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Volume 42 • Number 3 • 2009

Assessing Rates and Predictors of Tachyphylaxis During the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study

Anthony J. Rothschild, Boadie W. Dunlop, David L. Dunner, Edward S. Friedman, Alan J. Gelenberg, Peter Holland, James H. Kocsis, Susan G. Kornstein, Richard Shelton, Madhukar H. Trivedi, John M. Zajecka, Corey Goldstein, Michael E. Thase, Ron Pedersen, Martin B. Keller

Analysis of Depressive Symptoms in Patients With Major Depressive Disorder Treated With Desvenlafaxine or Placebo

Susan G. Kornstein, Maurizio Fava, Qin Jiang, Karen A. Tourian Drug Disposition & Pharmacokinetics

Efficacy of Omega 3 Fatty Acids in Mood Disorders: A Systematic Review and Metaanalysis

Nina V. Kraguljac, Victor M. Montori, Mani Pavuluri, High S. Chai, Brian S. Wilson, Sencan S. Unal General Psychiatry

A Systematic Review of Augmentation Strategies for Patients with Major Depressive Disorder

Rachael Fleurence, Quynh-Van Tran, Rebecca Williamson, Yonghua Jing, Edward Kim, Quynh-Van Tran, Andrei Pikalov, Michael E. Thase Complicated Case Histories

Neonatal Outcomes with the Use of Lamotrigine for Bipolar Disorder in Pregnancy and Breastfeeding: A Case Series and Review of the Literature

Laura Wakil, C. Neill Epperson, Juan Gonzalez, John P. O’Reardon, Deborah R. Kim

Switching to Duloxetine Remits Ziprasidone - Associated Urinary Incontinence and Improves Neuropsychiatric Behavior in Dementia:Possible Relationship of Incontinence to 5HT2 Receptor Blockade

Edward C. Lauterbach, Florence T. Baralatei


Volume 42 • Number 2 • 2009

Clinical Significance of Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Depression: Synthesis of Recent Data

Mark A. Demitrack, Michael E. Thase

Statistical Strategies for Randomized Controlled Clinical Trials to Detect Differential Onset of Action

Andrew C. Leon

Desvenlafaxine and Venlafaxine Exert Minimal In Vitro Inhibition of Human Cytochrome P450 and P-Glycoprotein Activities

Aram Oganesian, Adam D. Shilling, Ruth Young-Sciame, Judy Tran, Adiba Watanyar, Farooq Azam, John Kao, Louis Leung

Revisiting the Effectiveness of Standard Antidepressants in Bipolar Disorder: Are Monoamine Oxidase Inhibitors Superior?

Alan G. Mallinger, Michelle M. Barwell, Nancy DiazGranados, David A. Luckenbaugh, David J. Kupfer Brain Imaging

Recent-Onset Schizophrenia and Adolescent Cannabis Use: MRI Evidence for Structural Hyperconnectivity?

Bart D. Peters, Lieuwe de Haan, Erik-Jan Vlieger, Charles B. Majoie, Gerald J. den Heeten, Don H. Linszen 

Hypomania Induced by Escitalopram: 2 Case Reports

Ravi C. Sharma

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Psychopharmacology BULLETIN Newsletter

the advance newsletter of Psychopharmacology BULLETIN
Summary—Index of This Issue On-Press

• ORIGINAL RESEARCH
  EVIDENCE-BASED MEDICINE
  
  
  ORIGINAL RESEARCH: The Trials and Travails
  Atypical Antipsychotic Drugs and Diabetes in the US Adverse Event Database
  Bipolar-I Patient Characteristics
  PTSD Following Short-Term Paroxetine Treatment
  Aripiprazole in the Treatment of PTSD
  Memantine: An Open-Label Trial — OCD v. GAD
  
  Atypical Antipsychotic Drugs and Diabetes Mellitus in the US Food and Drug Administration AdverseEvent Database: A Systematic Bayesian Signal Detection Analysis—p.2
  Ross A. Baker, Andrei Pikalov, Quynh-Van Tran, Tatyana Kremenets, Ramin B. Arani, P. Murali Doraiswamy
  
  Bipolar-I Patient Characteristics Associated with Differences in Antimanic Medication Prescribing
  Alisa B. Busch, Richard G. Frank, Gary Sachs, Sharon-Lise T. Normand
  
  Neuropsychological Functioning in Patients with Posttraumatic Stress Disorder Following
  Short-Term Paroxetine Treatment
  Negar Fani, Noriyuki Kitayama, Ali Ashraf, Lai Reed, Nadeem Afzal, Farhan Jawed, J. Douglas Bremner
  
  An Open-Label Assessment of Aripiprazole in the Treatment of PTSD
  Sophie Robert, Mark B. Hamner, Valerie L. Durkalski, Mary W. Brown, Helen G. Ulmer
  
  Differential Efficacy of Memantine for Obsessive-Compulsive Disorder vs. Generalized Anxiety Disorder: An Open-Label Trial
  Jamie D. Feusner, Lauren Kerwin, Sanjaya Saxena, Alexander Bystritsky
  
  EVIDENCE-BASED MEDICINE: THE BOTTOM LINE
  Early Symptom Change Prediction of Remission in Depression Treatment
  Martin M. Katz, Adam L. Meyers, Apurva Prakash, Paula J. Gaynor, John P. Houston

Atypical Antipsychotic Drugs and Diabetes Mellitus in the US Food and
Drug Administration Adverse Event Database: A Systematic Bayesian Signal Detection Analysis

Prior literature suggests that the risk of diabetes-related adverse events (DRAEs) differs between
atypical antipsychotics. The present study evaluated the potential association between atypical antipsychotics or haloperidol and diabetes using data from the FDA AERS database.
Methods: Analysis of AERS data was conducted for clozapine, risperidone, olanzapine, quetiapine,
ziprasidone, aripiprazole or haloperidol with 24 DRAEs from the Medical Dictionary for Regulatory Activities using a Multi-item Gamma Poisson Shrinker (MGPS) data-mining algorithm. Using MGPS, adjusted reporting ratios (Empiric Bayes Geometric Mean or EBGM) and 90% confidence intervals
(CIs; EB05–EB95) were calculated to estimate the degree of drug–event association relative to all drugs
and events. Logistic regression odds ratios and 90% CIs (LR05–LR95) were calculated for diabetes
mellitus events.
Conclusions: In the AERS database, lower associations with DRAEs were seen for haloperidol, aripiprazole and ziprasidone, and higher associations were seen for olanzapine, risperidone, clozapine and quetiapine. Our findings support differential risk of diabetes across atypical antipsychotics, reinforcing the need for metabolic monitoring of patients taking antipsychotics.
Ross A. Baker PhD, MBA, Andrei Pikalov MD, PhD, Quynh-Van Tran PharmD, Tatyana Kremenets PhD, Ramin B. Arani PhD, P. Murali Doraiswamy MD
Psychopharmacology Bulletin. 2009;42(1):In Press.


Bipolar-I Patient Characteristics Associated with Differences in Antimanic Medication Prescribing

Second-generation antipsychotics offer more choice in antimanic pharmacologic treatment. Unclear though is whether they are expanding antimanic treatment, replacing mood stabilizers, or if/which patient characteristics influence prescribing choices. We studied the association between patient characteristics and patient-reported antimanic medication use upon entry in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).
Principal Observations: At study entry over 80% of participants reported receiving at least one antimanic medication; 73% a mood stabilizer specifically. Measures of psychiatric severity or complexity were more likely to be associated with differences in the drugs used; co-occurring medical conditions were not. Depressed states were associated with similar odds of antipsychotic monotherapy as elevated or mixed
states. Compared to whites, blacks had greater odds of entering on antipsychotic monotherapy relative to a mood stabilizer.
Conclusions: Despite increasing pharmacotherapy options, we found no evidence that over time more patients received antimanic medication. Not all prescribing differences were consistent with the medical literature. Also, blacks were more likely to receive antipsychotic monotherapy, even after adjusting for clinical characteristics. Future research examining provider characteristics that influence prescribing is needed.
Alisa B. Busch MD, Richard G. Frank MD, Gary Sachs MD, Sharon-Lise T. Normand MD
Psychopharmacology Bulletin. 2009;42(1):In Press.


Neuropsychological Functioning in Patients with Posttraumatic Stress Disorder Following Short-Term Paroxetine Treatment

A previous study found improvements in verbal declarative memory in patients with Posttraumatic Stress Disorder (PTSD) following one year of open-label paroxetine treatment. The purpose of the present study was to replicate prior findings and to extend the previous study by comparing the effects of paroxetine versus placebo on cognition in patients with PTSD.
Methods: Eighteen participants with PTSD underwent assessment of neuropsychological function, following which they were randomized to receive controlled-release (CR) paroxetine or placebo, given in a variable dose in a double-blind manner for three months. Neuropsychological testing was then repeated. Subjects who had received placebo were then treated with open-label paroxetine CR and re-assessed.
Results: Paroxetine CR treatment resulted in a significant increase in verbal declarative memory function in the group as a whole, as measured by the Wechsler Memory Scale-Revised, the Selective Reminding Test, and novel paragraph recall, and explicit recall of neutral words. Although we found patterns of improved test performance with paroxetine versus placebo treatment, these differences were not statistically significant.
Conclusion: These findings replicate an earlier finding that open label treatment with paroxetine CR is associated with improvements in verbal declarative memory function. The current study did not show a statistically significant difference between the effects of paroxetine and placebo on memory function, which may in part be related to our small sample size.
Negar Fani, MS, Noriyuki Kitayama, MD, Ali Ashraf, MD, Lai Reed, MBA, Nadeem Afzal, MD,
Farhan Jawed, MD, J. Douglas Bremner, MD
Psychopharmacology Bulletin. 2009;42(1):In Press.


An Open-Label Assessment of Aripiprazole in the Treatment of PTSD

Recent studies suggest that atypical antipsychotics may be effective augmentation strategies for the treatment of posttraumatic stress disorder (PTSD). Limited data were available on the newest agent, aripiprazole, so we aimed to evaluate its efficacy and tolerability in the treatment of PTSD.
Results: All 17 subjects were male, with an average age of 57 years. Total CAPS scores decreased from 78.2 (SD=17.8) at baseline to 60.0 (23.5) at study end (p=0.002). Re-experiencing (CAPS-B) and avoidance/numbing symptoms (CAPS-C) were significantly improved, and trend level reductions were observed in hyperarousal symptoms (CAPS-D). Fifty-three percent (9/17) were considered responders, as defined by a decrease in total CAPS scores of at least 20%. Reductions in the Positive and Negative Symptom Scale (PANSS) total score and positive and general psychopathology subscale scores were statistically
significant. The final average dose of aripiprazole was 13.06 (SD=6.45) mg daily. Nine patients discontinued because of side effects. The most common adverse events consisted of gastro-intestinal disturbances,
sedation, and psychomotor activation. Tolerability was improved with lower starting doses (e.g. 5 mg daily) and slow titration.
Conclusions: Addition of aripiprazole to ongoing treatment further reduced PTSD symptoms in military veterans with severe PTSD. These preliminary findings await confirmation in randomized, controlled trials.
Sophie Robert, PharmD, Mark B. Hamner, MD, Valerie L. Durkalski, PhD, MPH, Mary W. Brown, RN, Helen G. Ulmer MSN
Psychopharmacology Bulletin. 2009;42(1):In Press.


Differential eEfficacy of Memantine for Obsessive-Compulsive Disorder vs. Generalized Anxiety Disorder: An Open-Label Trial

A substantial proportion of patients with obsessive-compulsive disorder (OCD) and generalized anxiety disorder (GAD) do not respond to, or are intolerant of, standard treatments. Additional treatment strategies are therefore necessary. Excessive action of the excitatory neurotransmitter glutamate may play a role in the pathophysiology of OCD and possibly GAD. Memantine blocks the excitatory action of glutamate at the
N-methyl-D-aspartate (NMDA) receptor under pathological conditions. The objective of this study was to compare the efficacy and safety of memantine in OCD and GAD, and to probe relative effects on OCD and anxiety symptoms.
Results: The OCD group experienced a significant mean 40.6% reduction in YBOCS scores at endpoint (t=4.75, p<0.001). Three of 10 of OCD subjects were classified as responders, although 7 of 10 experienced a ?45% reduction in YBOCS scores. The GAD group experienced a mean 22.4% reduction in HARS scores (t=3.56, p=0.012). None of the GAD subjects were responders, and none experienced a ?50% reduction in HARS scores. Memantine was well tolerated, and there were no serious adverse effects.
Conclusions: These results suggest that memantine may have preferential efficacy in the treatment of OCD versus GAD. These preliminary findings warrant larger, placebo-controlled studies in OCD.
Jamie D. Feusner, MD, Lauren Kerwin, BA, Sanjaya Saxena, MD, Alexander Bystritsky, MD, PhD
Psychopharmacology Bulletin. 2009;42(1):In Press.


Early Symptom Change Prediction of Remissionin Depression Treatment
This study investigated hypothesized early symptom changes as differential predictors of long-term remission for duloxetine and escitalopram.

Principal Observations: For both drugs, 2-week HAMD-17 improvement on all symptom subscales (except sleep for duloxetine) significantly predicted remission with ORs >2.0. In a follow-up analysis, specific subscale items for psychological anxiety, motor retardation, and suicidality significantly predicted remission for duloxetine, and psychological and somatic anxiety for escitalopram. Notably, high NPVs on the Maier subscale indicated that a lack of 20% improvement on the “core” depression factor by Week 2 was highly predictive of unsuccessful treatment outcome over 8 months.
Conclusions: In accord with hypotheses, early symptom changes were specific to treatment, with early response in the core depression factor (Maier subscale), anxiety, and motor activity for duloxetine, and core factor and anxiety for escitalopram. Lack of early response in depression symptom subscales was highly predictive of lack of sustained remission.
Martin M. Katz, PhD, Adam L. Meyers, MS, Apurva Prakash, BA, Paula J. Gaynor, PhD,
John P. Houston, MD
Psychopharmacology Bulletin. 2009;42(1):In Press.

• ORIGINAL RESEARCH • EVIDENCE-BASED MEDICINE
• GENERAL PSYCHIATRY

Seroquel Once a Day: A Randomized, Double-Blind, Placebo-Controlled Study—
This 6-week, randomized, double-blind study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia resulting in the efficacy of quetiapine XR versus placebo in patients with schizophrenia was demonstrated for quetiapine XR 600 mg/day.
Jean-Pierre Lindenmayer, David Brown, Sherry Liu, Martin Brecher, and Didier Meulien, on behalf of the Study 41 investigators

New Patient-Rated Symptom Scale for GAD—
The majority of clinical outcome assessments developed for generalized anxiety disorder (GAD) may not efficiently and sensitively reflect heterogeneous symptom clusters from a patient perspective. The Patient-Rated Troubling Symptoms Scale for Anxiety (PaRTS-A) instrument was developed to provide an individualized assessment of patient relevant GAD symptoms.
Gahan J. Pandina, Dennis A. Revicki, Leah Kleinman, Ibrahim Turkoz, Jasmanda Wu, Ramy Mahmoud, Georges M. Gharabawi

Take Your Corners: Benzodiazepines vs. Newer Antidepressants in Anxiety Disorders —
The investigators performed a systematic review of controlled trials on anxiety disorders treatment (generalized anxiety disorder, panic disorder, social phobia and post-traumatic stress disorder) published from 1980 to 2006, and identified trials comparing the efficacy of benzodiazepines with that of antidepressants.
Patricia Berney, Demian Halperin, Rodrigo Tango, Isabelle Daeniker-Dayer, Pierre Schulz

REVAMP: Augmenting Meds with Psychotherapy—Rationale & Design—
This report presents the rationale, design, and baseline sample characteristics for the REVAMP study. This project is a multisite clinical trial designed to evaluate the efficacy of augmenting state-of-the-art pharmacotherapy with psychotherapy in chronically depressed patients who fail to respond or respond incompletely to an initial trial of antidepressant medication.
Madhukar H. Trivedi, James H. Kocsis, Michael E. Thase, David W. Morris, Stephen R. Wisniewski, Andrew C. Leon, Alan J. Gelenberg, Daniel N. Klein, George Niederehe, Alan F. Schatzberg, Philip T. Ninan, Martin B. Keller

Bipolar REDUX: Stimulant-Associated Mania/Hypomania in Bipolar Patients—
Stimulants have been used to treat ADHD or augment bipolar depression treatment in patients with bipolar disorder. However, the effects of stimulant treatment in BD patients have been insufficiently studied. To date, this is the largest study on amphetamine/methylphenidate treatment and associated mania/hypomania in BD patients.
Aliza P. Wingo, S. Nassir Ghaemi

The 500—STEP-BD and the Correlates of Functioning—
The study included the first 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Its primary aim was to describe unique correlates of functioning in bipolar disorder.
Laszlo Gyulai, Mark S. Bauer, Lauren B. Marangell, Ellen B. Dennehy, Michael E. Thase, Michael W. Otto, Hongwei Zhang, Stephen R. Wisniewski, David J. Miklowitz, Mark H. Rapaport, Claudia F. Baldassano, and Gary S. Sachs, for the STEP-BD Investigators

Newsletter No. 3, 2008 www.psychopharmbulletin.com Volume 41 • Number 3 • 2008

Psychopharmacology BULLETIN Newsletter

the advance newsletter of Psychopharmacology BULLETIN
Summary—Index of This Issue On-Press

• ORIGINAL RESEARCH
• EVIDENCE-BASED MEDICINE

Cocaine is a Major Risk Factor for Antipsychotic Induced Akathisia, Parkinsonism and Dyskinesia

abstract ~ Objective: To assess the relative contribution of different drugs of abuse to extrapyramidal side effects (EPS) of antipsychotic drugs. Method: 106 consecutively contacted or admitted male patients in the Psychiatric Center of Surinam (PCS) with schizophrenia or a related disorder were included. Prevalence and severity of EPS were measured with the Unified Parkinson’s Disease Rating Scale (UPDRS), the Abnormal Involuntary Movement rating Scale (AIMS), the Barnes Akathisia Rating Scale (BARS) and the Dystonia rating scale. Recent use of cigarettes, cannabis, alcohol, and cocaine were assessed. Standard multiple regression analyses were used to evaluate the relative contribution of above-mentioned drugs of abuse controlled for milligrams haloperidol equivalent a day and use of anticholinergic medication. Results: Recent cocaine use was significantly associated with severity of dyskinesia (p 5 0.001), parkinsonism (p 5 0.007), and akathisia (p , 0.001) (n 5 106). Conclusions: Recent cocaine use is a major risk factor for antipsychotic induced EPS.
Arija Maat, Annemarie Fouwels, Lieuwe de Haan, Psychopharmacology Bulletin. 2008;41(3):5–10.

The Efficacy and Tolerability of Once-Daily Extended Release Quetiapine Fumarate in Hospitalized Patients with Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Study

abstract ~ Objectives: This study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia. Methods: In this 6-week, randomized, double-blind study (5077IL/0041) patients were randomized to receive quetiapine XR (300, 600, or 800 mg/day), quetia- pine fumarate immediate release (quetiapine IR) [300 or 600 mg/day], or placebo. Primary endpoint was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Day 42. Secondary variables included PANSS response rate at Day 42 ($30% decrease in PANSS total score from baseline) and Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures. Results: Of 532 patients randomized, 222 (41.7%) completed the study. Improvements in PANSS total scores from baseline to Day 42 across treatment groups were: quetiapine XR 300 mg/day 25.01, 600 mg/day 213.01 and 800 mg/day 211.17, quetiapine IR 300 mg/day 29.42 and 600 mg/day 26.97, and placebo 25.19; the difference in change was statistically significant only for quetiapine XR 600 mg/day (p 5 0.033). There were no statistically significant differences between active treatment groups and placebo for PANSS response rates. Several post hoc analyses were conducted to explain the study efficacy outcome but these were inconclusive. Quetiapine XR was generally well tolerated with the majority of AEs being mild or moderate in intensity and no unexpected AEs. Conclusions: Superior efficacy of quetiapine XR versus placebo in patients with schizophrenia was demonstrated for quetiapine XR 600 mg/day. The safety and tolerability profile of quetiapine XR was similar to that of quetiapine IR.
Jean-Pierre Lindenmayer, David Brown, Sherry Liu, Martin Brecher, and Didier Meulien, on behalf of the Study 41 inv,estigators, Psychopharmacology Bulletin. 2008;41(3):11-35.

A Major Change of Prescribing Pattern in Absence of Adequate Evidence: Benzodiazepines Versus Newer Antidepressants in Anxiety Disorders

abstract ~ We performed a systematic review of controlled trials on anxiety disorders treatment (generalized anxiety disorder, panic disorder, social phobia and post-traumatic stress disorder) published from 1980 to 2006, and identified trials comparing the efficacy of benzodiazepines (BZD) with that of antidepressants, in particular comparisons between BZD and newer antidepressants. Among 969 publications, 274 double-blind randomized controlled studies remained after using our exclusion criteria. These studies comprised altogether 439 comparisons. There were in total 23 comparisons of antidepressants versus BZD. Among these, 22 compared the efficacy of older antidepressants versus BZD, whereas only 1 concerned the comparison of a newer antidepressant versus BZD. It showed comparable efficacy between venlafaxine and diazepam in the treatment of generalized anxiety disorder. Our study shows that the major change of prescribing pattern from BZD to newer antidepressants in anxiety disorders has occurred in absence of comparative data of high level of proof.
Patricia Berney, Demian Halperin, Rodrigo Tango, Isabelle Daeniker-Dayer, Pierre Schulz, Psychopharmacology Bulletin. 2008;41(3):39–47.

Developing and Testing Adaptive Treatment Strategies Using Substance-Induced Psychosis
as an Example

Abstract ~ Decisions concerning treatment changes pervade the management of chronic psychiatric disorders that resist definitive cure, yet empirical evidence for the comparative clinical effectiveness of treatment strategies remains underdeveloped. In this paper we exploit the example of psychosis following substance use to illustrate some new developments in clinical trials design that can provide the most solid evidence base for defining successful strategies. The intent is to explore the strengths and limitations of the methodological approach through a meaningful clinical example, with an emphasis on concepts and issues. Both methodology and clinical science are overviewed.
Ree Dawson, Alan I. Green, Robert E. Drake, Thomas H. McGlashan, Bella Schanzer, Philip W. Lavori Psychopharmacology Bulletin. 2008;41(3):51–67.

Psychometric Evaluation of a Patient-Rated Troubling Symptom Scale for Generalized Anxiety Disorder Clinical Trials

ABSTRACT ~ Background: The majority of clinical outcome assessments developed for generalized anxiety disorder (GAD) may not efficiently and sensitively reflect heterogeneous symptom clusters from a patient perspective. The Patient-Rated Troubling Symptoms Scale for Anxiety (PaRTS-A) instrument was developed to provide an individualized assessment of patient relevant GAD symptoms. Objective: The objective of this analysis was to evaluate the psychometric characteristics of the PaRTS-A. Methods: Data were taken from a 6-week clinical trial evaluating the efficacy of adjunctive risperidone therapy in GAD patients undergoing standard treatment. Patients completed the PaRTS-A, the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS) as well as impressions of improvement. Physicians completed the Hamilton Anxiety Rating Scale (HAM-A). A instrument characteristics were assessed through statistical tests of reliability, reproducibility, construct and discriminant validity, and responsiveness. Results: In the item response theory (IRT) analysis, the PaRTS-A items fit into a single construct of anxiety. Internal consistency reliability exceeded 0.70. The PaRTS-A total score was moderately correlated with the Q-LES-Q and the SDS. The PaRTS-A distinguished between patients with high and low HAM-A scores (p,0.001). The PaRTS-A was responsive to changes in clinical status and the minimal important difference was identified. Conclusion: The PaRTS-A provides a unique patient-rated assessment of anxiety symptoms. The instrument may provide clinicians with useful information regarding patient’s self-rated anxiety disorder symptoms and the hierarchy of symptoms that they considered most troubling. Our analysis suggests that the PaRTS-A is an internally consistent, valid, and responsive instrument that may be a beneficial adjunct to other instruments in clinical trials.
Gahan J. Pandina, Dennis A. Revicki, Leah Kleinman, Ibrahim Turkoz, Jasmanda Wu, Ramy Mahmoud, Georges M. Gharabawi, Psychopharmacology Bulletin. 2008;41(3):68–90.

Placebo Response in Depression: A Perspective for Clinical Practice

abstract ~ Practicing clinicians appreciate that depression is not an easy disorder to treat and manage. Despite the plethora of new treatments—both pharmacological and non pharmacological—that has flooded the market in the past years, we are still nowhere close to obtaining full symptom relief for all patients and eradicating the morbidity and mortality associated with depression.

In this context, recent methodological research, concentrating on the effectiveness of antidepressants has raised doubts about their therapeutic index. Because of obtuseness of the methodology and biased interpretations, we are submitting this perspective to clinicians so that they can appreciate some of the deficits of the recent research publications. For the practicing clinician, the best available data suggest that clinically depressed patients warrant treatment and the most robust available body of data (published and unpublished) would favor the use of antidepressants.
Arif Khan, Shirin Khan, Psychopharmacology Bulletin. 2008;41(3):91–98.

Newsletter No. 2, 2008        www.psychopharmbulletin.com           Volume 41 • Number 2 • 2008  

Psychopharmacology BULLETIN Newsletter

the advance newsletter of Psychopharmacology BULLETIN
Summary—Index of This Issue On-Press

• ORIGINAL RESEARCH
• EVIDENCE-BASED MEDICINE

Are SNRIs More Effective than SSRIs? A Review of the Current State of the Controversy—p.2
The selective serotonin reuptake inhibitors (SSRI) are widely considered to be the first choice for antidepressant therapy. There is evidence from inpatient studies dating to 1986, however, suggesting that the tricyclic antidepressant clomipramine, which inhibits reuptake of both serotonin and norepinephrine, may have greater efficacy than some SSRIs for severe depression. There is controversy whether the newer, better tolerated, and safer serotonin norepinephrine reuptake inhibitors (SNRIs; venlafaxine, duloxetine, and—in some countries—milnacipran and desvenlafaxine) are more efficacious than SSRIs.
Michael E. Thase, MD

Criteria for Defining Symptomatic and Sustained Remission in Bipolar I Disorder: a Post-Hoc Analysis of a 26-Week Aripiprazole Study—pp.2/3
In aripiprazole-treated patients, symptomatic remission rates were consistent at weeks 8, 16, and 26; sustained remission rates at week 8 were retained at weeks 16 and 26. The authors concluded that when discerning an operational definition of remission in patients with a recent manic or mixed episode, the YMRS 7 criterion and sustaining this criterion for 8 weeks can be a useful clinical or research tool for assessing clinical recovery.
Prakash S.Masand, MD, James Eudicone, MS, Andrei Pikalov, MD, PhD, Robert D.McQuade, PhD, Ronald N.Marcus, MD, Estelle Vester-Blokland, MD, and Berit X. Carlson, PhD

Bipolar I Depression Outpatient Treatment Quality and Costs in Usual Care Practice —p.3
Fifty-six percent of the patients diagnosed with bipolar I depression received both an antimanic agent and psychotherapy during their acute phase depression treatment, whereas 15 percent received an antimanic agent without psychotherapy. Eighteen to 28 percent of spending was accounted for by treatment that did not meet the standards of practice guidelines—and two-thirds to three-quarters of it was treatment that included an antidepressant without anantimanic agent (care that is advised by guidelines).
Alisa B.Busch, MD, MS, Richard G.Frank, PhD, and Gary Sachs, MD

Addressing Methodological Issues in Studying Antidepressant Onset Efficacy Using Prespecified Sensitivity Analyses—p.4
Assessing antidepressant onset efficacy presents substantial methodological challenges. Most assessments of onset efficacy are based on post hoc analyses. This article presents a case study of a prospectively designed trial to compare antidepressant onset efficacy. The authors concluded that prospectively designed studies (as opposed to retrospective comparisons) can be implemented and sensitivity analyses can be used to address concerns regarding assumptions and arbitrary decisions.
Ilya Lipkovich, PhD, Craig H.Mallinckrodt, PhD, Apurva Prakash, BA, and Andrew A.Nierenberg, MD

Are SNRIs More Effective than SSRIs? A Review of the Current State of the Controversy

Within 5 years of the introduction of fluoxetine in late 1987, the selective serotonin reuptake inhibitor (SSRI) class of antidepressants had supplanted the tricyclic antidepressants (TCA) as the first-line pharmacotherapy for major depressive disorder throughout much of the industrialized world. There is no doubt that pharmaceutical marketing played a large role in the rapid ascendance of the SSRI class (i.e., the TCAs were no longer patented drugs and, as such, were not marketed, whereas the SSRIs were vigorously promoted). Nevertheless, the SSRIs had a number of real advantages over the TCAs, including being easier to prescribe, better tolerated, and much safer in overdose.

The controversy about the relative efficacy of different types of antidepressants continues in part because there are numerous problems that limit the sensitivity of randomized controlled trials (RCTs) to detect efficacy differences between active antidepressants. Although there is only a partial solution to the problem of inadequately powered studies, meta-analysis permits quantitative synthesis of results from a group of relevant RCTs comparing various types of antidepressants. Meta-analyses of RCTs comparing the SSRIs with two of the SNRIs—venlafaxine and duloxetine—may have greater efficacy, though there is essentially no evidence that either of these drugs is superior to escitalopram. For venlafaxine, which is so far the most extensively studied SNRI, the magnitude of this advantage versus SSRIs other than escitalopram is modest in unselected patient groups (NNT values range between 10 and 15) and appears to be greater versus fluoxetine than other members of the class. For duloxetine, the advantage versus paroxetine and fluoxetine appears to be limited to more severely depressed patients, and confidence in this finding is limited by the fact that the studies used minimum therapeutic doses of SSRIs. With respect to the other two SNRIs, there are no data yet available to evaluate the relative efficacy of desvenlafaxine. Available data suggest that there is no efficacy advantage for milnacipran. The latter finding, coupled with the failure of both venlafaxine and duloxetine to significantly separate from escitalopram, highlights the limited clinical utility of comparisons across particular classes of medication.
Michael E. Thase, MD. Psychopharmacology Bulletin. 2008;41(2):In Press.


Criteria for Defining Symptomatic and Sustained Remission in Bipolar I Disorder:
a Post-Hoc Analysis of a 26-Week Aripiprazole Study (Study CN138-010)
   
Bipolar I disorder is a lifelong episodic illness that is characterized by manic or depressive episodes followed by symptom-free periods. Remission is a key goal after treating an acute episode of bipolar I disorder; however, there are no established definitions to measure clinical recovery, and recurrence occurs frequently in this patient population. Further understanding is needed for the correlation between attaining remission at a specific time point and maintaining sustained remission during treatment. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) examined time to recurrence of mania, hypomania, mixed state, or a depressive episode in subjects who were symptomatic at study entry but subsequently achieved recovery and determined that recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery.

In conclusion, the use of more rigorous criteria to define symptomatic or sustained remission for fewer patients with bipolar I disorder and may be more useful in assessing remission in clinical trials compared with the standard criterion. These data confirm that sustaining remission is challenging and there is fluctuation in symptomatic stability in the bipolar population. Sustained remission for 8 weeks appears to be a good predictor for continued remission, as shown by the high retention rate of sustained remission at weeks 16 and 26 in aripiprazole-treated patients with bipolar I disorder using either standard or more rigorous criteria. The more rigorous YMRS criterion of 7 also appears to be a more discriminative indicator for the potential to relapse than the standard criterion (YMRS 12). When discerning an operational definition of remission in patients with a recent manic or mixed episode, the YMRS 7 criterion and sustaining this criterion for 8 weeks can bea useful clinical or research tool for assessing clinical recovery.
Prakash S. Masand, MD, James Eudicone, MS, Andrei Pikalov, MD, PhD, Robert D.McQuade, PhD, Ronald N. Marcus, MD, Estelle Vester-Blokland, MD, and Berit X. Carlson, PhD.
Psychopharmacology Bulletin. 2008;41(2):In Press.


Bipolar I Depression Outpatient Treatment Quality and Costs in Usual Care Practice
   
Bipolar disorder treatment is complicated and evolving. Maximizing lithium therapy has historically been recommended as the first-line treatment. More recently, other agents such as lamotrigine, quetiapine, and a combination of olanzapine and fluoxetine have begun to demonstrate efficacy. The role of antidepressants in the treatment of bipolar depression has been uncertain, including concerns that they may induce mania or mood cycling, thus worsening the course of illness. And while practice guidelines have long recommended psychotherapy in the treatment of bipolar depression, only recently have specific psychotherapies been shown to demonstrate efficacy in randomized controlled trials.
   
This study provides new information regarding the longitudinal quality and costs of care for bipolar depression. A sizable proportion of the treatment dollars spent on persons with new episodes of bipolar I depression went toward care that did not meet the standards of practice guidelines—and much of that represented treatment advised against by guidelines because it could worsen the course of the illness. This observation provides an important clinical and policy opportunity to redirect resources to be consistent with practice guideline standards. This study also provides evidence that when conducting studies using administrative data, hospital admissions alone do not adequately describe affective instability for patients with bipolar disorder, since much switch in polarity occurred in the outpatient setting. This knowledge is useful to researchers and policy makers when using administrative data in conducting quality assessment for systems of care.
Alisa B. Busch, MD, MS, Richard G. Frank, PhD, and Gary Sachs, MD.
Psychopharmacology Bulletin. 2008;41(2):In Press.







Addressing Methodological Issues in Studying Antidepressant Onset Efficacy Using Prespecified Sensitivity Analyses
   
Antidepressant medications typically exhibit a delay of at least 2 weeks following the start of therapy before patients experience clinically relevant improvement. During this latency period, patients remain symptomatic and functionally impaired,  with an associated risk for suicide and morbidity, a prolonged reduction in quality of life, and a continued loss of work productivity. In contrast, antidepressants with a more rapid onset of action may offer potential benefits. Therefore, the development of new pharmacotherapies, with rapid onset of action, is an active area of research.
   
Studying onset of antidepressant action poses formidable methodological challenges.  This article illustrates,  however, that prospectively designed studies (as opposed to retrospective comparisons) can be implemented and that sensitivity analyses can be used to address concerns regarding assumptions and arbitrary decisions. Based on these results, we offer the following recommendations when developing future studies to assess antidepressant onset efficacy: A unidimensional subscale assessing core depressive symptoms (such as the HAMD Maier subscale) may be able to better distinguish differing drug effects when compared with the multidimensional HAMD Total score. A traditional assessment schedule (weekly visits) is adequate for assessing treatment group differences when used in conjunction with a categorical repeated measures analytic approach and does not increase the burden of implementing the study, the study cost, or the risk of increased placebo response (as would be more likely for a study using more frequent study visits). Onset of action can be based on 20–30% initial improvement, and the additional requirement that the improvement be sustained or exceeded throughout acute treatment may better differentiate drug effects from placebo.
Ilya Lipkovich, PhD, Craig H.Mallinckrodt, PhD, Apurva Prakash, BA, and Andrew A. Nierenberg, MD
Psychopharmacology Bulletin. 2008;41(2):In Press.