Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive-compulsive disorder: lack of efficacy. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762]. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study. Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double-blind cross-over study. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. Pindolol augmentation in treatment-resistant obsessive compulsive disorder: a double-blind placebo controlled trial. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Quetiapine addition to serotonin reuptake inhibitors in patients with severe obsessive-compulsive disorder: a double-blind, randomized, placebo-controlled study. Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients. Cognitive and behavioral therapies alone versus in combination with fluvoxamine in the treatment of obsessive compulsive disorder. Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: a crossover study. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. Cognitive-behaviour therapy and medication in the treatment of obsessive-compulsive disorder: a controlled study. A novel augmentation strategy for treating resistant major depression. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. Do selective serotonin re-uptake inhibitors enhance the efficacy of very brief cognitive behavioral therapy for panic disorder? A pilot study. A randomized effectiveness trial of collaborative care for patients with panic disorder in primary care.
Recently, atypical antipsychotics have been used for the management of the patients with refractory obsessive-compulsive disorder (OCD). The aim of the present study was to evaluate the results of quetiapine augmentation to a serotonin reuptake inhibitor (SRI) in the patients with refractory OCD. Fifty-two patients with OCD according to DSM-IV entered 3 months of an open-label phase treatment with a SRI with or without concomitant adjunctive treatment regimen. Of them, 27 patients were refractory OCD. These patients were randomly divided into two groups, SRI plus quetiapine and SRI plus placebo, for an 8-week single-blind phase. The course of OCD was evaluated by Yale-Brown Obsession-Compulsion (Y-BOCS) and Clinical Global Impression-Severity of Illness and Improvement (CGI-SI and I) Scales every other week for 8 weeks. Of the 14 patients in group I, nine (64.4%) showed significant improvement with 60% or greater improvement on the Y-BOCS and one (7.1%) partial improvement with 30% or greater improvement on the Y-BOCS, whereas no improvement was observed in group II. The addition of quetiapine to ongoing SRI therapy has been found to be effective and well-tolerated approach in patients with refractory OCD. Two- and 4-week double-blind placebo-controlled trials of lithium augmentation of ongoing fluvoxamine treatment trials were conducted in 20 and 10 patients, respectively, with primary obsessive-compulsive disorder (OCD) who had failed to respond to fluvoxamine alone. Although 2 weeks of double-blind lithium augmentation produced a small but statistically significant reduction in obsessive-compulsive symptoms, most patients did not have a clinically meaningful response. Furthermore, there was no statistical or clinical improvement in obsessive-compulsive symptoms during the subsequent 4-week double-blind, placebo-controlled trial of lithium augmentation. On the basis of treatment response criteria, only 18% and 0% of the patients responded to lithium augmentation of fluvoxamine during the 2- and 4-week treatment trials, respectively. In light of the previously reported 44% response rate to lithium augmentation in treatment-resistant depressed patients on fluvoxamine, the results of this study suggest that pathophysiological differences may exist between OCD and depression. The routine use of lithium augmentation in the management of patients with OCD who are refractory to serotonin reuptake inhibitors is not supported by these findings. Although serotonin reuptake inhibitors are effective in the treatment of OCD, many patients fail to respond to these agents. Growing evidence from open-label and placebo-controlled trials suggests a role for augmentation of SRIs with atypical antipsychotics in OCD. Quetiapine is generally well tolerated and previous open-label data has produced mixed results in OCD and additional controlled data is needed.
                We undertook a double-blind, randomised, parallel-group, flexible-dose, placebo-controlled study of quetiapine augmentation in subjects who had responded inadequately to open-label treatment with an SRI for 12 weeks. Following informed consent and screening, forty-two subjects were randomised to either placebo or quetiapine for six weeks.
                There was significant improvement from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale in both the quetiapine and placebo groups (quetiapine, n = 20, p < 0.0001; placebo, n = 21, p = 0.001) with 40% (n = 8) of quetiapine and 47.6% (n = 10) of placebo treated subjects being classified as responders. Quetiapine did not demonstrate a significant benefit over placebo at the end of the six-week treatment period (p = .636). Similarly quetiapine failed to separate from placebo in the subgroup of subjects (n = 10) with co-morbid tics. Quetiapine was generally well tolerated.
                In this study, quetiapine augmentation was no more effective than placebo augmentation of SRIs. A number of limitations in study design make comparisons with previous studies in this area difficult and probably contributed to our negative findings. Future work in this important clinical area should address these limitations. This study aimed to determine the efficacy and tolerability of adding quetiapine to a serotonin reuptake inhibitor in treatment-resistant obsessive-compulsive disorder (OCD). Twenty-one adult treatment-resistant OCD patients were randomized to 16 weeks of augmentation with either quetiapine (n = 11) or placebo (n = 10). Patients with significant comorbidities, including tic-spectrum disorders, were not included. The treatment was well tolerated, with only one premature dropout in each treatment-group. The primary analysis showed that individuals in the quetiapine-treated group showed a 14% mean improvement in baseline Yale-Brown Obsessive-Compulsive Scale scores at study endpoint compared with a 6% improvement in those treated with placebo, but this difference did not reach statistical significance (F<1). Three patients treated with quetiapine met criteria for clinical response, compared to one patient who was treated with placebo. Larger studies are needed to explore the efficacy of second generation antipsychotics, such as quetiapine, when used as adjunct treatment in resistant OCD. Current serotonin reuptake inhibitor (SRI) treatments for obsessive-compulsive disorder (OCD) provide only partial benefit. A previous study suggested that inositol alone is efficacious in OCD. Ten DSM-IV OCD patients completed a study of 18 g inositol or placebo for 6 wk each in addition to ongoing SRI treatment in a double-blind randomized cross-over design. Weekly assessments included the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Hamilton Depression and Anxiety scales. No significant difference was found between the two treatment phases. This double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 wk of risperidone augmentation of serotonin reuptake inhibitor (SRI) treatment in adult subjects with treatment-resistant obsessive-compulsive disorder (OCD) (failure of at least two SRI trials). Sixteen adult treatment-resistant OCD patients were randomly assigned to augmentation with 8 wk of either risperidone (n=10) (0.5-3.0 mg/d) or placebo (n=6) following at least 12 wk of SRI treatment. Four patients on risperidone (40%) and none (0%) on placebo were responders with both a Clinical Global Impression - Improvement (CGI-I) score of 1 or 2 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease >/=25%. Risperidone was generally well tolerated: there were 3 dropouts, 1 on risperidone and 2 on placebo. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation. Risperidone may be an effective and well-tolerated augmentation strategy in treatment-resistant OCD subjects, but larger sample size studies are required to demonstrate this. To evaluate the efficacy of pindolol augmentation in treatment-resistant obsessive compulsive disorder (OCD) patients who were unsuccessfully treated with serotonin reuptake inhibitors.
                Fourteen treatment-resistant OCD patients were treated with paroxetine for 17.4+/-2.1 weeks up to 60 mg/d after they failed at least two other serotonin reuptake inhibitor trials. The patients, who did not respond to open-label paroxetine treatment, were assigned to a double-blind, placebo-controlled pindolol (2.5 mgx3/d) augmentation. All the subjects were evaluated biweekly for a six-week period with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Anxiety Scale (HAM-Anx), and Montgomery Asberg Depression Rating Scale (MADRS). Data was analyzed by paired t-test, and ANOVA with repeated measures.
                Pindolol augmentation to paroxetine (n=8) as compared to placebo augmentation (n=6), was associated with a significant (P<0.01) improvement in Y-BOCS as measured by paired t-test after the fourth week of the treatment and by ANOVA with repeated measures (df: 4.9, f: 3,3, P<0.006). Although no significant differences were found between placebo and pindolol groups on HAM-Anx and MADRS, a trend for improvement in the pindolol group was noted.
                The results of our study demonstrated that pindolol may augment the therapeutic effect of paroxetine in treatment-resistant OCD patients. The purpose of this study was to explore the efficacy of adding an atypical antipsychotic, olanzapine, to a serotonin reuptake inhibitor (SRI) in treatment-refractory obsessive-compulsive disorder (OCD).
                Twenty-six patients aged between 18 and 65 (mean = 41.2, SD = 11.9) years meeting DSM-IV criteria for OCD, who had not responded to SRIs, were treated for 6 weeks in a double-blind, placebo-controlled augmentation study with either olanzapine (up to 20 mg/day) or placebo. Severity of illness was assessed biweekly by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Analysis of covariance with baseline Y-BOCS score included as a covariate was used to compare improvement in Y-BOCS scores in the 2 groups. Response was defined as a 25% or greater improvement in Y-BOCS score. Data were collected between April 2001 and May 2003.
                Outcome was assessed for all patients using the last observation carried forward. Subjects in the olanzapine group had a mean decrease of 4.2 (SD = 7.9) in Y-BOCS score compared with a mean increase in score of 0.54 (SD = 1.31) for subjects in the placebo group (F = 4.85, df = 2,23; p =.04). Six (46%) of 13 subjects in the olanzapine group showed a 25% or greater improvement in Y-BOCS score compared with none in the placebo group. The final mean dose of olanzapine was 11.2 (SD = 6.5) mg/day. Medication was well tolerated. Only 2 (15%) of 13 subjects who received olanzapine discontinued because of side effects: sedation (N = 1) or weight gain (N = 1).
                These results provide preliminary evidence that adding olanzapine to SRIs is potentially efficacious and well tolerated in the short-term treatment of patients with refractory OCD. Controlled studies with larger sample sizes are necessary to more definitively address this treatment strategy. To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone.
                Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition.
                For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personalty disorder. Other than mild, transient sedation, risperidone was well tolerated.
                These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy. There has been little systematic study of "next-step" interventions for patients with generalized anxiety disorder (GAD) who remain symptomatic despite initial pharmacotherapy. We present one of the first randomized controlled trials for refractory GAD, comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine.
                Patients remaining symptomatic after 6 weeks of fluoxetine (20 mg/day) were randomized to 6 weeks of olanzapine (mean dose 8.7 +/- 7.1 mg/day) or placebo augmentation.
                Twenty-four of 46 fluoxetine-treated patients were randomized. Olanzapine resulted in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale (CGI-S) end point score of 1 or 2 (Fisher's exact test [FET] p < .05) or a 50% reduction in Hamilton Anxiety Scale (HAMA-A) score (FET p < .05). There were no other statistically significant differences for olanzapine compared with placebo augmentation in outcome measures, though rates of remission (HAM-A <or= 7) on olanzapine were higher at the level of a trend (FET, p = .1). Average weight gain for completers was greater with olanzapine than placebo augmentation (11.0 +/- 5.1 vs. -0.7 +/- 2.4 pounds: t = 6.32, p < .001).
                Olanzapine may have a salutary effect on anxiety for some GAD patients remaining symptomatic despite initial serotonin selective reuptake inhibitor (SSRI) therapy, but the emergence of significant weight gain represents an important clinical consideration. Although many patients with obsessive-compulsive disorder (OCD) benefit from treatment with serotonin reuptake inhibitors (SRIs), it is estimated that 40% to 60% of them do not respond. The objective of the present study was to evaluate the efficacy of quetiapine added to baseline treatment with SRIs for the treatment of OCD in severely ill adult subjects.
                Forty patients (21 men, 19 women) with primary OCD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria participated in a 12-week, double-blind, placebo-controlled trial. They were randomly assigned to dosages of quetiapine titrated up to 400 mg/d (n = 20) or to placebo (n = 20) in addition to their SRI treatment. During the continuation phase (weeks 6-12), subjects received different dosages between 400 and 600 mg/d depending on clinical response. At entry, all patients were unresponsive to at least 1 course of at least 12 weeks of treatment with SRIs at defined doses. The total Yale-Brown Obsessive-Compulsive Scale score was the primary efficacy parameter.
                Intention-to-treat, last-observation-carried-forward analysis demonstrated a mean +/- SD decrease in Yale-Brown Obsessive-Compulsive Scale score of 5.2 +/- 5.4 in the quetiapine group and 3.9 +/- 4.9 in the placebo group. The analysis of treatment effects between the 2 groups showed no significant difference. There were no significant group differences in any of the other self-rating scales or clinician-administered rating scales.
                In this study, augmentation of SRI treatment with quetiapine in severe OCD had no additional effect. Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study.
                Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study.
                Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium.
                Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation. The purpose of this treatment package design study was to investigate the differential efficacy of cognitive therapy or exposure in vivo with response prevention for obsessive compulsive disorder (OCD) versus the sequential combination with fluvoxamine. Patients with OCD (N = 117) were randomized to one of the following five conditions: a) cognitive therapy for weeks 1 to 16, b) exposure in vivo with response prevention for weeks 1 to 16, c) fluvoxamine for weeks 1 to 16 plus cognitive therapy in weeks 9 to 16, d) fluvoxamine for weeks 1 to 16 plus exposure in vivo with response prevention in weeks 9 to 16, or e) waiting list control condition for weeks 1 to 8 only. Assessments took place before treatment (pretest) and after 8 (midtest), and 16 weeks (posttest). In the first 8 weeks, six treatment sessions were delivered. During weeks 9 to 16, another 10 sessions were given. Thirty-one patients dropped out. Outcome was assessed by patient-, therapist- and assessor-ratings of the Anxiety Discomfort Scale, the Yale-Brown Obsessive Compulsive Scale, and the Padua Inventory-Revised. In contrast with the four treatments, after 8 weeks the waiting list control condition did not result in a significant decrease of symptoms. After 16 weeks of treatment, all four treatment packages were effective on these OCD ratings, but they did not differ among each other in effectiveness. In OCD, the sequential combination of fluvoxamine with cognitive therapy or exposure in vivo with response prevention is not superior to either cognitive therapy or exposure in vivo alone. More data are needed to guide "next step" strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic despite initial pharmacotherapy.
                This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy.
                Adult outpatients with GAD were recruited from 2004 to 2007 at two academic centers. Phase 1 consisted of 10 weeks of open-label paroxetine CR flexibly dosed to a maximum of 62.5 mg/day. Those remaining symptomatic (Hamilton Anxiety Scale [HAM-A] >or= 7) at week 10 were randomized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day.
                For participants receiving paroxetine CR (n = 50), there was a significant reduction in HAM-A scores (baseline mean +/- SD = 22.4 +/- 4.2 to endpoint mean +/- SD = 11.2 +/- 6.9; paired t = 12.1, df = 49, t < 0.0001) with 40% (n = 20) achieving remission. Counter to our hypothesis, we did not find significant benefit for quetiapine augmentation of continued paroxetine CR (HAM-A reduction mean +/- SD = 2.6 +/- 5.8 points quetiapine, 0.3 +/- 5.5 points placebo; t = 0.98, df = 20, p = n.s.) in the randomized sample (n = 22) with relatively minimal additional improvement overall in phase 2.
                Although conclusions are considered preliminary based on the relatively small sample size, our data do not support the addition of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospective antidepressant pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed. To investigate if ethyl-eicosapentaenoic acid (E-EPA) augmentation improves antipsychotic efficacy and tolerability in first-episode psychosis (FEP).
                We performed a 12-week, randomized, double-blind, placebo-controlled trial of 2-g E-EPA augmentation in 80 FEP patients. Sixty-nine patients were eligible for analysis; a post hoc analysis was computed for a subgroup of nonaffective FEP patients (N = 53). The first participant was included in November 2000 and the last participant completed the trial in August 2003. Primary outcome measures were symptom change scores and time to first response, while tolerability measures and cumulative antipsychotic dose were secondary outcome measures.
                Analysis of covariance controlling for baseline symptoms found no significant mean difference between E-EPA and placebo at week 12 for symptom change scores. Cox regression analysis revealed a significant treatment by diagnosis interaction (p = .024) for time to first response favoring E-EPA in nonaffective psychosis. Post hoc analysis for cumulative response rates further confirmed a higher response rate at week 6 (42.9% [15/35] vs. 17.6% [6/34] for all participants, p = .036; 54.2% [13/24] vs. 17.2% [5/29] for the nonaffective psychosis subset, p = .008); however, the difference at week 12 was no longer significant. Analysis of secondary outcome measures revealed that E-EPA-augmented participants needed 20% less antipsychotic medication between weeks 4 through 6 (p = .03), had less extrapyramidal side effects in the initial 9 weeks (p < .05 for all participants and for all timepoints), and reported less constipation (p = .011) and fewer sexual side effects (p = .016) than those treated with antipsychotic medication alone.
                The findings suggest that E-EPA may accelerate treatment response and improve the tolerability of antipsychotic medications. However, it was not possible to demonstrate a sustained symptomatic benefit of E-EPA in early psychosis, possibly due to a ceiling effect, since a high proportion of first-episode patients already achieve symptomatic remission with antipsychotic medication alone. Further controlled trials in nonaffective early psychosis seem warranted.
                Australian Clinical Trials Registry identifier 12605000267651 (http://actr.org.au). Although serotonin reuptake inhibitors (SRIs) are the first-line treatment for obsessive-compulsive disorder (OCD), approximately half of patients with OCD do not respond adequately to SRI monotherapy. Patients with predominant obsessions are common in OCD and are often difficult to treat, necessitating adjunctive treatment.
                This was a 9-week, double-blind, placebo-controlled, crossover study comparing the benefits of 2-week adjunctive treatments with risperidone, haloperidol, and placebo in patients with OCD (DSM-IV criteria) who continued to have severe symptoms despite taking a stable dose of an SRI. Eligible patients must have been receiving a therapeutic dose of an SRI for at least 12 weeks and at the screening visit had a score > or = 10 on items 1-5 (obsession) and a total score > or = 16 on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Data were collected from January 1999 through April 2002.
                Sixteen patients were enrolled and 12 completed the study. On the YBOCS, both risperidone and haloperidol significantly reduced obsession (p < .05) when compared with placebo. There was a tendency that haloperidol, and to a lesser degree risperidone, also reduced the compulsion and the total YBOCS scores. These results were accompanied by a reduction in the Hopkins Symptom Checklist 90-revised (SCL-90R) anxiety scale score. According to the 17-item Hamilton Rating Scale for Depression, the SCL-90R depression scale, and the Profile of Mood States, risperidone, but not halo-peridol, also improved depressed mood. Neither risperidone nor haloperidol changed neurocogni-tive function during the 2-week treatment. All 12 patients completed the 2-week risperidone treatment, but 5 of the 12 terminated haloperidol treatment early owing to intolerable side effects.
                Adjunctive risperidone improved obsessions and depressed mood and was well tolerated in patients with SRI-refractory OCD. We examined the efficacy and tolerability of augmentation with an extended release formulation of methylphenidate (OROS MPH, Concerta) in patients with major depression who were nonresponders or partial responders to antidepressants. Sixty subjects with treatment-resistant depression (TRD) participated in a 4-week, randomized, double-blind, placebo-controlled study of augmentation with methylphenidate (18-54 mg/d). The preexisting antidepressant dose was unchanged. The primary efficacy measure was change in the 21-item Hamilton Depression Rating Scale from randomization to end of treatment. Data were analyzed with intent-to-treat with last observation carried forward approach. There were no statistically significant differences between the methylphenidate (n = 30) and placebo (n = 30) groups in reduction in 21-item Hamilton Depression Rating Scale scores (drug, -6.9; placebo, -4.7) from baseline to end of treatment (F1,47 = 1.24, P = 0.22), although responders were numerically higher in the extended-release methylphenidate group (40.0%) than in the placebo group (23.3%). On the secondary efficacy measures of changes in Clinical Global Impression-Improvement and Severity scores and Beck Depression Inventory-Second Edition, the drug failed to separate from placebo, although the proportion of responders in the drug group were numerically higher than placebo. There were no significant differences in weight, heart rate, and blood pressure changes between the 2 groups. The common adverse events were loss of appetite, nausea, headache, and anxiety. The mean dose of drug was 34.2 mg/d. The study did not demonstrate a statistically significant benefit for augmentation with methylphenidate in TRD. Combination of methylphenidate with antidepressants was well tolerated. Adequately powered, randomized, controlled trials are necessary to fully evaluate the efficacy of extended-release methylphenidate in TRD. To evaluate the effect of combining cognitive-behaviour therapy (CBT) and medication in the treatment of obsessive-compulsive disorder (OCD).
                Twenty-nine subjects diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria were recruited through the Anxiety Clinic of Louis-H Lafontaine Hospital. They were evaluated at baseline and after treatment on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) by a psychiatrist who was blind to treatment modality. Subjects rated their degree of resistance to their rituals and the strength of their obsessional beliefs. Subjects then received 1 of 4 treatments: medication and CBT simultaneously (n = 9), CBT only (n = 6), medication while on a wait-list for CBT (n = 6), or no treatment while on a wait-list for CBT (n = 5).
                Multivariate analysis revealed that Y-BOCS scores and clinical ratings significantly improved posttreatment in all groups except the nontreatment wait-list control group. Subjects in the 2 active treatment groups receiving CBT showed reduced strength in their obsessional beliefs. The subsequent administration of CBT to those groups on the wait-list also decreased the strength of their primary obsessional beliefs and beliefs about the consequences of not performing the rituals.
                Our results suggest that either CBT or medication alone is more effective than no treatment. The combination of CBT and medication seems to potentiate treatment efficacy, and we found it more clinically beneficial to introduce CBT after a period of medication rather than to start both therapies simultaneously. Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression.
                An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine.
                Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions.
                Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone. The effect of risperidone augmentation of citalopram for relapse prevention in older patients with antidepressant-resistant depression was evaluated.
                Patients with major depression aged > or =55 years who had failed at least one adequate trial of an antidepressant received citalopram monotherapy (20-40 mg) for 4 to 6 weeks to confirm nonresponse (<50% reduction in Hamilton Rating Scale for Depression [HAM-D] scores). Those who achieved remission (HAM-D score < or =7 or Clinical Global Impressions severity score 1 or 2) after 4 to 6 weeks of open-label risperidone augmentation (0.25-1 mg) then entered a 24-week double-blind maintenance phase during which they received citalopram augmented with risperidone or placebo.
                The patients' mean age was 63.4 +/- 7.9 years; 58% were women; 61% had received two or more antidepressants during the current episode; 93 met the criterion for citalopram nonresponse and entered open-label risperidone augmentation. Of the 89 patients who completed risperidone augmentation, 63 achieved symptom resolution and entered the 6-month double-blind maintenance phase: 32 received risperidone augmentation and 31 received placebo augmentation. The median time to relapse (Kaplan-Meier estimates) was 105 days in the risperidone group and 57 days in the placebo group (Wilcoxon chi(2): 3.2, df = 1, p = 0.069). Overall, 18 of 32 (56%) from the risperidone group and 20 of 31 (65%) from the placebo group relapsed. Treatment was well tolerated.
                In older patients with resistant depression and poor response to standard treatments, risperidone augmentation resulted in symptom resolution in a substantial number of patients and a nonsignificant delay in time to relapse. Although serotonin reuptake inhibitors (SRIs) are the most effective pharmacologic treatment currently available for patients with obsessive-compulsive disorder (OCD), 40% to 60% of patients do not respond to this treatment. This study was conducted to evaluate the efficacy and tolerability of quetiapine in addition to an SRI for treatment-refractory patients with OCD.
                Forty patients (10 men/30 women, mean +/- SD age = 35.2 +/- 12.1 years; range, 18-60 years) with primary OCD according to DSM-IV criteria who were recruited between February 2001 and December 2002 were randomly assigned in an 8-week, double-blind, placebo-controlled trial to receive dosages titrated upward to 300 mg/day of quetiapine (N = 20) or placebo (N = 20) in addition to their SRI treatment. At entry, all patients were unresponsive to courses of treatment with at least 2 different SRIs at a maximum tolerated dose for 8 weeks. During the study, primary efficacy was assessed according to change from baseline on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). A responder was defined as having a final Clinical Global Impressions-Improvement scale rating of "very much improved" or "much improved" and a decrease of > or = 35% in Y-BOCS score.
                An intent-to-treat, last-observation-carried-forward analysis demonstrated a mean +/- SD decrease in Y-BOCS score of 9.0 +/- 7.0 (31%) in the quetiapine group and 1.8 +/- 3.4 (7%) in the placebo group (F=16.99, df=1,38; p <.001). Eight (40%) of 20 patients in the quetiapine group and 2 (10%) of 20 patients in the placebo group were responders (chi2=4.8, df=1, p=.028). The most common side effects in the quetiapine group were somnolence, dry mouth, weight gain, and dizziness.
                The results of this study show that quetiapine in addition to an SRI is beneficial for patients with OCD who do not respond to SRI treatment alone. According to previous data, the addition of risperidone in obsessive-compulsive patients refractory to serotonin reuptake inhibitors (SRIs) is shown to be a safe and effective treatment strategy. The aims of our study were to evaluate the efficacy of risperidone addition, in comparison to placebo, in fluvoxamine-refractory obsessive-compulsive patients and to investigate whether risperidone could boost the efficacy of fluvoxamine in fluvoxamine-responder patients. Subjects were 45 obsessive-compulsive inpatients, consecutively recruited at the Department of Neurosciences at the San Raffaele Hospital, Milan. Thirty-nine patients completed the study. All patients received 12 weeks of a standardized open-label fluvoxamine monotherapy and then continued for 6 weeks with placebo or risperidone in a double-blind design. Results showed a significant effect of risperidone addition, at the end of the double-blind phase (18th week), only for fluvoxamine-refractory patients. Five patients on risperidone (50%) and two (20%) on placebo became responders, with a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease > or =35%. Risperidone was generally well tolerated, except for a mild transient sedation and a mild increase in appetite. This preliminary study suggests that even very low (0.5 mg) risperidone doses are effective in OC patients who were nonresponders to a standardized treatment with fluvoxamine. Bipolar patients are at risk for relapses of their illness even when undergoing optimal pharmacotherapy. This study was performed to determine whether combining family-focused therapy (FFT) with pharmacotherapy during a postepisode interval enhances patients' mood stability during maintenance treatment.
                In a randomized controlled trial, 101 bipolar patients were assigned to FFT and pharmacotherapy or a less intensive crisis management (CM) intervention and pharmacotherapy. Outcome assessments were conducted every 3 to 6 months for 2 years. Participants (mean +/- SD age, 35.6 +/- 10.2 years) were referred from inpatient or outpatient clinics after onset of a manic, mixed, or depressed episode. FFT consisted of 21 sessions of psychoeducation, communication training, and problem-solving skills training. Crisis management consisted of 2 sessions of family education plus crisis intervention sessions as needed. Both protocols lasted 9 months. Patients received pharmacotherapy for 2 study years. Main outcome measures included time to relapse, depressive and manic symptoms, and medication adherence.
                Rates of study completion did not differ across the FFT (22/31, 71%) and CM groups (43/70, 61%). Patients undergoing FFT had fewer relapses (11/31, 35%) and longer survival intervals (mean +/- SD, 73.5 +/- 28.8 weeks) than patients undergoing CM (38/70, 54%; mean +/- SD, 53.2 +/- 39.6 weeks; hazard ratio, 0.38; 95% confidence interval, 0.20-0.75; P =.003; intent to treat). Patients undergoing FFT showed greater reductions in mood disorder symptoms and better medication adherence during the 2 years than patients undergoing CM.
                Combining family psychoeducation with pharmacotherapy enhances the postepisode symptomatic adjustment and drug adherence of bipolar patients. We present results of a feasibility test of a sequential treatment strategy using continuation phase cognitive-behavioral therapy (CBT) to prevent relapse in youths with major depressive disorder (MDD) who have responded to acute phase pharmacotherapy.
                Forty-six youths (ages 11-18 years) who had responded to 12 weeks of treatment with fluoxetine were randomized to receive either 6 months of continued antidepressant medication management (MM) or antidepressant MM plus relapse prevention CBT (MM+CBT). Primary outcome was time to relapse, defined as a Childhood Depression Rating Scale-Revised score of 40 or higher and 2 weeks of symptom worsening or clinical deterioration warranting alteration of treatment to prevent full relapse.
                Cox proportional hazards regression, adjusting for depression severity at randomization and for the hazard of relapsing by age across the trial, revealed that participants in the MM treatment group had a significantly greater risk for relapse than those in the MM+CBT treatment group (hazard ratio = 8.80; 95% confidence interval 1.01-76.89; chi = 3.86, p =.049) during 6 months of continuation treatment. In addition, patient satisfaction was significantly higher in the MM+CBT group. No differences were found between the two treatment groups on attrition rate, serious adverse events, and overall global functioning.
                These preliminary results suggest that continuation phase CBT reduces the risk for relapse by eightfold compared with pharmacotherapy responders who received antidepressant medication alone during the 6-month continuation phase. Selective serotonin re-uptake inhibitors (SSRIs) and cognitive behavioral therapies (CBTs) are both considered as first-line treatments for panic disorder, but the advantages of a combined therapy have yet to be definitively demonstrated. We evaluated in this pilot study the effects of combining SSRIs (vs. a placebo) with a very brief form of cognitive-behavioral therapy provided to all participants. Thirty-three subjects with DSM-IV panic disorder, with or without agoraphobia, were randomized to receive either paroxetine or a placebo with flexible dosing (10-50 mg/day). Medication visits were brief (15 min), infrequent (6 in total) and non-directive. An expert cognitive-behavior therapist administered one initial 45-min session and one subsequent 30-min session of very brief CBT (vbCBT) at weeks 5 and 7, respectively. Sessions were supplemented with educational and directive reading materials. Patients in both groups (i.e. vbCBT+paroxetine; vbCBT+placebo) improved similarly and substantially on most measures during the 10 weeks of acute treatment. At week 10, the proportion of panic-free patients was significantly higher in the paroxetine-treated group than in the placebo group (80 vs. 25%; P<0.007), as was the proportion of subjects who rated themselves as 'very much improved' at week 10 (60 vs. 13%; P<0.017). These findings point to the need for additional studies to confirm the effectiveness of very brief forms of CBT, and to document the circumstances in which combined treatment with an SSRI would be warranted. Effectiveness studies have tested interventions to improve quality of care for depression in primary care, but none, to our knowledge, have been completed for panic disorder (PD) in this setting. This study sought to test the clinical effectiveness of PD pharmacotherapy embedded in a disease management framework of "collaborative care" (CC).
                One hundred fifteen patients with PD from 3 primary care clinics were randomized to CC or "usual care" (UC). Patients in CC (n = 57) received educational videotapes and pamphlets; pharmacotherapy with the selective serotonin reuptake inhibitor paroxetine; 2 psychiatrist visits and 2 telephone calls in the first 8 weeks; and up to 5 telephone calls between 3 and 12 months' follow-up. Usual care patients (n = 58) were treated by their primary care physician. Telephone assessments of panic, anxiety sensitivity, depression, and disability variables were performed at 3, 6, 9, and 12 months' follow-up. Adequacy of pharmacotherapy was assessed with an algorithm based on a review of efficacy studies.
                Patients in CC were more likely to receive adequate (type, dose, duration) medication and more likely to adhere to this medication at 3 and 6 months. Random regression analyses showed that CC patients improved significantly more over time compared with UC patients on anxiety, depression, and disability measures, with the greatest effects at 3 and 6 months.
                Compared with UC, CC interventions significantly improved both quality of care and clinical and functional outcomes in primary care PD patients. Clinical differences were greatest in the first 6 months, corresponding to the greater quality of care and the greater intensity of intervention.
Medication augmentation can be an effective and well-tolerated short-term treatment strategy for non-responders to first-line pharmacotherapy of anxiety disorders. However, any conclusions must be tentative in view of methodological and clinical heterogeneity, and the fact that much of the relevant database is based on antipsychotic augmentation trials in OCD patients resistant to serotonin reuptake inhibitors (SRIs). Additional data are needed to address several areas, including the efficacy of augmentation over the longer-term, and the value of medication augmentation in comparison to other strategies (eg switching medication, adding psychotherapy).