Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures.

OBJECTIVE: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. METHODS: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. RESULTS: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. CONCLUSIONS: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. LEVEL OF EVIDENCE: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p = 0.29), adjusting for differences at baseline.

An adjunctive Management of Depression Program for difficult-to-treat depressed patients and their families.

BACKGROUND: The goal of this open-label feasibility trial was to test a short-term, adjunctive intervention, the Management of Depression (MoD) Program, to determine if patients with difficult-to-treat forms of depression and their family members could learn to cope more effectively with their illness. METHODS: Nineteen patients meeting The Diagnostic and Statistical Manual IV criteria for major depressive disorder, dysthymia, or chronic/recurrent depression and their family members participated in an open-label study testing the efficacy of the MoD Program. The intervention consisted of nine sessions over 16 weeks, followed by an 8-month maintenance phase. Outcome measures focused on quality of life, psychological and family functioning, and level of depression. RESULTS: Fourteen patients and their family members improved significantly in psychosocial and family functioning, and depression severity (all P-values <.05) by the end of the 16-week intervention. There was also significant improvement in quality of life, psychosocial and family functioning, and depression scores (all P-values<.05) for the 10 patients who completed the maintenance phase. CONCLUSION: The MoD Program is a useful adjunctive intervention that helped patients and their family members deal more effectively with their persisting depression. The disease management approach improved the patient's perceived quality of life and functioning, reduced depressive symptoms, and improved perception of their family's functioning.

Effectiveness of St John's wort in major depression: a randomized controlled trial.

CONTEXT: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation. OBJECTIVE: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States. PARTICIPANTS: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20. INTERVENTION: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I). RESULTS: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively). CONCLUSION: In this study, St John's wort was not effective for treatment of major depression.

Family functioning and suicidality in depressed adults.

This study examined the association between suicidality, family factors, and clinical and diagnostic variables in depressed adult inpatients. The subjects were 121 depressed adult inpatients living with a family member or significant other. Demographic, clinical, and diagnostic information about the patient, and subjective and observer ratings of family functioning were obtained. Trained interviewers rated families of suicidal depressed patients as more dysfunctional than families of patients with no history of attempted suicide. In a logistic regression model, earlier age of depression onset, number of psychiatric hospitalizations, and objectively rated poorer family communication were associated with a history of a prior suicide attempt. Also, modest evidence suggested that patients with a prior suicide attempt perceived their families as more dysfunctional than did their respective family members. Variations in family functioning are associated with different degrees of suicidality. However, prospective longitudinal designs would elucidate the causal relation between family dysfunction and suicidal behavior.

Personality and family functioning in families of depressed patients.

In this cross-sectional study, the authors attempted to identify correlates of family functioning in 86 couples with a depressed member during the acute phase of the patient's depression. Demographic variables, psychiatric status, and personality traits of both the patient and spouse were investigated as potential predictors of family functioning. Regression analyses indicated that lower levels of personality pathology in the patient, higher levels of patient conscientiousness, and less psychological distress in the spouse were associated with healthier family functioning. Future research implications and clinical importance of these findings are discussed.

Why fix what isn't broken? A rejoinder to Ridenour, Daley, & Reich.

Ridenour, Daley, & Reich (2000) suggest that the Family Assessment Device should be reorganized. We disagree and provide further reasons why such a reorganization is unwise.

Gender differences in treatment response to sertraline versus imipramine in chronic depression.

OBJECTIVE: The authors examined gender differences in treatment response to sertraline, a selective serotonin reuptake inhibitor (SSRI), and to imipramine, a tricyclic antidepressant, in chronic depression. METHOD: A total of 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were randomly assigned to 12 weeks of double-blind treatment with sertraline or with imipramine after placebo washout. RESULTS: Women were significantly more likely to show a favorable response to sertraline than to imipramine, and men were significantly more likely to show a favorable response to imipramine than to sertraline. Gender and type of medication were also significantly related to dropout rates; women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the study. Gender differences in time to response were seen with imipramine, with women responding significantly more slowly than men. Comparison of treatment response rates by menopausal status showed that premenopausal women responded significantly better to sertraline than to imipramine and that postmenopausal women had similar rates of response to the two medications. CONCLUSIONS: Men and women with chronic depression show differential responsivity to and tolerability of SSRIs and tricyclic antidepressants. The differing response rates between the drug classes in women was observed primarily in premenopausal women. Thus, female sex hormones may enhance response to SSRIs or inhibit response to tricyclics. Both gender and menopausal status should be considered when choosing an appropriate antidepressant for a depressed patient.

Gender differences in chronic major and double depression.

BACKGROUND: While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. METHODS: 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. RESULTS: Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. LIMITATIONS: Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. CONCLUSIONS: Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

The relationship between quality of interpersonal relationships and major depressive disorder: findings from the National Comorbidity Survey.

BACKGROUND: The current study compared the quality of interpersonal relationships in individuals with major depressive disorder to individuals with dysthymia, comorbid depression, nonaffective disorders, and no psychiatric disorders. METHODS: Using data from the National Comorbidity Study, a series of logistic regressions, controlling for demographic variables, were conducted to examine the strength of the association between a major depressive disorder and interpersonal dysfunction (positive and negative interactions) in contrast to other psychiatric disorders. RESULTS: Respondents with current major depressive disorder reported significantly fewer positive interactions and more negative interactions with their spouse or live-in partner than those with nonaffective disorders, and than those with no psychiatric disorders. There were no significant differences in quality of interpersonal relationships between respondents with major depressive disorder and those with dysthymia. Among those with major depressive disorder, comorbidity or treatment-seeking behavior did not significantly contribute to degree of interpersonal difficulties. The strength of the association between interpersonal dysfunction and depression were, in general, comparable for men and women with major depressive disorder. LIMITATIONS: The cross-sectional design of this report precludes inferences regarding causality between quality of interpersonal relationship and current major depressive disorder. CONCLUSIONS: The results of this study indicate that, relative to psychiatric illness in general, poor intimate relationships are characteristic of a current major depressive disorder.

"Factor analyses of the family assessment device," by Ridenour, Daley, & Reich.

Ridenour, Daley, and Reich conducted a series of factor analyses using the correlational matrix of the subscale scores of the Family Assessment Device (FAD), published in Family Process, December, 1999. They conclude that "the FAD subscales be reorganized from their current seven-subscale format" (p. 507). We propose that this suggestion for reorganization is premature and based on the inappropriate application of an "internal consistency" model of scale construction to the FAD. We further suggest that the most important criteria regarding an assessment instrument are those of reliability, validity, and clinical utility. In the absence of this kind of data regarding alternative organizations of the FAD, we believe that the original subscales remain the best choice.

Increases in manic symptoms after life events involving goal attainment.

Bipolar disorder has been conceptualized as an outcome of dysregulation in the behavioral activation system (BAS), a brain system that regulates goal-directed activity. On the basis of the BAS model, the authors hypothesized that life events involving goal attainment would promote manic symptoms in bipolar individuals. The authors followed 43 bipolar I individuals monthly with standardized symptom severity assessments (the Modified Hamilton Rating Scale for Depression and the Bech-Rafaelsen Mania Rating Scale). Life events were assessed using the Goal Attainment and Positivity scales of the Life Events and Difficulties Schedule. As hypothesized, manic symptoms increased in the 2 months following goal-attainment events, but depressed symptoms were not changed following goal-attainment events. These results are congruent with a series of recent polarity-specific findings.

Combined treatment for patients with double depression.

BACKGROUND: Patients with double depression (major depression + dysthymia) have a particularly chronic course of illness, yet few studies have investigated treatments for these patients. METHODS: 26 inpatients with double depression were assigned to two types of treatment: (1) pharmacotherapy and (2) combined treatment (pharmacotherapy + cognitive-behavioral psychotherapy). Treatment began while the patients were in the hospital and continued for 20 weeks after discharge. Comprehensive assessments were conducted at the end of treatment as well as at 6- and 12-month follow-up assessments. RESULTS: The results indicated that double-depressed patients who received the combined treatment had significantly lower levels of depression and higher social functioning at the end of treatment. However, no significant differences between groups were found at the follow-up assessments. CONCLUSIONS: These results suggest that the addition of cognitive-behavioral psychotherapy may produce an improved short-term outcome for patients with double depression.

The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine.

BACKGROUND: Previous research has suggested that depressed patients, and particularly chronically depressed patients, have significant impairments in many areas of their lives. While previous studies suggested that these "psychosocial" impairments improve following pharmacologic treatment, no large scale definitive study using multiple measures of psychosocial functioning has been reported. METHOD: We assessed multiple domains of psychosocial functioning using interviewer-rated and self-report measures within the context of a 12-week acute treatment trial of sertraline and imipramine for patients with chronic depression (double depression and chronic major depression). We also compared the psychosocial functioning data of this sample before and after treatment with normative data available from published community samples. RESULTS: Chronically depressed patients manifested severe impairments in psychosocial functioning at baseline. After treatment with sertraline or imipramine, psychosocial functioning improved significantly. Significant improvements appeared relatively early in treatment (week 4). Despite these highly significant improvements in functioning during acute treatment, the study sample as a whole did not achieve levels of psychosocial functioning comparable to a comparator nondepressed community sample. However, patients who reached full symptomatic response (remission) during acute treatment did have levels of psychosocial functioning in most areas at endpoint that approached or equaled those of community samples. CONCLUSION: These results indicate that successful antidepressant treatment with sertraline or imipramine can alleviate the severe psychosocial impairments found in chronic depression.

Lithium plus valproate as maintenance polypharmacy for patients with bipolar I disorder: a review.

Standard pharmacotherapy for the maintenance treatment of patients with bipolar I disorder consists of lithium, valproate, or carbamazepine. However, many patients fail to respond to monotherapy with any of these agents, and as a result, psychiatrists often resort to polypharmacy. Findings from some open-label trials and retrospective chart reviews suggest this approach may be useful, but in the few controlled trials that have been conducted, the results have been negative. One drug combination that warrants further study as maintenance therapy is lithium plus valproate. Each is approved by the U.S. Food and Drug Administration for treatment of acute mania, and lithium has demonstrated efficacy for maintenance treatment as well. Some preliminary evidence suggests that the combination can be effective for patients who do not respond to monotherapy, and it seems to be no more dangerous than monotherapy. Concomitant administration of lithium plus valproate does not significantly alter lithium pharmacokinetics, and statistically significant changes that arise in valproate pharmacokinetics are not clinically significant. Although it is not known whether the drugs interact to augment response, many of their effects in the central nervous system do differ, and there is no indication of pharmacodynamic interactions that oppose each other. Finally, some evidence suggests that lithium and valproate may differ with regard to clinical variables that predict response to treatment.

Psychosocial factors and the long-term course of major depression.

Fifty-nine subjects participated in a telephone follow-up interview 6 years after being hospitalized with a severe major depressive episode and 5 years after completing a 12 month follow-up study. Patient information was used to provide a rating of symptom-free (n = 19), episodic (n = 30), or chronic (n = 10) that described each patient's long-term course of illness. Few variables from the acute stage were related to long-term course of illness; however, early patterns of global and family functioning, number of life events, and rapid reduction in depressive symptomatology were found to be of prognostic significance. For patients whose depression is severe enough to warrant hospitalization, the pattern of functioning in the first few months after discharge from hospital is a strong indicator of the future long-term course.

A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder.

BACKGROUND: This pilot study compared the efficacy of lithium plus divalproex sodium with the efficacy of lithium alone for the continuation and maintenance treatment of patients with bipolar I disorder. METHOD: Twelve patients with bipolar I disorder as defined by the DSM-III-R were recruited and followed prospectively for up to 1 year. Each subject received lithium at serum levels of 0.8 to 1.0 mmol/L and a management/education session weekly or every 2 weeks. By random assignment, subjects received either divalproex sodium or placebo in conjunction with lithium. Divalproex sodium was adjusted to achieve a serum concentration of 50 to 125 micrograms/mL. Adjunctive medications were used on an as needed basis to treat psychosis, depression, and anxiety. The course of illness was monitored through use of the Longitudinal Interval Follow-up Examination. RESULTS: Subjects treated with the combination of lithium and divalproex were significantly less likely to suffer a relapse or recurrence (p = .014), but were significantly more likely to suffer at least one moderate or severe adverse side effect (p = .041). There was no significant difference between groups in the use of adjunctive medication. CONCLUSION: These results provide preliminary evidence of the risks and benefits of combining lithium with divalproex sodium for the continuation and maintenance treatment of bipolar I disorder.

Family functioning and mental illness: a comparison of psychiatric and nonclinical families.

The primary objective of the present investigation was to examine adaptive functioning in the families of patients with a wide range of psychiatric disorders. Seven dimensions of family functioning, as measured by the Family Assessment Device (FAD), were compared across families of patients with a schizophrenia spectrum disorder (n = 61), bipolar disorder (n = 60), major depression (n = 111), anxiety disorder (n = 15), eating disorder (n = 26), substance abuse disorder (n = 48), and adjustment disorder (n = 46). Families in each psychiatric group were also compared to a control group of nonclinical families (N = 353). Results indicated that regardless of specific diagnosis, having a family member in an acute phase of a psychiatric illness was a risk factor for poor family functioning compared to the functioning of control families. However, with few exceptions, the type of the patient's psychiatric illness did not predict significant differences in family functioning. Thus, having a family member with a psychiatric illness is a general stressor for families, and family interventions should be considered for most patients who require a psychiatric hospitalization for either the onset of, or an acute exacerbation of, any psychiatric disorder.

Prodromal and residual symptoms in bipolar I disorder.

The objective of the current study was to better understand the nature of prodromal and residual symptoms of mania and depression, as reported by patients with bipolar I disorder and their family members. Prodromal and residual symptoms of mania and depression were elicited from 74 patients with bipolar I disorder. In 45 cases, an adult family member provided similar information. Three clinicians classified the symptoms into six broad categories: behavioral, cognitive, mood, neurovegetative, social, and other. The clinicians also categorized symptoms as typical or idiosyncratic. Seventy-eight percent of the patients reported prodromal depressive symptoms and 87% reported prodromal manic symptoms; greater than half of the patients disclosed residual symptoms of depression (54%) and mania (68%). Within each of these four illness categories, cognitive symptoms were consistently the most common symptoms reported by patients. A substantial number of symptoms were idiosyncratic, particularly those reported for residual depression. Agreement between patient and family members on reported symptoms was strong for the prodromal phase of both polarities, but less so for the residual phases. These preliminary results suggest that patients with bipolar I disorder and their family members can identify prodromal and residual symptoms, that these symptoms are quite common, and that prodromal symptoms may be more prevalent or easier to identify than residual symptoms. Cognitive symptoms were consistently the most common symptoms reported by patients.

Social-vocational adjustment in unipolar mood disorders: results of the DSM-IV field trial.

430 patients participating in the DSM-IV field trial receiving a DSM-III-R SCID-derived diagnosis of episodic major depression (n = 131), dysthymic disorder (n = 37) and double depression (n = 262) completed the social adjustment scale-self-report (Weissman and Bothwell, 1976). Patients with double depression demonstrated greater social morbidity than those suffering from episodic major depression or dysthymic disorder (P < 0.05). Significant predictors of high social morbidity in double depressives included severity of symptoms (P < 0.0001), followed by age of onset of first major depression (P < 0.04). Subscale analysis revealed that double depressives were significantly more impaired in work outside the home and in terms of their financial status (P < 0.05).