Abstracts: for Psychopharmacology Treatment-Resistant Disorders

van Apeldoorn FJ, Timmerman ME, Mersch PP, van Hout WJ, Visser S, van Dyck R, den Boer JA.

Objective: To establish the long-term effectiveness of 3 treatments for DSM-IV panic disorder with or without agoraphobia: cognitive-behavioral therapy (CBT), pharmacotherapy using a selective serotonin reuptake inhibitor (SSRI), or the combination of both (CBT + SSRI). As a secondary objective, the relationship between treatment outcome and 7 predictor variables was investigated. Method: Patients were enrolled between April 2001 and September 2003 and were randomly assigned to treatment. Academic and nonacademic clinical sites participated. Each treatment modality lasted 1 year. Pharmacotherapists were free to choose between 5 SSRIs currently marketed in The Netherlands. Outcome was assessed after 9 months of treatment (posttest 1), after discontinuation of treatment (posttest 2), and 6 and 12 months after treatment discontinuation (follow-up 1 and follow-up 2). Results: In the sample (N = 150), 48% did not suffer from agoraphobia or suffered from only mild agoraphobia, while 52% suffered from moderate or severe agoraphobia. Patients in each treatment group improved significantly from pretest to posttest 1 on the primary outcome measures of level of anxiety (P < .001), degree of coping (P < .001), and remitter status (P < .001), as well as on the secondary outcome measures of depressive symptomatology (P < .001), and from pretest to posttest 2 for health-related quality of life (P < .001). Gains were preserved from posttest 2 throughout the follow-up period. Some superiority of CBT + SSRI and SSRI as compared with CBT was observed at posttest 1. However, at both follow-ups, differences between treatment modalities proved nonsignificant. Client satisfaction appeared to be high at treatment endpoint, while patients receiving CBT + SSRI appeared slightly (P < .05) more satisfied than those receiving CBT only. Conclusions: No fall-off in gains was observed for either treatment modality after treatment discontinuation. SSRIs were associated with adverse events. Gains produced by CBT were slower to emerge than those produced by CBT + SSRI and SSRI, but CBT ended sooner.

George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, Sackeim HA.

Context: Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions. Objective: To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. Design: Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers. Setting: Four US university hospital clinics. Patients: Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder. Intervention: We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. Main Outcome Measure: In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. Results: Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32–13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). Conclusion: Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.

Binder EB, Owens MJ, Liu W, Deveau TC, Rush AJ, Trivedi MH, Fava M, Bradley B, Ressler KJ, Nemeroff CB

Context: The corticotropin-releasing factor (CRF, or corticotropin-releasing hormone) and arginine vasopressin systems have been implicated in the pathophysiology of anxiety and depressive disorders and response to antidepressant treatment. Objective: To study the association of genetic variants in 10 genes that regulate the CRF and arginine vasopressin systems with treatment response to citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample (N = 1768). Design: Pharmacogenetic association study derived from the STAR*D study, a multicenter, prospective, open, 12-week effectiveness trial. Setting: Outpatient primary care and psychiatric clinics. Patients Individuals with nonpsychotic major depressive disorder for whom DNA was available who were subsequently treated with citalopram hydrobromide for 4 to 12 weeks. Intervention Flexible doses of citalopram. Main Outcome Measure Association of genetic polymorphisms in genes encoding the CRF system with response and remission to citalopram treatment at exit visit. Results: One single-nucleotide polymorphism (SNP) (rs10473984) within the CRHBP locus showed a significant association with both remission (P = 6.0 × 10(−6); corrected, P = .0026) and reduction in depressive symptoms (P = 7.0 × 10(−7); corrected, P = .00031) in response to citalopram. The T allele of this SNP was associated with poorer treatment outcome in 2 of the 3 ethnic subsamples (African American and Hispanic), despite large differences in minor allele frequency. This association was more pronounced in patients with features of anxious depression (P = .008). The nonresponse allele was shown to be associated with overall higher plasma corticotropin levels and more pronounced dexamethasone suppression of corticotropin. Conclusions: These data indicate that a genetic variant within the CRHBP locus affects response to citalopram in African American and Hispanic patients, suggesting a role for this gene and for the CRF system in antidepressant treatment response.

Blanco C, Heimberg RG, Schneier FR, Fresco DM, Chen H, Turk CL, Vermes D, Erwin BA, Schmidt AB, Juster HR, Campeas R, Liebowitz MR.

Context: Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment. Objective: To determine whether combined medication and cognitive behavioral treatment is superior to either monotherapy or pill placebo. Design: Randomized, double-blind, placebo-controlled trial. Setting: Research clinics at Columbia University and Temple University. Participants: One hundred twenty-eight individuals with a primary DSM-IV diagnosis of social anxiety disorder. Interventions: Cognitive behavioral group therapy (CBGT), phenelzine sulfate, pill placebo, and combined CBGT plus phenelzine. Main Outcome Measures: Liebowitz Social Anxiety Scale and Clinical Global Impression (CGI) scale scores at weeks 12 and 24. Results: Linear mixed-effects models showed a specific order of effects, with steepest reductions in Liebowitz Social Anxiety Scale scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test = 4.97, P < .01). The CGI response rates in the intention-to-treat sample at week 12 were 9 of 27 (33.3%) (placebo), 16 of 34 (47.1%) (CBGT), 19 of 35 (54.3%) (phenelzine), and 23 of 32 (71.9%) (combined treatment) (chi(2)(1) = 8.76, P < .01). Corresponding remission rates (CGI = 1) were 2 of 27 (7.4%), 3 of 34 (8.8%), 8 of 35 (22.9%), and 15 of 32 (46.9%) (chi(2)(1) = 15.92, P < .01). At week 24, response rates were 9 of 27 (33.3%), 18 of 34 (52.9%), 17 of 35 (48.6%), and 25 of 32 (78.1%) (chi(2)(1) = 12.02, P = .001). Remission rates were 4 of 27 (14.8%), 8 of 34 (23.5%), 9 of 35 (25.7%), and 17 of 32 (53.1%) (chi(2)(1) = 10.72, P = .001). Conclusion: Combined phenelzine and CBGT treatment is superior to either treatment alone and to placebo on dimensional measures and on rates of response and remission.

Aberg K, Adkins DE, Bukszár J, Webb BT, Caroff SN, Miller del D, Sebat J, Stroup S, Fanous AH, Vladimirov VI, McClay JL, Lieberman JA, Sullivan PF, van den Oord EJ.

Background: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. Methods: We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia. Results: Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 × 10(−10) and p = 3.8 × 10(−7), respectively, and one for AIMS, rs7669317 with p = 7.7 × 10(−8), reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. Conclusions: Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.

Otto MW, Tolin DF, Simon NM, Pearlson GD, Basden S, Meunier SA, Hofmann SG, Eisenmenger K, Krystal JH, Pollack MH.

Background: Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders. Enhancement of cognitive-behavior therapy with d-cycloserine (DCS) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder. Method: This is a randomized, double-blind, placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg d-cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy. Randomized participants were 31 outpatients meeting DSM-IV criteria for panic disorder with or without agoraphobia, who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations (interoceptive exposure) but also including informational, cognitive, and situational exposure interventions. Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5. The primary outcome measures were the Panic Disorder Severity Scale (PDSS) and Clinicians' Global Impressions of Severity. Results: Results indicated large effect sizes for the additive benefit of d-cycloserine augmentation of cognitive-behavior therapy for panic disorder. At posttreatment and 1 month follow-up, participants who received d-cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinically significant change status (77% vs. 33%). There were no significant adverse effects associated with DCS administration. Conclusions: This pilot study extends support for the role of d-cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder.

Simon NM, Otto MW, Worthington JJ, Hoge EA, Thompson EH, Lebeau RT, Moshier SJ, Zalta AK, Pollack MH.

Background: More data are needed to guide next-step interventions for panic disorder refractory to initial intervention. Method: This 24-week randomized clinical trial (RCT) enrolled 46 patients with DSM-IV-defined panic disorder from November 2000 to April 2005 and consisted of 3 phases. Patients who failed to meet remission criteria were eligible for randomization in the next treatment phase. Phase 1 was a 6-week lead-in with open-label sertraline flexibly dosed to 100 mg (or escitalopram equivalent) to prospectively define treatment refractoriness (lack of remission). Phase 2 was a 6-week double-blind RCT of (1) increased-dose selective serotonin reuptake inhibitor (SSRI) versus (2) continued SSRI plus placebo. Phase 3 was a 12-week RCT of added cognitive-behavioral therapy (CBT) compared to “medication optimization” with SSRI plus clonazepam. Primary endpoints were remission and change in Panic Disorder Severity Scale (PDSS) score in the intent-to-treat sample in each phase. Results: In phase 1, 20.5% (8/39) of the patients achieved remission, and only baseline severity predicted endpoint PDSS score (beta [SE] = 1.04 [0.15], t = 6.76, P < .001). In phase 2, increasing the SSRI dose did not result in greater improvement or remission rates (placebo 15% [n = 2] vs increased dose 9% [n = 1]: Fisher exact test P = NS). In phase 3, remission was minimal (medication optimization = 11% [n = 1]; CBT = 10% [n = 1]), with a lack of group difference in PDSS score reduction (t(17) = 0.51, P > .60) consistent with a small effect size (d = 0.24). Conclusions: Although power was limited and larger studies are needed, we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose. Further, augmentation with CBT or medication optimization with clonazepam augmentation in nonremitted panic after 12 weeks of an SSRI did not differ, suggesting that both are reasonable next-step options. However, low overall remission rates in this comorbid refractory population suggest that better predictors of response to specific treatments over time and additional interventions are needed.

Yood MU, DeLorenze G, Quesenberry CP Jr, Oliveria SA, Tsai AL, Willey VJ, McQuade R, Newcomer J, L'Italien G.

Purpose: The purpose of this study was to examine the association between atypical antipsychotics, including the newer agents, aripiprazole and ziprasidone, and newly treated diabetes, using the largest post-marketing cohort of patients exposed to these newer treatments that has been studied to date. Methods: Identified two overlapping cohorts-a simple cohort (all antipsychotic users) and an inception cohort (new users of antipsychotics)-using automated data from three United States sites (60.4 million covered lives). Patients exposed to antipsychotics > or = 45 days were identified and followed for incident diagnoses of treated diabetes. Data analysis accounted for drug switching and non-consistent drug use. Results: In the 55 287-member inception cohort, 357 cases of newly treated diabetes were identified. Compared with current use of typical antipsychotics, current users of aripiprazole (adjusted hazard ratio (aHR) 0.93, 95% confidence interval (CI) 0.50–1.76), quetiapine (aHR 1.04, 95%CI, 0.67–1.62), risperidone (aHR 0.85, 95%CI, 0.54–1.36) and ziprasidone (aHR 1.05, 95%CI, 0.54–2.08) had similar low risk of diabetes. Patients exposed to olanzapine had an increased risk of diabetes (aHR 1.71, 95%CI, 1.12–2.61), and although the effect estimate is imprecise, clozapine-exposed patients had a trend towards an elevated hazard ratio (aHR 2.58, 95%CI, 0.76–8.80). Results for the simple cohort were similar. Conclusions: Relative to typical antipsychotics, aripiprazole, ziprasidone, risperidone and quetiapine were not associated with an increased risk of diabetes; olanzapine and clozapine were associated with an increased risk. This analysis constitutes the largest post-marketing pharmacoepidemiologic study to date that includes the newer agents.

Schutter DJ.

Background: For more than a decade high-frequency repetitive transcranial magnetic stimulation (rTMS) has been applied to the left dorsolateral prefrontal cortex (DLPFC) in search of an alternative treatment for depression. The aim of this study was to provide an update on its clinical efficacy by performing a meta-analysis involving double-blind sham-controlled studies. Method: A literature search was conducted in the databases PubMed and Web of Science in the period between January 1980 and November 2007 with the search terms ‘depression’ and ‘transcranial magnetic stimulation’. Thirty double-blind sham-controlled parallel studies with 1164 patients comparing the percentage change in depression scores from baseline to endpoint of active versus sham treatment were included. A random effects meta-analysis was performed to investigate the clinical efficacy of fast-frequency rTMS over the left DLPFC in depression. Results: The test for heterogeneity was not significant (QT=30.46, p=0.39). A significant overall weighted mean effect size, d=0.39 [95% confidence interval (CI) 0.25–0.54], for active treatment was observed (z=6.52, p<0.0001). Medication resistance and intensity of rTMS did not play a role in the effect size. Conclusions: These findings show that high-frequency rTMS over the left DLPFC is superior to sham in the treatment of depression. The effect size is robust and comparable to at least a subset of commercially available antidepressant drug agents. Current limitations and future prospects are discussed.

de Maat S, Dekker J, Schoevers R, van Aalst G, Gijsbers-van Wijk C, Hendriksen M, Kool S, Peen J, Van R, de Jonghe F.

The efficacy of Short Psychodynamic Supportive Psychotherapy (SPSP) has not yet been compared with pharmacotherapy. A mega-analysis Based on Three Original Randomized Clinical Trials (RCTs) was Performed. Patients with (mild to moderate) major depressive disorder were randomized in (24 weeks) SPSP (n = 97), pharmacotherapy (n = 45), or their combination (n = 171). Efficacy was assessed by the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression of Severity and of Improvement (CGI-S), the Symptom Checklist (SCL; depression subscale) and the Quality of Life Depression Scale (QLDS). Pearson chi(2) calculations were used to compare success rates. Analyses of covariance (ANCOVAs) were used to test inter-group differences. Success rates indicated that independent observers (HDRS) found no differences in symptom reduction between SPSP and pharmacotherapy (P = 0.214), but therapists (CGI-S, P = 0.026), and patients (SCL, P = 0.036) favored SPSP. Combined therapy was found superior to pharmacotherapy by all three (patients (P = 0.000), therapists (P = 0.024), independent observers (P = 0.024)). Independent observers (P = 0.062) and therapists (P = 0.430) found no differences between combined therapy and SPSP, but patients (P = 0.016) found combined therapy to be superior. As far as quality of life is concerned, success rates indicated that patients (QLDS) found no differences between SPSP and pharmacotherapy (P = 0.073) or between SPSP and combined therapy (P = 0.217). However, they found combined therapy superior to pharmacotherapy (P = 0.015). The results of the mega-analysis suggest that combined therapy is more efficacious than pharmacotherapy. SPSP and pharmacotherapy seem equally efficacious, except for some indications that patients and therapists favor SPSP for symptom reduction. Combined therapy and SPSP also seem equally efficacious, except that patients think that the first is better in symptom reduction.

Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C.

Background: Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression. Methods: We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis. Findings: Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine. Interpretation: Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.

Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W, Gillespie CF, Berg T, Evces M, Newport DJ, Stowe ZN, Heim CM, Nemeroff CB, Schwartz A, Cubells JF, Ressler KJ.

Context: Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene x environment interaction at this locus may be important in depression. Objective: To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene. Design: Association study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms. Setting: General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia. Participants: The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished). Main Outcome Measures: Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders. Results: Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199). Conclusions: These data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene x environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.

Raskind MA, Peskind ER, Hoff DJ, Hart KL, Holmes HA, Warren D, Shofer J, O'Connell J, Taylor F, Gross C, Rohde K, McFall ME.

Background: Excessive brain responsiveness to norepinephrine appears to contribute to post-traumatic stress disorder (PTSD), particularly at night. Prazosin, a brain active alpha-1 adrenergic receptor antagonist, significantly reduced trauma nightmares and sleep disturbance in 10 Vietnam War combat veterans in a previous placebo-controlled crossover study. The current parallel group trial in a larger sample of veterans evaluated prazosin effects on trauma nightmares, sleep quality, global clinical status, dream characteristics, and comorbid depression. Methods: Forty veterans (mean age 56 +/− 9) with chronic PTSD and distressing trauma nightmares and sleep disturbance were randomized to evening prazosin (13.3 +/− 3 mg/day) or placebo for 8 weeks. Results: In the evaluable sample (n = 34), primary outcome measures demonstrated that prazosin was significantly superior to placebo for reducing trauma nightmares and improving sleep quality and global clinical status with large effect sizes. Prazosin shifted dream characteristics from those typical of trauma-related nightmares toward those typical of normal dreams. Blood pressure changes from baseline to end study did not differ significantly between prazosin and placebo. Conclusions: Prazosin is an effective and well-tolerated treatment for trauma nightmares, sleep disturbance and global clinical status in veterans with chronic PTSD.