Clinical outcomes following switch from venlafaxine ER to desvenlafaxine in nonresponders and responders.

OBJECTIVE: This post hoc analysis examined efficacy and tolerability of open-label desvenlafaxine in patients with major depressive disorder switched from blinded placebo, venlafaxine extended release (ER), or desvenlafaxine. RESEARCH DESIGN AND METHODS: Patients who completed 8 weeks of double-blind therapy with placebo (n = 176), venlafaxine ER (n = 175), or desvenlafaxine (n = 143) enrolled in a 10-month, open-label extension study and received desvenlafaxine 200 to 400 mg/d. Efficacy (17-item Hamilton Depression Rating Scale [HDRS(17)]) was assessed separately for nonresponders and responders to double-blind treatment. Tolerability during the first month of open-label desvenlafaxine was assessed. RESULTS: Among nonresponders (n = 134) to double-blind placebo, venlafaxine ER, and desvenlafaxine, mean decreases in HDRS(17) scores were -10.9, -7.3, and -7.7, respectively; HDRS(17) response rates were 67%, 53%, and 48%, respectively. Although responders (n = 360) to double-blind placebo, venlafaxine ER, and desvenlafaxine had more modest decreases on the HDRS(17), response rates were higher (84%, 87%, and 83%, respectively). Rates of adverse events were highest during week 1, and decreased afterward for the remainder of the first month of treatment. CONCLUSIONS: Among nonresponders to 8 weeks of double-blind venlafaxine ER, desvenlafaxine, or placebo, 48% to 67% subsequently responded to open-label desvenlafaxine. Over 80% of responders to double-blind therapy maintained response on open-label desvenlafaxine. The switch from venlafaxine ER to desvenlafaxine was well tolerated.

Insight and treatment outcome in obsessive-compulsive disorder.

To determine whether (1) insight in obsessive-compulsive disorder (OCD) improves when OCD symptoms improve, and whether (2) degree of insight in OCD predicts response to sertraline, data were obtained from five sites participating in a larger multisite study of relapse in OCD. During the first 16 weeks of the study, 71 patients received open-label treatment with sertraline and were assessed using the Yale-Brown Obsessive-Compulsive Rating Scale (Y-BOCS) and a rating scale to evaluate insight, the Brown Assessment of Beliefs Scale (BABS), at study baseline and termination. Baseline total BABS score was not significantly correlated with change in Y-BOCS score. Change in BABS total score and change in Y-BOCS total score were significantly correlated. There was no significant difference in mean endpoint Y-BOCS scores for patients with poor insight (n = 14) compared to patients with good insight at baseline (n = 57). Thus, insight improved with decrease in OCD symptom severity. Degree of insight at baseline did not predict response to sertraline, i.e., patients with poor insight were just as likely to respond to sertraline as patients with good insight.

Dissolving the burden of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a common disorder marked by excessive anxiety, worry, and somatic manifestations lasting over 6 months. GAD occurs relatively early in life in the majority of individuals; it is often chronic and comorbid with other anxiety disorders, affective disorders, and/ or medical conditions. GAD is as functionally debilitating as major depression even without comorbidity and, hence, is associated with considerable economic and societal burdens as well as health care utilization. Underrecognition of GAD and undertreatment of this disorder are major factors contributing to the individual and societal burden of GAD. Earlier long-term studies in GAD reported low remission rates despite treatment. More recent data support the potential for achieving remission in GAD with appropriate treatment. There is a critical need to enhance mental health literacy programs and translate the efficacy data into effectiveness schemes in clinical practice by improving disease management strategies. A conceptual basis for achieving these goals is provided by moving from a disorder model to a disease model in psychiatric practice. This move allows for staging of psychiatric illnesses, with GAD as a prototypical example. For the clinician, the critical paradigm shift is in modifying the treatment goal from the attenuation of symptoms, as in a "response," to the achievement of a state of "remission" (i.e., a virtually asymptomatic state). Remission of symptoms allows for improvement of psychosocial functioning and quality of life and potentially wellness. In this review, a synopsis of the epidemiology, natural history, economic and social cost, and clinical management issues is given as a road map to dissolving the burden of GAD.

Symptomatic and syndromal anxiety and depression.

The diagnosis of anxiety disorders and major depression can be reliably made based on signs and symptoms. However there are significant limitations to the current system of classification including overlapping criteria, high comorbidity, and the issue of subthreshold syndromes. The literature on treatment response documents that selective serotonin reuptake inhibitors are effective in the treatment of the various anxiety disorders, including when comorbid major depression is present. The literature also suggests that tricyclic antidepressant medications have superior benefits over selective serotonin reuptake inhibitors in major depression. Examination of the functional anatomy of the fear and reward systems may shed light on the underlying processes in the anxiety and depressive disorders. Such an approach points out the importance of addressing avoidance behaviors, which may be more responsive to cognitive behavioral treatments than pharmacological agents.

Recent perspectives on the diagnosis and treatment of generalized anxiety disorder.

Anxiety disorders are common mental disorders, encompassing a group of conditions that share extreme or pathological anxiety as the primary disturbance in mood or emotional tone. Anxiety disorders include generalized anxiety disorder (GAD), panic disorder, agoraphobia, specific phobias, social anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Individual anxiety disorders have considerable symptomatic overlap in their expression. The life-time prevalence of all anxiety disorders in the general population is about 25%. There is familial aggregation of anxiety and mood disorders such as major depression. Genetic factors and life experiences both contribute to the likelihood of developing anxiety disorders. GAD is characterized by excessive anxiety and uncontrollable worry, is present for longer than 6 months, and tends to occur comorbidly with other conditions, including other anxiety disorders and major depression as well as general medical conditions. GAD, given its chronic nature, is associated with significant impairment. GAD is responsive to pharmacological treatments, such as anxiolytics and antidepressants, as well as psychotherapies such as cognitive therapy.

Pharmacokinetically induced benzodiazepine withdrawal.

Pharmacokinetic interactions between medications can have clinically significant effects. Concern usually arises when a medication is added to a continuing regimen, though discontinuation of a medication can also have an impact. A case is presented of a patient who experienced benzodiazepine withdrawal symptoms on discontinuation of nefazodone, an antidepressant that inhibits the cytochrome P450 3A4 isoenzyme. Plasma levels of alprazolam, a substrate for the 3A4 isozyme, fell rapidly when nefazodone was discontinued, presumably because of renewed 3A4 isoenzyme activity. The management of the patient's withdrawal symptoms is described.

Use of venlafaxine in other psychiatric disorders.

Venlafaxine is a medication available by prescription in the U.S. both in an immediate release and an extended release formulation. Preclinical studies indicate it has the effect of potently blocking the serotonin and norepinephrine transporters. Venlafaxine is approved by the FDA for the treatment of major depressive disorder and generalized anxiety disorder. Suggestive evidence, mostly from open label case series, indicates efficacy of venlafaxine in several other conditions including panic disorder, social anxiety disorder, obsessive compulsive disorder, trichotillomania, ADHD, chronic pain, and fibromyalgia. The limited evidence supporting efficacy in these conditions is reviewed. Additional randomized clinical trials with placebo controls are indicated.

Conceptual issues in trichotillomania, a prototypical impulse control disorder.

Impulse control disorders (ICDs) are characterized by irresistible urges to perform acts that result in a reduction of tension and possibly gratification, but also have negative consequences. Trichotillomania, an ICD, is characterized by a recurrent failure to resist impulses to pull out one's hair, resulting in noticeable hair loss. Limited information is available about structural and neurochemical differences in individuals with trichotillomania. Cognitive behavioral techniques are promising treatments for trichotillomania. Pharmacologic treatments have focussed on clomipramine and venlafaxine as potentially effective for the short term control of symptoms in trichotillomania. Selective serotonin reuptake inhibitors, though promising in open trials, seem to be largely ineffective in reducing hair pulling in controlled studies. Durability of pharmacologic benefit for the symptoms of trichotillomania, both in a small trial and in clinical experience, appears to be poor.

Placebo-controlled study of fluvoxamine in the treatment of patients with compulsive buying.

Compulsive buying is a syndrome characterized by the impulsive and/or compulsive buying of unneeded objects that results in personal distress, impairment in vocational or social functioning, and/or financial problems. Results from a two-site, double-blind, placebo-controlled 13-week trial of fluvoxamine are presented. Subjects had problematic buying behavior that they could not control for the previous 6 months or longer and met DSM-IV criteria for impulse control disorder-not otherwise specified (ICD-NOS) and the University of Cincinnati criteria for compulsive buying. Assessments included clinician-rated scales-the Yale-Brown Obsessive Compulsive Scale modified for compulsive buying, the Clinical Global Impression Scale, the Global Assessment of Functioning, and the Hamilton Rating Scale for Depression-and patient self-reports using daily diaries, which measured episodes of compulsive buying. Forty-two subjects gave informed consent, with 37 subjects providing evaluable information and 23 completing the study. Current or past psychiatric comorbidity was present in 74% of subjects. Intent-to-treat and completer analyses failed to show a significant difference between treatments on any measures of outcome. A high placebo-response rate, possibly from the behavioral benefits of maintaining a daily diary, prevents any definitive statement on the efficacy of fluvoxamine in treating compulsive buying.

A placebo-controlled trial of cognitive-behavioral therapy and clomipramine in trichotillomania.

BACKGROUND: The major treatments reported to be effective in the treatment of trichotillomania are cognitive-behavioral therapy (CBT) with habit reversal and serotonin-norepinephrine reuptake inhibitors such as clomipramine. However, the 2 treatments have not been previously compared with each other. This study examines the efficacy of CBT and clomipramine compared with placebo in the treatment of trichotillomania. METHOD: Twenty-three patients with trichotillomania as determined by the Structured Clinical Interview for DSM-III-R entered and 16 completed a 9-week, placebo-controlled, randomized, parallel-treatment study of CBT and clomipramine. Efficacy was evaluated by the Trichotillomania Severity Scale, the Trichotillomania Impairment Scale, and the Clinical Global Impressions-Improvement scale, which were conducted by an independent assessor blinded to the treatment condition. RESULTS: CBT had a dramatic effect in reducing symptoms of trichotillomania and was significantly more effective than clomipramine (p = .016) or placebo (p = .026). Clomipramine resulted in symptom reduction greater than that with placebo, but the difference fell short of statistical significance. Placebo response was minimal. CONCLUSION: Clinicians should be aware of the potential treatments available for trichotillomania. A larger and more definitive study comparing CBT and a serotonin-norepinephrine reuptake inhibitor is indicated.

Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders.

BACKGROUND: Serotonin reuptake inhibitors (SRIs) have demonstrated consistent efficacy in the treatment of obsessive-compulsive disorder (OCD), while agents that are primarily norepinephrine reuptake inhibitors have not. Comparable efficacy has been demonstrated for SRI and non-SRI antidepressants in uncomplicated major depressive disorder (MDD). This multicenter trial is the first comparison of an SRI (sertraline) and a non-SRI antidepressant (desipramine) in the treatment of OCD with concurrent MDD. METHODS: One hundred sixty-six patients diagnosed using structured clinical interviews and recruited from 16 treatment sites were randomly assigned to double-blind treatment with either sertraline (up to 200 mg/d) or desipramine (up to 300 mg/d) over 12 weeks. Measures of severity of OCD and MDD symptoms, as well as adverse effects of the medications, were monitored over the course of the treatment period. RESULTS: Patients assigned to sertraline responded significantly better at end point on measures of OCD and MDD symptoms compared with patients assigned to desipramine. Sertraline was also associated with a significantly greater number of patients who achieved a "robust" improvement in OCD symptoms (> or =40% reduction) compared with desipramine. More patients receiving desipramine than sertraline discontinued treatment because of adverse events. CONCLUSIONS: The SRI sertraline was more effective in reducing MDD and OCD symptoms than the primarily norepinephrine reuptake inhibitor desipramine for patients with concurrent OCD and MDD.

Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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 functional anatomy, neurochemistry, and pharmacology of anxiety.

The functional anatomy of anxiety involves amygdala-based neurocircuits with critical reciprocal connections to the medial prefrontal cortex. Traumatic experiences leave emotional imprints involving the amygdala, with facilitated fear-conditioned associations involving declarative memory traces. Avoidance conditioning is an additional component. An understanding of the functional anatomy of anxiety allows for a new perspective on the various anxiety disorders. The neurotransmitters involved in these circuits are reviewed for their relevance to the pharmacologic choices in the treatment of anxiety. Potent serotonin reuptake inhibitors appear to have superior efficacy in many of the anxiety disorders, with indications that norepinephrine reuptake inhibitors have an advantage in severe forms of major depression. Medications with dual effects--blocking reuptake of both serotonin and norepinephrine (e.g., clomipramine and venlafaxine XR)--have superior benefits in achieving remission in major depression and GAD. These medications may also offer a faster onset of action and theoretically superior benefits in patients with comorbid anxiety disorder and major depression.

A controlled trial of venlafaxine in trichotillomania: interim phase I results.

This article reports the preliminary findings of a two-phase trial examining the efficacy of venlafaxine in trichotillomania. Phase 1 is a 12-week, open-label, prospective trial of venlafaxine in trichotillomania. Venlafaxine was effective in significantly reducing the symptoms of trichotillomania; 8 of 12 patients were considered responders. The implications of the efficacy of venlafaxine in trichotillomania are discussed, including its important advantages over other available antidepressant and anxiolytic medications.

Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment.

BACKGROUND: Previous studies have examined dose reduction and family treatment in schizophrenia, but none has examined their interaction. This study assessed the impact of dose reduction of antipsychotic medication and family treatment on relapse and rehospitalization during maintenance treatment. METHODS: Subjects were 313 male and female outpatients at 5 centers with a DSM-III-R diagnosis of schizophrenia or schizoaffective disorder. In a 3 x 2 design, subjects were randomized to 1 of 3 medication strategies using fluphenazine decanoate under double-blind conditions: continuous moderate dose (standard) (12.5-50 mg every 2 weeks); continuous low dose (2.5-10 mg every 2 weeks); or targeted, early intervention (fluphenazine only when symptomatic). Subjects also were randomized to 1 of 2 family treatment strategies (supportive or applied). Supportive family management involved monthly group meetings. The more intensive applied family management involved monthly group meetings and home visits where communication and problem-solving skills were taught. Patients and families were treated and assessed for 2 years. RESULTS: Both continuous low-dose and targeted treatment increased use of rescue medication and relapse; only targeted treatment increased rehospitalization. This pattern was consistent across both family treatments; there were no differences between family treatments. CONCLUSIONS: These findings reaffirm the value of antipsychotic medication in preventing relapse and rehospitalization. The absence of family treatment differences may be because both conditions engaged families.

Issues in the assessment of treatment response in panic disorder with special reference to fluvoxamine.

Assessment of treatment response in panic disorder is complicated by the multidimensional aspects of panic disorder and agoraphobia, the short-term benefits from nonspecific aspects of treatment, and placebo response. Response to treatment with psychological and pharmacologic treatments of panic disorder is reviewed in this context. The experience of several Phase III studies of fluvoxamine in the treatment of panic disorder is examined as an illustrative example. When the response to placebo or comparison treatment in a study is high, no conclusion can be drawn about the true efficacy of the active treatment.

Sertraline in the treatment of rape victims with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a significant problem following rape, yet reports on the efficacy of pharmacological agents in this population are lacking. The results of an open 12-week clinical trial utilizing sertraline (mean dose 105 mg) in the treatment of adult female rape victims with chronic PTSD are presented. The five completers were, on average, 41.6 years old and 15.6 years postassault. Sertraline reduced PTSD and related symptoms in these rape victims. The mean Clinician Administered PTSD Scale (CAPS) scores decreased by 53%, with four out of five participants responding positively to treatment. These preliminary results support the need for systematic assessment of sertraline in this population.