Evidence for neuroplastic compensation in the cerebral cortex of persons with depressive illness.

We yoked anatomical brain magnetic resonance imaging to a randomized, double-blind, placebo-controlled trial (RCT) of antidepressant medication for 10-week's duration in patients with dysthymia. The RCT study design mitigated ascertainment bias by randomizing patients to receive either duloxetine or placebo, and it supported true causal inferences about treatment effects on the brain by controlling treatment assignment experimentally. We acquired 121 anatomical scans: at baseline and end point in 41 patients and once in 39 healthy controls. At baseline, patients had diffusely thicker cortices than did healthy participants, and patients who had thicker cortices had proportionately less severe symptoms. During the trial, symptoms improved significantly more in medication-compared with placebo-treated patients; concurrently, thicknesses in medication-treated patients declined toward values in healthy controls, but they increased slightly, away from control values, in placebo-treated patients. Changes in symptom severity during the trial mediated the association of treatment assignment with the change in thickness, suggesting that the beneficial effects of medication on symptom severity were at least partially responsible for normalizing cortical thickness. Together our findings suggest that baseline cortical hypertrophy in medication-free patients likely represented a compensatory, neuroplastic response that attenuated symptom severity. Medication then reduced symptoms and lessened the need for compensation, thereby normalizing thickness. This is to the best of our knowledge the first study to report within an RCT a differential change in cortical morphology during medication treatment for depressive illness and the first to provide within an RCT in vivo evidence for the presence of neuroanatomical plasticity in humans.

Prediction of compliance with outpatient referral in patients with schizophrenia and psychoactive substance use disorders.

BACKGROUND: Most patients with concurrent schizophrenia and psychoactive substance use disorders may be adequately treated as outpatients. However, many do not comply with outpatient referrals and are therefore at heightened risk for rehospitalization. METHOD: Drawing on standardized interview data collected during an index hospitalization, we developed a logistic regression model to predict compliance with outpatient treatment. The model was tested on a confirmatory sample, and its sensitivity and specificity were further evaluated in a cross-validation study of 1000 random samples. RESULTS: In a reference sample, the logistic function distinguished compliant from noncompliant patients in 37 (76%) of 49 cases. In a confirmatory sample, compliance status was predicted for 11 (78%) of 14 patients with a sensitivity of 1.00 and a specificity of 0.67. Women and patients with negative syndrome schizophrenia were compliant with outpatient referral, whereas those with mixed syndromes were most likely to be noncompliant. Cross-validation supports the stability of the model. CONCLUSION: While most persons with schizophrenia and concurrent substance abuse comply with integrated outpatient treatment, most who cannot may be predicted in advance.

Outpatient group therapy for schizophrenic substance abusers.

A once-a-week outpatient therapy group was designed for schizophrenic substance abusers. Over 1 year, the group members (including dropouts) had a marked decrease in days of hospitalization.

Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: effects on personality.

OBJECTIVE: Although previous studies have shown that dysthymia, or chronic depression, commonly responds to antidepressant medications (with improvements in depressive symptoms and psychosocial functioning), there have been no systematic studies of the impact of antidepressant treatment on personality variables in patients with this disorder. METHOD: In a multicenter study, 410 patients with early-onset primary dysthymia were treated in a randomized prospective fashion with sertraline, imipramine, or placebo. The data were analyzed in terms of the subjects' scores on the Tridimensional Personality Questionnaire, a 100-item self-report instrument that measures four temperamental dimensions: harm avoidance, reward dependence, novelty seeking, and persistence. RESULTS: At baseline, the harm avoidance scores of the dysthymic subjects were approximately 1.5 standard deviations higher than those of a previously reported community sample. After treatment, there was a significant decrease in harm avoidance scores, with no significant between-group differences. Remission of dysthymia was associated with significantly greater improvement in harm avoidance, with the greatest numerical change found in the patients treated with sertraline. Subjects' Tridimensional Personality Questionnaire scores were correlated at a 0.50 level with the Social Adjustment Scale both pre- and posttreatment, suggesting that a high degree of harm avoidance may be associated with poor social functioning. CONCLUSIONS: Before treatment, chronically depressed patients demonstrate an abnormality in temperament, as measured by elevated degrees of harm avoidance. Remission of dysthymia is associated with improvement in this aspect of temperament.

A randomized double-blind study of fluoxetine versus placebo in the treatment of dysthymia.

OBJECTIVE: The purpose of this study was to assess the efficacy of fluoxetine, a selective serotonergic antidepressant, in the treatment of dysthymia. METHOD: Thirty-five patients who met criteria for dysthymia, but not major depression, began randomized, double-blind 8-week trials of fluoxetine or placebo. RESULTS: Of 32 patients who completed the study, 10 (62.5%) of the 16 patients given fluoxetine and three (18.8%) of the 16 given placebo responded to treatment. Response was defined as 1) 50% or greater decrease in Hamilton Rating Scale for Depression score and 2) a score of 1 or 2 on the Clinical Global Impression (CGI) improvement subscale. Fluoxetine subjects showed significantly greater improvement at week 8 than placebo subjects on the Hamilton depression and CGI scales, but not on the Hopkins Symptom Check-list (58-item) or the Cornell Dysthymia Rating Scale. CONCLUSIONS: When compared to placebo, fluoxetine showed short-term effectiveness in treating dysthymic symptoms.

Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: psychosocial outcomes.

OBJECTIVE: The purpose of this study was to determine the effects of antidepressant pharmacotherapy on mood symptoms and psychosocial outcomes in dysthymia. METHOD: In a multicenter, double-blind, parallel-group trial, 416 patients with a diagnosis of early-onset primary dysthymia (DSM-III-R) of at least 5 years' duration without concurrent major depression were randomly assigned to 12 weeks of acute-phase therapy with sertraline, imipramine, or placebo. The psychosocial outcome measures used in the study were the Global Assessment of Functioning Scale, the Social Adjustment Scale, the Longitudinal Interval Follow-up Evaluation psychosocial ratings, and the Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Sertraline and imipramine were significantly better than placebo in improving psychosocial outcomes as measured by the first three instruments. The Quality of Life Enjoyment and Satisfaction Questionnaire scores demonstrated significant improvements from baseline, and both active treatments produced significantly greater improvements than placebo. Significantly fewer patients discontinued sertraline (6.0%) than discontinued imipramine (18.4%) because of adverse events. CONCLUSIONS: Pharmacotherapy is an effective treatment for dysthymia in terms of psychosocial functioning as well as depressive symptoms, even when the dysthymia is long-standing.

Venlafaxine in the treatment of dysthymia: an open-label study.

BACKGROUND: Numerous studies have demonstrated the effectiveness of antidepressant medications in the treatment of dysthymia, or chronic mild depression. Venlafaxine blocks reuptake of both serotonin and norepinephrine and may produce a more complete antidepressant response than do single-mechanism selective serotonin reuptake inhibitors. The purpose of this open-label study was to provide preliminary data on the tolerability and effectiveness of venlafaxine for patients with dysthymia. METHOD: Twenty-two dysthymic subjects (DSM-III-R criteria) were enrolled in this 10-week, open-label trial, and 5 dropped out prior to their second visit. Seventeen subjects (77.3%) received more than 1 week of medication. RESULTS: Of these 17 subjects, 13 (76.5%) were treatment responders. Results of paired sample t tests were highly significant, indicating that, on average, there was significant improvement on all measures of symptomatology and functioning, with mean +/- SD scores on the Hamilton Rating Scale for Depression decreasing from 20.95 +/- 6.50 at baseline to 6.06 +/- 5.49 at week 10. The mean +/- SD final dose was 178.68 +/- 70.80 mg/day. Side effects were reported by 17 (85%) of the 20 subjects for whom tolerability was assessed (the most common were fatigue, dry mouth, and nausea); 5 (22.7%) of 22 patients discontinued treatment because of side effects, primarily nausea (N = 3). CONCLUSION: These findings suggest the benefit of venlafaxine in the treatment of chronic depression and the need for more rigorous studies.

Current Perspectives on the Diagnosis and Treatment of Double Depression.

In recent years, the frequency with which patients present with 'double depression', i.e. coexisting chronic depression (dysthymia) and acute major depression, has become increasingly evident. A growing research literature demonstrates that patients with double depression are at increased risk for poor outcome, including poor psychosocial functioning, high usage of medical services, high rates of suicide attempts, and increased recurrence of major depression. Furthermore, naturalistic studies have shown that when these patients are treated in the community, they often do not receive adequate antidepressant medication to treat their acute or chronic depressive disorders.In this article, we introduce a typology that is designed to assist clinicians in determining useful strategies in the short and long term treatment of double depression. This differentiates between those patients with double depression who present primarily with acute depression; those presenting primarily with chronic depression (where treatment can focus on the single, more severe disorder, and may be time-limited or episodic); and those presenting with severe acute depression and severe chronic depression, in whom lifelong medication is often required. Aggressive treatment is recommended for all patients with double depression, but refined treatment strategies based on depressive typology may help to increase compliance, consolidate therapeutic gains and forestall relapse.A growing psychopharmacology literature shows that several different classes of medication [tricyclic antidepressants, monamine oxidase inhibitors, selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors and others] are effective in the treatment of double depression, although perhaps somewhat less effective than in the treatment of acute major depression.

Long-term treatment of double depression: a preliminary study with serotonergic antidepressants.

1. There is increasing evidence that many patients with major depression also have coexisting dysthymia, and that antidepressant treatment may alleviate both conditions. 2. Open-label study of fluoxetine and trazodone for 18 patients meeting DSM-III-R criteria for concurrent dysthymia and major depression. 3. Fourteen patients completed three-month medication trials, and seven (50%) of completers) responded to treatment. At five months, eight (57.1%) were in remission. Fluoxetine was significantly better tolerated than trazodone, with respective dropout rates of 7.7% and 80%. 4. Findings are consistent with efficacy of serotonergic agents in this condition.

Follow-up assessment of medication-treated dysthymia.

1. The objective was to assess long-term efficacy of antidepressant medications in dysthymia. 2. In a naturalistic study, patients with DSMIII-R dysthymia who had participated in previous antidepressant trials with fluoxetine and trazodone were evaluated at a mean of 40.0 weeks of follow-up to assess whether medication response persisted over time. A multivariate analysis was performed for patients on vs. off medication. Relapse rates (with relapse defined as HDRS score > 13) were also compared for these two groups. 3. Of 40 patients, the 24 still on medication showed significantly lower scores on most rating scales (HDRS, Cornell Dysthymia Rating Scale, and CGI, but not on the SCL-58) than the heterogeneous group of 16 patients not taking medication. Relapse was low (17.4%) among patients remaining on medication. 4. These preliminary findings suggest that dysthymia patients who remain on medication maintain improvement over time.

A preliminary study of serotonergic antidepressants in treatment of dysthymia.

There is increasing evidence that antidepressants may alleviate symptoms of dysthymia, but few prior studies on selective serotonergic agents. Twenty patients meeting criteria for dysthymia, but not meeting criteria for major depression, received open label trials of a serotonergic antidepressant, either fluoxetine or trazodone. Seventeen (85%) completed three-month medication trials, and of these, twelve (70.6% of completers) responded to treatment. Seven (41.2% of completers) were still in remission on follow-up at five months. Both fluoxetine and trazodone were well tolerated in dysthymics, and showed similar short-term effectiveness in treating dysthymic symptoms.

Assessing HIV risk in the general hospital psychiatric clinic.

Of 101 new admissions to an urban outpatient psychiatric clinic, 17 (16.8%) were known to be at high risk and 11 (10.9%) at suspected high risk for developing or transmitting HIV infection, but apparently few were appropriately counseled. This suggests a need for implementing specific policies and procedures for HIV assessment and counseling.

Dysthymic disorder: integrating research findings into clinical treatment.

Dysthymic disorder, a form of chronic depression, has been studied over the past two decades. A variety of forms of research, from epidemiological research to psychopharmacology and psychotherapy outcome studies, has provided data that may help clinicians who treat patients with dysthymic disorder. This article reviews clinically relevant research studies and applies their findings to the clinical setting. Epidemiological research and prospective follow-up studies can define the risks of untreated and under-treated chronic depression. Studies on the phenomenology of dysthymic disorder can help the clinician assess target symptoms. Psychopharmacology and psychotherapy research can help guide treatment choices. The emerging literature on combining medication and psychotherapy can clarify goals for different phases of treatment. Thus the clinician has a significantly greater chance of helping patients with dysthymic disorder now than only 20 years ago.

Positive and negative syndrome typology in schizophrenic patients with psychoactive substance use disorders.

Our objective was to begin to elucidate the interrelationship between psychoactive substance use disorders (PSUD) and schizophrenia in patients who concurrently have both disorders. A series of 29 psychiatric inpatients with concurrent Research Diagnostic Criteria (RDC)-diagnosed schizophrenia and PSUD (PSUD/S patients) were evaluated with rating inventories including the Schedule for Assessment of Negative Symptoms (SANS) and the Schedule for Assessment of Positive Symptoms (SAPS). Subjects had chronic schizophrenia with a mean duration of 9.9 years, and virtually all (93.1%) regularly abused cocaine and alcohol, as well as marijuana. The majority of subjects (58.6%) had mixed-syndrome typology, as defined by Andreasen; 24.1% had negative syndrome; and 16.7% had positive syndrome. Contrary to predictions, negative-syndrome PSUD/S patients had fewer years post-onset of schizophrenia than those patients with positive syndrome. In contrast to other schizophrenic patients, in whom the trajectory of symptoms is believed to change from a predominance of positive symptoms to a predominance of negative symptoms over the course of illness, in a sample of patients with comorbid PSUD/S we found the opposite pattern. This may have implications in the development of PSUD among certain schizophrenics, and may help to guide both psychiatric and substance abuse treatment of such patients.

Integrated services for treatment of schizophrenic substance abusers: demographics, symptoms, and substance abuse patterns.

We have previously described a model of outpatient integrated treatment for patients with comorbid psychoactive substance use disorders and schizophrenia (PSUD/S)(1). Here we review relevant literature on comorbidity and outline the rationale for integrated services. Further, we describe results from 3 related studies: First, we document the approximate incidence of PSUD among a heterogeneous group of 602 schizophrenic inpatient admissions to our hospital. Second, we describe in greater detail the psychiatric symptoms and patterns of substance abuse among a subsample of 106 inpatients with PSUD/S, contrasting them with 112 patients with PSUD and mixed psychotic disorders, but who are not schizophrenic. Third, we present a prospective research project and describe a sample of 30 patients with PSUD/S, detailing demographic characteristics, psychiatric symptoms and substance abuse history. Attention is given to current issues in the differential diagnosis of patients with PSUD/S using standardized instruments.

Integrating services for schizophrenia and substance abuse.

Over the past decade, several studies have attempted to determine whether integrating psychiatric and substance abuse treatment leads to better outcome for patients with comorbid schizophrenia and substance use disorders. A recent (1999) Cochrane Review (1) analyzed the effectiveness of prospective randomized studies of integrated treatment approaches, and concluded that there was no clear evidence for superiority of integrated treatment. This paper describes one such integrated treatment approach, in Beth Israel Medical Center's COPAD (Combined Psychiatric and Addictive Disorders) program. We summarize findings from an initial outcome study and a recent replication study; and describe clinical and research issues relevant to this population. Our data suggests the benefits of integrated treatment for patients with addictive disorders and schizophrenia, at least with regard to treatment retention. Clinical issues for such patients include identification of patients at risk, proper assessment and treatment planning, decision-making about mainstreaming vs. referral to specialized programs, and the importance of initial engagement and ongoing reengagement in successful treatment.

Bupropion sustained-release for the treatment of dysthymic disorder: an open-label study.

Many studies of antidepressants in the treatment of dysthymic disorder (DD) have been conducted, but none has included bupropion sustained-release (SR). The aim of this study was to provide preliminary data on the tolerability and effectiveness of bupropion SR for patients with DD. Twenty-one adult subjects meeting DSM-IV criteria for DD were enrolled in this 8-week open-label study. Bupropion SR was initiated at 150 mg/day and was increased to a maximum of 200 mg, twice daily. Response was defined as a 50% or greater decrease in score on the Hamilton Rating Scale for Depression (HAM-D). Of these 21 subjects, 15 (71.4%) responded to treatment. All paired sample t-tests were highly significant, demonstrating average improvement on all measures of symptomatology and functioning. Subject scores on the HAM-D decreased from 21.7 +/- 5.6 at baseline to 5.9 +/- 3.6 at week 8 (t[19] = 12.74, p < 0.001). The average final dosage was 364 mg/day. None of the subjects dropped out during the trial. Patients with a history of alcohol or chemical abuse were significantly less likely to respond to bupropion. Side effects were reported by eight subjects (38.1%), and the most frequently reported effects were headache, decreased appetite, insomnia, gastrointestinal problems, restlessness, and tremulousness. These findings suggest the effectiveness and high tolerability of bupropion SR for the treatment of DD. Double-blind prospective studies are needed for the comparison of bupropion SR to both placebo and other medications, assessing both initial and sustained responses to treatment.

A rating inventory for resident case presentations.

We devised a rating scale, the Resident Case Presentation Inventory (RCPI), to evaluate psychiatry residents' case presentations at our hospital's disposition conference. A review of 69 inpatient cases presented prior to discharge revealed that residents' greatest deficiencies were in the following two areas: 1) knowing indications for specific outpatient treatments and 2) coordinating input from various clinical disciplines, both inpatient and outpatient. The RCPI allows early identification of residents' educational needs and can give ongoing feedback on their progress.

A clinical profile of patients affected by state regulation of benzodiazepine prescriptions.

OBJECTIVE: In 1989 New York State extended regulation of controlled substances to benzodiazepines. To study the effects on patients, the authors examined characteristics of patients who came to a psychiatric outpatient clinic seeking benzodiazepines during the year after the regulation took effect. METHODS: Demographic and clinical characteristics of 44 patients who sought benzodiazepines were compared with those of 297 other patients evaluated at the clinic during the same period. Compliance with clinic treatment recommendations by patients who sought benzodiazepines was assessed at six-month follow-up. RESULTS: Patients seeking benzodiazepines were predominantly impoverished minority women with a diagnosis of a mood disorder or anxiety disorder. Most were not drug or alcohol abusers. After evaluation at the clinic, nearly half received prescriptions for antidepressant medications instead of benzodiazepines. Although the patients seeking benzodiazepines had many psychosocial problems, they had poor compliance with clinic psychotherapy interventions. CONCLUSIONS: Regulation of benzodiazepine prescriptions appeared to significantly disrupt the treatment of some patients and to encourage them to seek treatment in a psychiatric setting. The high frequency of mood disorders among these patients suggests that some patients may have been misdiagnosed earlier as having anxiety disorder and raises questions about the appropriateness of their previous use of benzodiazepines.