Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment.

OBJECTIVE: This article presents the case that a more rapid, individualized approach to treating major depressive disorder (MDD) may increase the likelihood of achieving full symptomatic and functional recovery for individual patients and that studies show it is possible to make earlier decisions about appropriateness of treatment in order to rapidly optimize that treatment. DATA SOURCES: A PubMed search was conducted using terms including major depressive disorder, early improvement, predictor, duration of untreated illness, and function. English-language articles published before September 2015 were included. Additional studies were found within identified research articles and reviews. STUDY SELECTION: Thirty antidepressant studies reporting predictor criteria and outcome measures are included in this review. DATA EXTRACTION: Studies were reviewed to extract definitions of predictors, outcome measures, and results of the predictor analysis. Results were summarized separately for studies reporting effects of early improvement, baseline characteristics, and duration of untreated depression. RESULTS: Shorter duration of the current depressive episode and duration of untreated depression are associated with better symptomatic and functional outcomes in MDD. Early improvement of depressive symptoms predicts positive symptomatic outcomes (response and remission), and early functional improvement predicts an increased likelihood of functional remission. CONCLUSIONS: The approach to treatment of depression that exhibits the greatest potential for achieving full symptomatic and functional recovery is early optimized treatment: early diagnosis followed by rapid individualized treatment. Monitoring symptoms and function early in treatment is crucial to ensuring that patients do not remain on ineffective or poorly tolerated treatment, which may delay recovery and heighten the risk of residual functional deficits.

Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders.

BACKGROUND: Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated. METHODS: These guidelines were developed by Canadian experts in anxiety and related disorders through a consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were obtained through MEDLINE, PsycINFO, and manual searches (1980-2012). Treatment strategies were rated on strength of evidence, and a clinical recommendation for each intervention was made, based on global impression of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines. RESULTS: These guidelines are presented in 10 sections, including an introduction, principles of diagnosis and management, six sections (Sections 3 through 8) on the specific anxiety-related disorders (panic disorder, agoraphobia, specific phobia, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), and two additional sections on special populations (children/adolescents, pregnant/lactating women, and the elderly) and clinical issues in patients with comorbid conditions. CONCLUSIONS: Anxiety and related disorders are very common in clinical practice, and frequently comorbid with other psychiatric and medical conditions. Optimal management requires a good understanding of the efficacy and side effect profiles of pharmacological and psychological treatments.

Paroxetine versus placebo and other agents for depressive disorders: a systematic review and meta-analysis.

OBJECTIVE: To compare paroxetine with placebo and other antidepressants across multiple efficacy and tolerability outcomes. DATA SOURCES: Searches were conducted in MEDLINE (1966-2004), EMBASE (1980-2004), CINAHL (1982-2004), all Evidence-Based Medicine Reviews (1991-2004), HealthSTAR (1975-2004), BIOSIS (1980-2004), and PsycINFO (1840-2004). Medical Subject Headings (MeSH) included "paroxetine" OR "Paxil" exploded. The searches were not restricted by language, publication type, or study design. STUDY SELECTION: A study report was included if it described a randomized trial of paroxetine versus placebo or other antidepressants for patients with depressive disorders. Records were screened independently by 2 reviewers under the supervision of another reviewer. DATA EXTRACTION: Three investigators abstracted data, including study design, trial characteristics, and psychiatric assessment tools, using a prespecified form. Two investigators assessed quality of reporting using Jadad's scale. DATA SYNTHESIS: We included 62 unique randomized controlled trials. Paroxetine yielded consistently and significantly better remission (rate difference [RD]: 10% [95% CI = 6 to 14]), clinical response (RD: 17% [95% CI = 7 to 27]), and symptom reduction (effect size: 0.2 [95% CI = 0.1 to 0.3]) than placebo. Such consistency in the evidence base was not observed between paroxetine and other antidepressants. Pairwise comparisons of paroxetine and venlafaxine, mirtazapine, mianserin, or fluoxetine yielded inconsistent results across efficacy outcomes. Controlled-release paroxetine was the only antidepressant with significantly fewer dropouts due to adverse events than immediate-release paroxetine (RD: 5% [95% CI = 0.1 to 11]). CONCLUSIONS: There were no significant and valid differences between paroxetine and other antidepressants to suggest that multiple modes of action improve clinical outcomes.

Nefazodone in the treatment of generalized social phobia: a randomized, placebo-controlled trial.

OBJECTIVE: Numerous studies have demonstrated the efficacy of serotonergic antidepres-sants, particularly the selective serotonin reuptake inhibitors (SSRIs), in the treatment of social phobia. We evaluated the efficacy, safety, and tolerability of nefazodone, a 5-HT(2) antagonist, in patients with generalized social phobia (GSP). METHOD: One hundred five patients with GSP (confirmed using the Structured Clinical Interview for DSM-IV) from 4 Canadian outpatient anxiety clinics were assigned randomly to nefazodone (300-600 mg/day, flexible dose) or placebo for 14 weeks of double-blind treatment. Data were collected from October 12, 1999, through December 8, 2001. Primary efficacy outcomes were the Clinical Global Impressions-Improvement scale (CGI-I) score and the Liebowitz Social Anxiety Scale score. RESULTS: In the intent-to-treat sample, 16 (31.4%) of 51 subjects taking nefazodone and 12 (23.5%) of 51 subjects taking placebo were rated as much or very much improved on the CGI-I at endpoint (chi(2) = 0.79, p = .38). With the exception of the Social Phobia Scale, no significant differences were found in measures of social phobia when comparing the nefazodone and placebo groups. CONCLUSION: These findings suggest that nefazodone is not an effective agent in the treatment of GSP. These data parallel some recent findings with the use of the SSRI fluoxetine in GSP. The lack of efficacy of 2 serotonergic antidepressants in GSP suggests that serotonin reuptake inhibition may not be the only mechanism of action required for efficacy to occur in the treatment of GSP.

Striatal function in generalized social phobia: a functional magnetic resonance imaging study.

BACKGROUND: Although evidence suggests the involvement of the amygdala in generalized social phobia (GSP), few studies have examined other neural regions. Clinical, preclinical, and dopamine receptor imaging studies demonstrating altered dopaminergic functioning in GSP suggest an association with striatal dysfunction. This is the first functional magnetic resonance imaging (fMRI) study to use a cognitive task known to involve the striatum to examine the neural correlates of GSP. We examined whether subjects with GSP had differential activation in striatal regions compared with healthy control subjects while engaged in a cognitive task that has been shown to activate striatal regions reliably. METHODS: Ten adult, unmedicated subjects with a primary DSM-IV diagnosis of GSP and 10 age-, gender-, and education-matched healthy comparison subjects underwent fMRI while performing the implicit sequence learning task. RESULTS: The GSP and healthy comparison subjects did not differ significantly on the behavioral performance of the task. Subjects with GSP, however, had significantly reduced neural activation related to implicit learning compared with healthy comparison subjects in the left caudate head, left inferior parietal lobe, and bilateral insula. CONCLUSIONS: These findings support the hypothesis that GSP is associated with striatal dysfunction and further the neurobiological understanding of this complex anxiety disorder.

Venlafaxine extended release (XR) in the treatment of panic disorder.

Panic disorder is a chronic, recurrent illness, with a lifetime prevalence of about 5%. It is associated with substantial functional impairment, and studies suggest that treatment with medication alone (and no instruction in exposure to feared and avoided situations) is less than optimal. In fact, 40%-90% of patients in long-term follow-up studies in the late 1980s and early 1990s, treated with antidepressants or high potency benzodiazepines alone, remained somewhat symptomatic. Venlafaxine extended release (XR) was effective and well tolerated in both the short-term and long-term treatment of panic disorder. In 12-week trials, venlafaxine XR was significantly more effective than placebo in achieving a panic-free state (54%-70% vs 34%-48%, p

Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder.

OBJECTIVE: The purpose of the study was to test the relative and combined efficacy of clomipramine and exposure and ritual prevention in the treatment of obsessive-compulsive disorder (OCD) in adults. Serotonin reuptake inhibitors (SRIs) and cognitive behavior therapy by exposure and ritual prevention are both established treatments for OCD, yet their relative and combined efficacy have not been demonstrated conclusively. METHOD: A double-blind, randomized, placebo-controlled trial comparing exposure and ritual prevention, clomipramine, their combination (exposure and ritual prevention plus clomipramine), and pill placebo was conducted at one center expert in pharmacotherapy, another with expertise in exposure and ritual prevention, and a third with expertise in both modalities. Participants were adult outpatients (N=122 entrants) with OCD. Interventions included intensive exposure and ritual prevention for 4 weeks, followed by eight weekly maintenance sessions, and/or clomipramine administered for 12 weeks, with a maximum dose of 250 mg/day. The main outcome measures were the Yale-Brown Obsessive Compulsive Scale total score and response rates determined by the Clinical Global Impression improvement scale. RESULTS: At week 12, the effects of all active treatments were superior to placebo. The effect of exposure and ritual prevention did not differ from that of exposure and ritual prevention plus clomipramine, and both were superior to clomipramine only. Treated and completer response rates were, respectively, 62% and 86% for exposure and ritual prevention, 42% and 48% for clomipramine, 70% and 79% for exposure and ritual prevention plus clomipramine, and 8% and 10% for placebo. CONCLUSIONS: Clomipramine, exposure and ritual prevention, and their combination are all efficacious treatments for OCD. Intensive exposure and ritual prevention may be superior to clomipramine and, by implication, to monotherapy with the other SRIs.

Do antipsychotics ameliorate or exacerbate Obsessive Compulsive Disorder symptoms? A systematic review.

BACKGROUND: Paradoxically, some reports in the literature support the use of antipsychotics in the treatment of Obsessive Compulsive Disorder (OCD), while other reports suggest that antipsychotics can exacerbate OCD symptoms. To date, there is no published systematic review of the relationship between OCD symptoms and antipsychotic drugs. METHODS: A Medline and PsychInfo search (1980-2003) was conducted to collect published reports of the interactions between antipsychotics and OCD symptoms. RESULTS: In the treatment of refractory OCD, case series, open label trials and placebo-controlled trials were found suggesting efficacy of antipsychotic augmentation to ongoing antidepressant treatment. In the placebo-controlled trials with haloperidol, risperidone, olanzapine, and quetiapine, a significantly higher response rate (46-71%) was found for the antipsychotic groups, compared to no response for the placebo groups. Reports of exacerbation of OCD symptoms with the use of atypical antipsychotics were limited to individuals with a primary psychotic disorder. LIMITATIONS: Definition of response in most of these treatment studies was based on a modest reduction of OCD symptoms, and no studies were available on long-term efficacy. There were also no published reports that systematically evaluated the incidence of OCD symptoms associated with atypical antipsychotics. CONCLUSIONS: All antipsychotics mentioned above had short-term controlled evidence to support their use as augmenting agents in the treatment of refractory OCD. The suggested management of OCD induction/exacerbation due to atypical antipsychotics is to increase the dose of the atypical antipsychotic and/or add a selective serotonin reuptake inhibitor.

Deficits in perceived social support associated with generalized social phobia.

Social phobia is a common anxiety disorder associated with significant impairment in social and occupational functioning. To date, few studies have examined the relationship between social phobia and perceived social support, a construct with important relationships to physical and mental health. The present study examined data from 2 widely used measures of perceived social support administered to 132 individuals with DSM-IV generalized social phobia. These data were compared with those obtained from a healthy control group and from several clinical and non-clinical samples reported in the literature. Persons with generalized social phobia scored significantly lower on both measures of social support compared with all other groups. It is suggested that deficits in perceived social support associated with generalized social phobia may play a role in the development of co-morbid problems and should be explicitly targeted by treatments for social phobia. Low correlations between perceived social support and social anxiety measures suggest that perceived support should be specifically evaluated in this population.

Post-treatment effects of exposure therapy and clomipramine in obsessive-compulsive disorder.

We sought to determine whether adults with obsessive-compulsive disorder (OCD) who respond to intensive exposure and response (ritual) prevention (EX/RP) with or without clomipramine (CMI) fare better 12 weeks after treatment discontinuation than responders receiving CMI alone. After receiving 12 weeks of treatment (EX/RP, CMI, EX/RP+CMI, or pill placebo [PBO] in a randomized clinical trial conducted at three outpatient research centers), 46 adults with OCD who responded to treatment (18 EX/RP, 11 CMI, 15 EX/RP+CMI, 2 PBO) were followed after treatment discontinuation for 12 weeks. Patients were assessed every 4 weeks with the Yale-Brown Obsessive-Compulsive Scale, the National Institutes of Health Global Obsessive-Compulsive Scale, and the Clinical Global Impressions scale by an evaluator who was blind to original treatment assignment. The primary hypothesis was that EX/RP and EX/RP+CMI responders would be less likely to relapse 12 weeks after treatment discontinuation than responders to CMI alone. Twelve weeks after treatment discontinuation, EX/RP and EX/RP+CMI responders, compared to CMI responders, had a significantly lower relapse rate (4/33 = 12% versus 5/11 = 45%) and a significantly longer time to relapse. The CMI relapse rate was lower than previously reported. Nonetheless, responders receiving intensive EX/RP with or without CMI fared significantly better 12 weeks after treatment discontinuation than responders receiving CMI alone.

Long-term goals in the management of acute and chronic anxiety disorders.

Many anxiety disorders are not treated to remission (symptom-free state); however, this should be the minimum goal of therapy. Antidepressant therapies have shown significant beneficial effects in the management of anxiety disorders, with some variability in results in specific disorders. In social anxiety disorder, selective serotonin reuptake inhibitors and venlafaxine extended release (XR) have demonstrated efficacy, with response rates varying between 40% and 68%. Monoamine oxidase inhibitors and cognitive-behavioural therapies are also effective. In patients with generalized anxiety disorder, benzodiazepines, paroxetine, and venlafaxine XR have demonstrated remission rates that are 15% to 25% higher than placebo. In patients with posttraumatic stress disorder, about 60% to 70% of patients experienced a response with antidepressant therapy, compared with about 40% on placebo, while remission rates in one study were 30% with venlafaxine, 24% with sertraline, and 20% with placebo. In patients with obsessive-compulsive disorder, a 25% to 35% improvement in symptom scores was reported in 20% to 65% of patients. In the management of panic disorder, paroxetine and venlafaxine XR doubled the percentage of patients who were panic-free, compared with placebo. Ongoing antidepressant therapy further improved remission rates, and many patients with anxiety disorders required extended treatment trials before experiencing benefit. In most clinical trials, some benefits were seen within 3 to 4 weeks but continued to accrue throughout the 3- to 6-month duration of the trial. In the acute phase, patients with anxiety disorders should be treated aggressively with antidepressants for extended periods and may require long-term therapy to maintain benefits. Cognitive-behavioural therapy is another mainstay in the treatment of all anxiety disorders; exposure to feared situations is necessary to move beyond phobic avoidance and functional impairment to full recovery, the ultimate goal of therapy.

An open-label clinical trial of nefazodone in hypochondriasis.

Hypochondriasis is a common and challenging problem in general medical practice, but little research is available on pharmacotherapeutic treatment approaches. The purpose of the present study was to evaluate the use of nefazodone in the treatment of hypochondriasis in an open-label trial. Eleven patients with a primary diagnosis of DSM-IV hypochondriasis received an 8-week trial of nefazodone with a maximum dose of 600 mg/day and a mean dose of 432 mg. Clinician and self-ratings were completed at each of six visits. Nine of the 11 patients who started the trial completed 8 weeks of treatment. Five of the nine patients completing the trial were rated as much or very much improved on the clinician-rated global improvement scale. Self-ratings indicated statistically significant improvement on the Illness Attitudes Scales-Total Score (P <.01) and the Beck Depression Inventory (P <.04), and there was a trend toward improvement on the Whiteley Index (P <.06). The results of this study suggest that nefazodone is a promising treatment for hypochondriasis. More extensive evaluation in longer open-label trials and double-blind, placebo-controlled trials would be warranted.