychosocial approaches.


Residual Sleep Disturbances in Patients Remitted From Major Depressive Disorder: A 4-Year Naturalistic Follow-up Study

Li SX, Lam SP, Chan JW, et al
Sleep. 2012;35(8):1153-1161.

Objective: To investigate the prevalence and clinical, psychosocial, and functional correlates of residual sleep disturbances in remitted depressed outpatients.

Methods: A 4-yr prospective observational study in a cohort of psychiatric outpatients with major depressive disorder was conducted with a standardized diagnostic psychiatric interview and a packet of questionnaires, including a sleep questionnaire, Hospital Anxiety and Depression Scale, NEO personality inventory, and Short Form-12 Health Survey.

Results: Four hundred twenty-one depressed outpatients were recruited at baseline, and 371 patients (mean age 44.6 ± 10.4 yr, female 81.8%; response rate 88.1%) completed the reassessments, in which 41% were classified as remitted cases. One-year prevalence of frequent insomnia at baseline and follow-up in remitted patients was 38.0% and 19.3%, respectively. One-year prevalence of frequent nightmares at baseline and follow-up was 24.0% and 9.3%, respectively. Remitted patients with residual insomnia were more likely to be divorced (P < 0.05) and scored higher on the anxiety subscale (P < 0.05). Remitted patients with residual nightmares were younger (P < 0.05) and scored higher on neuroticism (P < 0.05) and anxiety subscales (P < 0.01). Residual insomnia and nightmares were associated with various aspects of impaired quality of life. Residual nightmares was associated with suicidal ideation (odds ratio = 8.40; 95% confidence interval 1.79-39.33).

Conclusions: Residual sleep disturbances, including insomnia and nightmares, were commonly reported in remitted depressed patients with impaired quality of life and suicidal ideation. A constellation of psychosocial and personality factors, baseline sleep disturbances, and comorbid anxiety symptoms may account for the residual sleep disturbances. Routine assessment and management of sleep symptoms are indicated in the integrated management of depression.

Clinical Commentary
The psychiatric literature has a growing body of evidence that many depressed persons continue to experience residual symptoms despite meeting criteria for remission. Continuing symptoms of insomnia may be the most common residual symptom in otherwise successfully treated cases of depression, and this symptom puts these patients at risk for relapse. The paper by Li et al now adds the additional concern that residual symptoms of insomnia/nightmares identify otherwise-remitted patients who will have a risk for ongoing suicidal ideation. This finding was true principally in female patients. This paper provides the clinician with one more reason to aggressively pursue symptoms of insomnia in depressed patients.


Role of Referrals in Mental Health Service Disparities for Racial and Ethnic Minority Youth

Alegría M, Lin JY, Green JG, et al
J Am Acad Child Adolesc Psychiatry. 2012;51(7):703-711.e2.

Objective: To investigate racial/ethnic differences in teachers and other adults' identification and/or encouragement of parents to seek treatment for psychiatric problems in their children and to evaluate if and whether identification/encouragement is associated with service use.

Method: Data on identification/encouragement to seek treatment for externalizing disorders (i.e., attention-deficit/hyperactivity disorder, oppositional-defiant disorder, and/or conduct disorder) and internalizing disorders (i.e., major depressive episode/dysthymia and/or separation anxiety disorder) and services used were obtained for 6,112 adolescents (13-17 years of age) in the National Comorbidity Survey Adolescent Supplement. Racial/ethnic differences were examined for Latinos, non-Latino blacks, and non-Latino whites.

Results: There were few racial/ethnic differences in rates of youth identification/encouragement and how identification/encouragement related to service use. Only non-Latino black youth with low severity internalizing disorders were less likely to be identified/encouraged to seek services compared with non-Latino white youth with the same characteristics (odds ratio [OR] = 0.4, 95% confidence interval [CI] = [0.2-0.7]). Identification/encouragement increased the likelihood of seeking services for externalizing and internalizing disorders for all youth. However, compared with their non-Latino white counterparts, non-Latino black youth who met criteria for internalizing disorders appeared less likely to have used any services (OR = 0.4, 95%, CI = 0.2-0.7), after adjusting for identification/encouragement, clinical, and sociodemographic characteristics. Non-Latino black youth with internalizing disorders and without identification/encouragement were less likely to use the specialty care sector than their non-Latino white counterparts.

Conclusions: In this study of a nationally representative sample of adolescents, almost no ethnic/racial differences in identification/encouragement were found. However, identification/encouragement may increase service use for all youth.

Clinical Commentary
The history of mental health treatment in the USA is replete with stories of misdiagnoses, inequities in access to care, and variability in treatment as a function of racial and ethnic differences. For this reason, the report of Alegría et al is somewhat of a pleasant surprise in that, for the most part, ethnicity and race were not related to differences in identification and encouragement for treatment in youth. Does this mean that teachers, counselors, and mental health providers are doing a better job at providing unbiased assessment of youth? Perhaps. But as the paper notes, there are areas still needing improvement, especially in obtaining treatment for depressive and anxiety disorders in black youths.


Prediction of Incident Dementia: Impact of Impairment in Instrumental Activities of Daily Living and Mild Cognitive Impairment-Results From the German Study on Ageing, Cognition, and Dementia in Primary Care Patients

Luck T, Luppa M, Wiese B, et al
Am J Geriatr Psychiatry. 2012 Jun 14. [epub ahead of print]

Objectives: There is an increasing call for a stronger consideration of impairment in instrumental activities of daily living (IADL) in the diagnostic criteria of Mild Cognitive Impairment (MCI) to improve the prediction of dementia. Thus, the aim of the study was to determine the predictive capability of MCI and IADL impairment for incident dementia.

Methods: This longitudinal cohort study consisted of four assessments at 1.5-year intervals over a period of 4.5 years. A primary care medical record registry sample was utilized. As part of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients, a sample of 3,327 patients from general practitioners, aged 75 years and older, was assessed. The predictive capability of MCI and IADL impairment for incident dementia was analyzed using receiver operating characteristics, Kaplan-Meier survival analyses, and Cox proportional hazards models were used.

Results: MCI and IADL impairment were found to be significantly associated with higher conversion to, shorter time to, and better predictive power for future dementia. Regarding IADL, a significant impact was particularly found for impairment in responsibility for one's own medication, shopping, and housekeeping, and in the ability to use public transport.

Conclusions: Combining MCI with IADL impairment significantly improves the prediction of future dementia. Even though information on a set of risk factors is required to achieve a predictive accuracy for dementia in subjects with MCI being clinically useful, IADL impairment should be a very important element of such a risk factor set.

Clinical Commentary
Mild cognitive impairment (MCI) is recognized as a prodrome for dementia, but its utility as a risk factor is limited by the finding that only a minority of older persons with MCI will progress to dementia. Luck et al now reports that the presence of limitations in instrumental activities of daily living (IADL) improves the predictive power of MCI in dementia risk assessment. Of course, mental health providers should routinely ask older persons about IADL function if for no other reason than to identify the proper level of care (outpatient versus inpatient, etc). Li et al further highlights the utility of IADL assessment in every older patient.


The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies

Howes OD, Kambeitz J, Kim E, et al
Arch Gen Psychiatry. 2012 Apr 2. [epub ahead of print]

Objective: Current drug treatments for schizophrenia are inadequate for many patients, and despite five decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. This study sought to investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.

Methods: The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011. A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function. Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.

Results: There was a highly significant elevation (P < .001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d = 0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d = 0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.

Conclusions: The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

Clinical Commentary
The CATIE study (along with other practical effectiveness studies such as STAR*D) have humbled psychiatrists. We now realize that our treatments for serious mental illness, while better than placebo, leave many patients with only minimal improvement. In the case of schizophrenia, the “road ahead” may be found by re-directing our attention to a new target for drug development. As noted by Howes et al, existing treatments of schizophrenia are focused on targets that are postsynaptic (downstream) from the dopamine neuron. This compelling meta-analysis makes the case that the real problem with dopamine function in persons with schizophrenia is presynaptic, not postsynaptic. For the clinician, this means that we should all anticipate new schizophrenia treatments that target pre-synaptic dopamine function.


Thu, 09/13/2012 - 12:39 -- admin
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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 6, September 2012 — Guest Commentator: Joseph P. McEvoy, Duke University


Disease-Modifying Properties of Long-Term Lithium Treatment for Amnestic Mild Cognitive Impairment: Randomized Controlled Trial

Forlenza OV, Diniz BS, Radanovic M, et al
Br J Psychiatry. 2011;198(5):351-356.

Objective: Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment.

Aims: To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI).

Methods: Forty-five participants with aMCI were randomized to receive lithium (0.25-0.5 mmol/l) (n=24) or placebo (n=21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ[42]), total tau (T-tau), phosphorylated-tau (P-tau). Trial registration: NCT01055392.

Results: Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P=0.03) and better performance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%.

Conclusions: The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.

Clinical Commentary
This group previously reported a lower prevalence of Alzheimer’s disease (AD) among elderly individuals with bipolar disorder (BD) treated with lithium than among elderly individuals with BD not treated with lithium.(1) Two additional cohort studies reported similar advantages for lithium-treated patients with BD. Lithium inhibits glycogen synthase kinase 3 beta, a tau-kinase in the brain that modulates the cleavage of amyloid precursor protein and contributes to the pathophysiology of AD.(2) However, two prospective studies of lithium in individuals with AD without BD failed to demonstrate any advantage for lithium. The present study, in patients with amnestic mild cognitive impairment, was based on the possibility that earlier intervention with lithium, prior to the presence of diagnosed AD, might be more effective. The investigators targeted lithium levels between 0.2–0.5 mEq/L which were very well tolerated by the participants, and benefits were seen in cognitive performance and on biomarkers for AD. The results offer initial promise that as methods become available to detect individuals at high risk for developing AD, early intervention with lithium may have mitigating potential.


Cortical Thinning in Psychopathy

Ly M, Motzkin JC, Philippi CL, et al
Am j Psychiatry. 2012; May 11. doi: 10.1176/appi.ajp.2012.11111627. [Epub ahead of print]

Objective: Psychopathy is a personality disorder associated with severely antisocial behavior and a host of cognitive and affective deficits. The neuropathological basis of the disorder has not been clearly established. Cortical thickness is a sensitive measure of brain structure that has been used to identify neurobiological abnormalities in a number of psychiatric disorders. The authors assessed cortical thickness and corresponding functional connectivity in psychopathic prison inmates.

Methods: Using T1 MRI data, the authors computed cortical thickness maps in a sample of adult male prison inmates selected on the basis of psychopathy diagnosis (21 psychopathic inmates and 31 nonpsychopathic inmates). Using resting-state functional MRI data from a subset of these inmates (20 psychopathic inmates and 20 nonpsychopathic inmates), the authors then computed functional connectivity within networks exhibiting significant thinning among psychopaths.

Results: Relative to nonpsychopaths, psychopaths had significantly thinner cortex in a number of regions, including the left insula and dorsal anterior cingulate cortex, the left and right precentral gyri, the left and right anterior temporal cortices, and the right inferior frontal gyrus. These neurostructural differences were not due to differences in age, IQ, or substance use. Psychopaths also exhibited a corresponding reduction in functional connectivity between the left insula and the left dorsal anterior cingulate cortex.

Conclusions: Psychopathy is associated with a distinct pattern of cortical thinning and reduced functional connectivity.

Clinical Commentary
Psychopathy is characterized by callous, unemotional traits. Psychopaths fail to resonate with other people’s distress and demonstrate impaired ability to recognize fear stimuli. Only 20% to 50% of individuals with antisocial personality disorder (ASPD) demonstrate psychopathy. However, ASPD with psychopathy is associated with increased likelihood of violence, and the heritability of ASPD with psychopathy is stronger than that for ASPD without psychopathy.(3) Psychopathy (callous unemotional traits) can also be present in children and adults without ASPD. As early as 4–8 years of age, children with callous unemotional traits can be shown to fail to attend to the eyes of attachment figures (e.g. their mothers); this impairment is independent of maternal behaviors but associated with “fearlessness” in their fathers.(4) Children with callous unemotional traits have increased risk for later antisocial behavior, poor peer relationships, and hyperactivity. The present article supports prior work demonstrating anatomical and functional imaging abnormalities in the brains of psychopaths.


Dialectical Behavior Therapy Compared with General Psychiatric Management for Borderline Personality Disorder: Clinical Outcomes and Functioning Over a 2-year Follow-up

McMain SF, Guimond T, Streiner DL, et al
Am J Psychiatry. 2012;169(6):650-661.

Objective: The authors conducted a 2-year prospective naturalistic follow-up study to evaluate posttreatment clinical outcomes in outpatients who were randomly selected to receive 1 year of either dialectical behavior therapy or general psychiatric management for borderline personality disorder.

Methods: Patients were assessed by blind raters 6, 12, 18, and 24 months after treatment. The clinical effectiveness of treatment was assessed on measures of suicidal and nonsuicidal self-injurious behaviors, health care utilization, general symptom distress, depression, anger, quality of life, social adjustment, borderline psychopathology, and diagnostic status. The authors conducted between-group comparisons using generalized estimating equation, mixed-effects models, or chi-square statistics, depending on the distribution and nature of the data.

Results: Both treatment groups showed similar and statistically significant improvements on the majority of outcomes 2 years after discharge. The original effects of treatment did not diminish for any outcome domain, including suicidal and nonsuicidal self-injurious behaviors. Further improvements were seen on measures of depression, interpersonal functioning, and anger. However, even though two-thirds of the participants achieved diagnostic remission and significant increases in quality of life, 53% were neither employed nor in school, and 39% were receiving psychiatric disability support after 36 months.

Conclusions: One year of either dialectical behavior therapy or general psychiatric management was associated with long-lasting positive effects across a broad range of outcomes. Despite the benefits of these specific treatments, one important finding that replicates previous research is that participants continued to exhibit high levels of functional impairment. The effectiveness of adjunctive rehabilitation strategies to improve general functioning deserves additional study.

Clinical Commentary
Exploratory, unstructured treatment for borderline personality disorder (BPD) proved to be of limited use, and counter-productive in some patients. Current general psychiatric treatment for patients with BPD is structured and based on manuals with recommendations for addressing common clinical problems. Clinicians providing treatment for patients with BPD should want and choose to do this. They must demonstrate empathy and engagement while providing coherent explanations linking the subjective experience of BPD to a model of pathology. Patients are expected to be active, to become preemptive, and to accept self-agency, in particular to accept links between actions and feelings.(5) With such treatments, most patients with BPD achieve symptomatic remission over 10 or more years of follow-up, although the majority demonstrates persistent functional impairment.(6)


Nocturnal Enuresis with Antipsychotic Medication

Barnes TR, Drake MJ, Paton C.
Br J Psychiatry. 2012;200(1):7-9.

Nocturnal enuresis can be discomfiting and troublesome. There is increasing evidence that as a side effect of second-generation antipsychotics, particularly clozapine, it may be under-recognized. Direct but sensitive questioning may be required to elicit this side effect. We briefly review possible mechanisms of this problem, and management and treatment options.

Clinical Commentary
Estimates of the incidence of nocturnal enuresis among patients taking clozapine have ranged up to 40%; the incidences on risperidone, olanzapine, or quetiapine appears to be lower (5% to 10%).(7) In many individuals enuresis occurs early during treatment and resolves spontaneously, but in some patients the problem persists. It is clear that many patients are deeply embarrassed by this side effect and it is commonly not discovered unless asked about by a trusted clinician. It is likely that this side effect leads to medication noncompliance in some patients, with loss of the therapeutic benefit of the antipsychotic treatment. Effective treatments for enuresis are available. We most commonly use ephedrine 25 mg at bedtime or twice daily(8) or pseudoephedrine if ephedrine is not available. Patients should be told about the possibility of this side effect and that the side effect can be readily and safely corrected should it occur.


Metformin for Treatment of Antipsychotic-Induced Amenorrhea and Weight Gain in Women With First-Episode Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Study

Wu RR, Jin H, Gao K, et al
Am J Psychiatry. 2012;169(8):813-821.

Objective: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia.

Methods: Eighty-four women (ages 18–40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1,000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis.

Results: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group.

Conclusions: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

Clinical Commentary
Many antipsychotic medications lead to weight gain and insulin resistance, contributing to accelerated cardiovascular risk and the striking disadvantage in mortality that afflicts patients with serious and persistent mental illnesses. The most problematic antipsychotic medications, clozapine and olanzapine, provide additional therapeutic benefit to many patients incompletely responsive to other antipsychotic medications, and they cannot be substituted for. Almost a decade passed after the availability of atypical antipsychotic medications before widespread awareness of these side effects among clinicians occurred, followed by calls to monitor (to what end?). Finally, we have evidence that intervention with metformin is not only effective, but safe, in qualified hands.(9) The value of metformin in diabetes prevention is well established.(10) These authors also call attention to the value of metformin in reducing amenorrhea in antipsychotic-treated women with schizophrenia. We can hope that other potential mitigating agents (e.g. omega-3 fatty acids, statins, aspirin) will be similarly well-studied and ultimately utilized if proven effective and safe.


Comparison of Oral Health Between Inpatients with Schizophrenia and Disabled People or the General Population

Chu KY, Yang NP, Chou P, et al
J Formos Med Assoc. 2012;111(4):214-219.

Objective: There is little comparative research evidence to support the claim that there is disparity in dental care between inpatients with schizophrenia and the disabled people or the general population. This study aimed to investigate whether schizophrenia inpatients had poorer dental care and worse oral health than the disabled people and the general population, respectively.

Methods: An oral health survey was conducted in a specific-psychiatric long-term care institution in Taiwan in 2006. The results of this survey were compared with the findings of oral health investigations of the disabled people or the general population in Taiwan using proportion test and t-test.

Results: This study used decayed, missing, and filled teeth index (DMFT) to describe the condition of dental caries. Compared with the disabled people, schizophrenia inpatients aged 19 to 44 years had a lower subjects' filling rate of DMFT index (FI) and a higher caries experience, but schizophrenia inpatients aged 45 or more had a lower mean number of DMFT. Compared with the general population, schizophrenia inpatients had higher caries experience, mean number of DMFT, percentage edentulous, and community periodontal index and lower FI and number of remaining tooth among various gender or age groups.

Conclusion: In Taiwan, inpatients with schizophrenia have a lower FI than the disabled people and a worse overall oral health status than the general population.

Clinical Commentary
When matched against normal control populations, individuals with schizophrenia are 3–4 times more likely to be edentulous, a condition that affects an individual’s ability to eat comfortably and speak clearly, as well as the individual’s appearance (and contributes to stigma). Among those who have teeth, individuals with schizophrenia have significantly higher rates of dental caries than matched normal control populations.(11) Severe periodontal disease as assessed by plaque index and bleeding on probing is also more prevalent among patients with schizophrenia.(12) Untreated caries and periodontal disease are the leading causes of becoming edentulous. Clinicians certainly should urge patients and their caregivers to support dental hygiene practices (e.g. brushing regularly) and to reduce smoking, but the most important action clinicians can take is to avoid prescribing medications that produce dry mouth. Saliva protects teeth through four mechanisms: diluting and eliminating sugars and other substances, buffer capacity, balancing demineralization/remineralization, and antimicrobial action.(13)

1. Nunez PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007;190:359-360.
2. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer disease. J Neurochem. 2008;104:1433-1439.
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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 5, August 2012 — Guest Commentator: Philip R. Muskin, MD, Columbia University


Responsiveness of Hypochondriacal Patients with Chronic Low-Back Pain to Cognitive-Behavioral Therapy

Nakao M, Shinozaki Y, Nolido N, et al

Psychosomatics. 2012;53(2):139-147.

Background: Evidence has suggested that cognitive-behavioral therapy (CBT) is effective in reducing hypochondriacal symptoms, and another line of evidence has suggested that CBT is also effective in reducing pain and the psychological conditions associated with chronic low-back pain (CLBP). The purpose of this study was to examine the effectiveness of CBT among hypochondriacal patients with and without CLBP.

: A total of 182 hypochondriacal patients were randomly assigned to a CBT or control group. The Somatic Symptom Inventory was used to define CLBP, and the Symptom Checklist 90R (SCL90R) was used to assess psychological symptoms. The outcome measures for hypochondriasis, the Whiteley Index (WI), and the Health Anxiety Inventory (HAI) were administered before the intervention and at 6 and 12 months after completion of the intervention.

: In the total sample, both WI and HAI scores were significantly decreased after treatment in the CBT group compared with the control group. Ninety-three (51%) patients had CLBP; the SCL90R scores for somatization, depression, phobic anxiety, paranoid ideation, and general severity were significantly higher in the CLBP(+) group than in the CLBP(-) group at baseline. Although the WI and HAI scores were significantly decreased after treatment in the CLBP(-) group, such significant pre- to post-changes were not found in the CLBP(+) group.

: CBT was certainly effective among hypochondriacal patients without CLBP, but it appeared to be insufficient for hypochondriacal patients with CLBP. The core psychopathology of hypochondriacal CLBP should be clarified to contribute to the adequate management of hypochondriacal symptoms in CLBP patients.

Clinical Commentary
Patients with complaints of CLBP suffer from physical and psychological disability. In this study of CBT treatment, hypochondriacal patients who scored 4 or more on the low back pain item of the Somatic Symptom Inventory were compared to those who did not have that complaint. The patients did not receive medical treatment for CLBP as part of the study. CBT was effective for the hypochondriasis as measured by the Whiteley Index and the Health Anxiety Inventory in CLBP (-) patients but not those who were CLBP (+).  The CLBP (+) group was significantly different from the CLBP (-) group in terms of ethnicity, with a larger proportion of Caucasians in the CLBP (-) group. Controlling for ethnicity, Caucasian CLBP (+) patients did not respond to CBT compared to Caucasian CLBP (-) patients. A major limitation of the study is that a single item on a rating scale defined CLBP arbitrarily. In spite of the limitations, the study raises interesting questions regarding psychological approaches to patients who experience themselves as having low back pain. Their lives may be dramatically impaired by their health beliefs, and psychological treatments typically effective for hypochondriasis may not be beneficial. It is hoped that further research will identify modifications to CBT that will aid these patients.

Fertility Treatment Response: Is It Better to be More Optimistic or Less Pessimistic?

Bleil ME, Pasch LA, Gregorich SE, et al

Psychosom Med. 2012;74(2):193-199.

Objective: To evaluate the prospective relation between dispositional traits of optimism and pessimism and in vitro fertilization (IVF) treatment failure among women seeking medical intervention for infertility.

: Among 198 women (aged 24-45 years, mean [standard deviation]=35.1 [4.1] years; white, 77%), the outcome of each participant's first IVF treatment cycle was examined. Treatment outcome was classified as being successful (versus failed) if the woman either delivered a baby or was pregnant because of the cycle by the end of the 18-month study period. At baseline, optimism and pessimism were measured as a single bipolar dimension and as separate unipolar dimensions according to the Life Orientation Test total score and the optimism and pessimism subscale scores, respectively.

: Optimism/pessimism, measured as a single bipolar dimension, predicted IVF treatment failure initially (B=-0.09, p=.02, odds ratio [OR]=0.917, 95% confidence interval [CI]=0.851-0.988), but this association attenuated after statistical control for trait negative affect (B=-0.06, p=.13, OR=0.938, 95% CI=0.863-1.020). When examined as separate unipolar dimensions, pessimism (B=0.14, p=.04, OR=1.146, 95% CI=1.008-1.303), not optimism (B=-0.09, p=.12, OR=0.912, 95% CI=0.813-1.023), predicted IVF treatment failure independently of risk factors for poor IVF treatment response and trait negative affect.

Conclusions: Being pessimistic may be a risk factor for IVF treatment failure. Future research should attempt to delineate the biological and behavioral mechanisms by which pessimism may negatively affect treatment outcomes.

Clinical Commentary
When a woman is unsuccessful in her attempts to conceive a child, there is often speculation about how psychological issues might have factored into the failure.  Meta-analyses have indicated that depression and anxiety do not predict the outcome of assisted reproductive technologies (ART), but that stress and state/trait anxiety do have an impact. In this study, optimism and pessimism were measured using the Life Orientation Test and, as the authors note, individuals can “embody traits of both optimism and pessimism concurrently.” They also measured negative trait affect using the 23-item neuroticism subscale of the Eysenck Personality Questionnaire.  Pessimism was negatively correlated with positive IVF treatment outcome, independent of negative trait affect and other risk factors for poor fertility treatment response.  Each 1-unit increase in the pessimism score increased the likelihood of IVF treatment failure by 17.8%. Optimism was not related to the IVF outcome. The authors speculate that pessimism reflects an accurate appraisal by women with poor prognosis; however, the women in the study were undergoing IVF for the first time and older age was related to less pessimism. Some data suggest that pessimism may be amenable to change. Results from this study might be incorporated into the evaluation of women in ART programs and into the psychiatric support provided to the patients.

Optimism, Response to Treatment of Depression, and Rehospitalization After Coronary Artery Bypass Graft Surgery

Tindle H, Belnap BH, Houck PR, et al

Psychosom Med. 2012;74(2):200-207.

Objective: Optimism has been associated with a lower risk of rehospitalization after coronary artery bypass graft (CABG) surgery, but little is known about how optimism affects treatment of depression in post-CABG patients.

: Using data from a collaborative care intervention trial for post-CABG depression, we conducted exploratory post hoc analyses of 284 depressed post-CABG patients (2-week posthospitalization score in the 9-item Patient Health Questionnaire ≥10) and 146 controls without depression who completed the Life Orientation Test-Revised (full scale and subscale) to assess dispositional optimism. We classified patients as optimists and pessimists based on the sample-specific Life Orientation Test-Revised distributions in each cohort (full sample, depressed, nondepressed). For 8 months, we assessed health-related quality of life (using the 36-item Short-Form Health Survey) and mood symptoms (using the Hamilton Rating Scale for Depression [HRSD]) and adjudicated all-cause rehospitalization. We defined treatment response as a 50% or higher decline in HRSD score from baseline.

: Compared with pessimists, optimists had lower baseline mean HRSD scores (8 versus 15, p=.001). Among depressed patients, optimists were more likely to respond to treatment at 8 months (58% versus 27%, odds ratio=3.02, 95% confidence interval=1.28-7.13, p=.01), a finding that was not sustained in the intervention group. The optimism subscale, but not the pessimism subscale, predicted treatment response. By 8 months, optimists were less likely to be rehospitalized (odds ratio=0.54, 95% confidence interval=0.32-0.93, p=.03).

: Among depressed post-CABG patients, optimists responded to depression treatment at higher rates. Independent of depression, optimists were less likely to be rehospitalized by 8 months after CABG. Further research should explore the impact of optimism on these and other important long-term post-CABG outcomes.

Clinical Commentary

Data indicate that optimistic postmenopausal women and older men have a lower risk of a first myocardial infarction, and optimistic people are at lower risk for cardiovascular disease progression. This paper investigates the role of optimism in post-CABG patients, suggesting that factors we do not usually measure may be operative in determining patients’ outcomes. The authors note that optimism and pessimism are not necessarily a bipolar trait and may independently contribute to health outcomes. They screened for depression in post-CABG patients using the PHQ-2 in the hospital, followed by the PHQ-9 via telephone 2 weeks after discharge. Those patients with a score of 10 or higher on the PHQ-9 (moderate depression) were included in the study. They were compared to a group of post-CABG patients who screened negative on the PHQ-2 and had a score of <5 on the follow-up questionnaire. Participants completed the Life Orientation Test-Revised (LOT-R) to measure their optimism/pessimism. Depressed patients were randomized to usual care (UC) or to a collaborative care intervention; however, the patients and their physicians in the UC group were informed of their depression status. After adjusting for intervention type, education level, physical functioning, perceived social support, and baseline depression severity, optimists were significantly more likely to respond to depression treatment. In the UC group the optimists were five times more likely to respond to treatment than the pessimists. Risk of rehospitalization was 46% lower in optimists overall (17% lower in the depressed patients and 65% lower in those not depressed). Optimism appeared to operate independently of pessimism in this study and pessimism was not correlated with outcomes, a finding that varies from other research. A limitation of the study is the failure to obtain LOT-R scores after treatment. Thus, we do not know if the LOT-R scores for depressed patients truly represent optimism/pessimism or depression. Nevertheless, this study points clinicians to investigate patients’ outlook as potentially modifiable factors in their health outcomes.

Pregnancy Outcome After Exposure to Antidepressants and the Role of Maternal Depression: Results From the Norwegian Mother and Child Cohort Study

Nordeng H, van Gelder MM, Spigset O, et al

J Clin Psychopharmacol. 2012;32(2):186-194.

Objective: Results of previous studies on the safety of antidepressants during pregnancy have been conflicting. The primary objective of this study was to investigate whether first-trimester exposure to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), was associated with increased risk of congenital malformations. The secondary objective was to examine the effects of exposure to antidepressants during pregnancy on birth weight and gestational age.

: We included 63,395 women from the Norwegian Mother and Child Cohort Study. The women had completed 2 self-administered questionnaires at gestational weeks 17 and 30 on medication use and medical, sociodemographic, and psychological factors. Data on pregnancy outcome were retrieved from the Medical Birth Registry of Norway.

: Of the 63,395 women, 699 (1.1%) reported using antidepressants during pregnancy, most frequently SSRIs (0.9%). Exposure to SSRIs during the first trimester was not associated with increased risk of congenital malformations in general (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 0.81-1.84) or cardiovascular malformations (adjusted OR, 1.51; 95% CI, 0.67-3.43). Exposure to antidepressants during pregnancy was not associated with increased risk of preterm birth (adjusted OR, 1.21; 95% CI, 0.87-1.69) or low birth weight (adjusted OR, 0.62; 95% CI, 0.33-1.16).

: This study does not suggest a strongly increased risk of malformations, preterm birth, or low birth weight following prenatal exposure to antidepressants. Without adjustments for level of maternal depression and various sociodemographic and lifestyle factors, antidepressant use during pregnancy would wrongly have been associated with an increased risk of preterm birth.

Clinical Commentary

Safe treatment for depression during pregnancy remains an unsolved problem. Both treating and not treating a depressed pregnant woman exposes the woman and her fetus to risks. Each study contributes something to our knowledge base. In this large study (N=63,395) from the Norwegian Mother and Child Cohort Study, 1.1% reported antidepressant use, with SSRIs being the most frequently used class of medication. There was no increase in risk of congenital malformations in general or cardiovascular malformations associated with first trimester antidepressant use. Antidepressant use was not associated with preterm birth or low birth weight. Women who used antidepressants were also more likely to use benzodiazepines, opioids, hypnotics, and antipsychotics during pregnancy. A major strength of the study is the prospective collection of data; however, major limitations of the study come from how the data were obtained, i.e., self-report, the low response rate (38%), the lack of data obtained about alcohol use, and the lack of data regarding antidepressant dose or duration of exposure. Nevertheless, this study adds to the information we can share with women who are pregnant and in need of treatment for their depression. Ideally, a study will be performed where women are interviewed to obtain accurate information regarding medication use, adherence to treatment, substance use, and outcome of pregnancy. While such a study will not resolve all of the safety issues, it would solve some of the methodological problems of research done to date.

Myocardial Infarction and Generalized Anxiety Disorder: 10-Year Follow-Up

Roest AM, Zuidersma M, de Jonge P

Br J Psychiatry. 2012;200:324-329.

Background: Few studies have addressed the relationship between generalized anxiety disorder (GAD) and cardiovascular prognosis using a diagnostic interview.

: To assess the association between GAD and adverse outcomes in patients with myocardial infarction.

: Patients with acute myocardial infarction (n=438) were recruited between 1997 and 2000 and were followed up until 2007. Current GAD and post-myocardial infarction depression were assessed with the Composite International Diagnostic Interview. The end-point consisted of all-cause mortality and cardiovascular-related readmissions.

: During the follow-up period, 198 patients had an adverse event. GAD was associated with an increased rate of adverse events after adjustment for age and gender (hazard ratio: 1.94; 95% confidence interval: 1.14-3.30; P=.01). Additional adjustment for measures of cardiac disease severity and depression did not change the results.

: GAD was associated with an almost twofold increased risk of adverse outcomes independent demographic and clinical variables and depression.

Clinical Commentary

Most studies investigating the impact of psychological factors on coronary artery disease (CAD) have looked at the role of depression. Depression is a risk factor for both the development of CAD and morbidity and mortality in patients with CAD. This group looked at the prognostic role of GAD over a 10-year period in patients who experienced a myocardial infarction. GAD was associated with an increased risk of cardiovascular events and mortality. Post-myocardial infarction depression was not a significant predictor of adverse outcome in this study. Patients with GAD were two times more likely to have an adverse prognosis even after adjustment for age, gender, and cardiac disease severity. One strength of this study is that the diagnosis was made by a standardized diagnostic interview. The study is also of long duration. It is not known if the patients were treated for their psychiatric disorders and thus we do not have information as to whether interventions would impact on the outcomes. This study does guide us to both inquire ourselves and teach our colleagues to assess patients for both anxiety and depression after a myocardial infarction.

Coping Flexibility and Complicated Grief: A Comparison of American and Chinese Samples

Burton CL, Yan OH, Pat-Horenczyk R, et al

Depress Anxiety. 2012;29(1):16-22.

Background: The ability to process a death and the ability to remain optimistic and look beyond the loss are both thought to be effective means of coping with loss and other aversive events. Recently, these seemingly contrary dimensions have been integrated into the idea of coping flexibility.

: In this study, we assessed the ability of married and bereaved individuals in the United States and Hong Kong to use both coping approaches as operationalized by the trauma-focused and forward-focused coping scales of a previously validated questionnaire. We also calculated a single flexibility score.

: Bereaved participants reported greater trauma-focused coping ability than did married participants. However, bereaved participants meeting criteria for complicated grief (CG) reported less forward-focused coping than both asymptomatic bereaved and married participants. The CG group also showed less overall coping flexibility than the asymptomatic bereaved and married groups. Country was not a factor.

: Findings suggest that deficits in coping flexibility are indicative of pathology in bereaved individuals, and that this relationship extends across cultures. Limitations of the study and directions for future research are discussed.

Clinical Commentary

Freud wrote that the “work” of mourning involved the intense processing of personal meanings and emotions associated with the loss of a loved one. Avoiding this process has been seen as pathological and putting the individual at risk for delayed grief syndromes. Emerging research suggests that flexibility in coping may be a better predictor of grief outcome. This study used a structured clinical interview for DSM-IV-TR for depression comparing married individuals and a group of conjugally bereaved individuals in the United States and Hong Kong. The bereaved participants were questioned about symptoms of complicated grief. Despite the cultural differences between the countries, the ability of bereaved individuals to use flexible coping strategies was more important in distinguishing pathological grief reactions than using a particular coping strategy. While the asymptomatic bereaved and complicated grief groups reported high trauma-focused coping than the married controls, the complicated grief group used less forward-focused coping. The complicated grief group was less flexible than either of the other groups. These results suggest that individuals who can focus on their loss and also move beyond the loss are less likely to develop complicated grief. The therapeutic implications are interesting and suggest how we might work with patients who have suffered a loss both to treat complicated grief and to possibly prevent the occurrence of this painful state.

Cardiac Transplantation in Adult Patients with Mental Retardation: Do Outcomes Support Consensus Guidelines?

Samelson-Jones E, Mancini DM, Shapiro PA

Psychosomatics. 2012;53(2):133-138.

Background: Selection criteria guidelines list mental retardation as a relative contraindication to heart transplantation, but not to kidney transplantation.

: The authors present a case series of adults with mental retardation or comparable acquired intellectual disability who underwent heart transplantation. They discuss the literature on heart and kidney transplantation in people with mental retardation and the ethical reasoning that guides how recipients of solid organ grafts are chosen.

: Literature review and retrospective review of long-term outcomes for five adult patients with mental retardation or comparable disability who received heart transplants.

: Among these cases, survival times to date ranged from 4 to 16 years, with a median survival of greater than 12 years. Medical non-adherence was a significant factor in only 1 of the 5 cases. In that case, the patient's medical non-adherence was due to a functional decline in the primary caretaker.

: People with mental retardation can receive long-term benefit from heart transplantation when they have the cognitive and social support necessary to ensure adherence to post-transplant regimens. There is no ethical or medical reason for guidelines to consider mental retardation, in and of itself, a contraindication to heart transplantation. The totality of the individual patient's circumstances should be considered in assessing transplant candidacy.

Clinical Commentary

Psychosocial factors are assessed as part of a pre-transplantation evaluation. Mental retardation is a relative contraindication to cardiac transplantation and concerns regarding adherence in these patients may limit their ability to be listed for transplantation. The authors reviewed the cases of four patients with mental retardation and one case of acquired intellectual disability (anoxic brain injury) out of the 2,199 heart transplantations performed at New York-Presbyterian hospital from 1978 to 2010.  They note that contraindications for transplantation have been modified over the decades since renal transplantation was first begun. For example, age limitations for transplantation have progressively increased. They note that patients with mental retardation are less frequently referred to transplantation centers and are less frequently listed for transplantation; however, the evidence from renal transplantation indicates that the outcome for these patients is comparable to patients without mental retardation. The survival time in the five patients reviewed ranged from four to fourteen years, with a mean survival time >12 years. Only one case demonstrated medical non-adherence and that was secondary to a functional decline in the patient’s caregiver. As they note, “Patients with mental retardation should not be held to a higher standard than other patients.”  Reviews such as this one inform how we as psychiatrists can contribute with our non-psychiatric colleagues in the decisions regarding this life-saving but extremely limited procedure.  


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