James C.-Y. Chou

Maintenance efficacy of divalproex in the prevention of bipolar depression

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2u2009:u20091u2009:u20091 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial

BACKGROUNDnEnhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide.nnnMETHODSnThis study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events.nnnRESULTSnTen baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinsons, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present.nnnCONCLUSIONSnThis is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

Family-focused treatment for caregivers of patients with bipolar disorder

OBJECTIVESnFamily members of patients with bipolar disorder experience high rates of subjective and objective burden which place them at risk for adverse physical health and mental health outcomes. We present preliminary efficacy data from a novel variation of Family Focused Treatment [Miklowitz DJ. Bipolar Disorder: A Family-Focused Treatment Approach (2(nd) ed.). New York: The Guilford Press, 2008] that aimed to reduce symptoms of bipolar disorder by working with caregivers to enhance illness management skills and self-care.nnnMETHODSnThe primary family caregivers of 46 patients with bipolar I (n = 40) or II (n = 6) disorder, diagnosed by the Structured Clinical Interview for DSM-IV Axis I Disorders, were assigned randomly to receive either: (i) a 12-15-session family-focused, cognitive-behavioral intervention designed to provide the caregiver with skills for managing the relatives illness, attaining self-care goals, and reducing strain, depression, and health risk behavior [Family-Focused Treatment-Health Promoting Intervention (FFT-HPI)]; or (ii) an 8- to 12-session health education (HE) intervention delivered via videotapes. We assessed patients pre- and post-treatment on levels of depression and mania and caregivers on levels of burden, health behavior, and coping.nnnRESULTSnRandomization to FFT-HPI was associated with significant decreases in caregiver depressive symptoms and health risk behavior. Greater reductions in depressive symptoms among patients were also observed in the FFT-HPI group. Reduction in patients depression was partially mediated by reductions in caregivers depression levels. Decreases in caregivers depression were partially mediated by reductions in caregivers levels of avoidance coping.nnnCONCLUSIONSnFamilies coping with bipolar disorder may benefit from family interventions as a result of changes in the caregivers ability to manage stress and regulate their moods, even when the patient is not available for treatment.

Cocaine craving and attentional bias in cocaine-dependent schizophrenic patients

Cocaine craving has been implicated as a major factor underlying addiction and drug relapse. From a cognitive viewpoint, craving may reflect, in part, attentional processing biased in favor of drug-related cues and stimuli. Schizophrenic individuals (SZ), however, abuse cocaine in high numbers but typically manifest baseline cognitive deficits that impair their ability to selectively allocate their attentional resources. In this study, we examined the relationship between attentional bias and craving in patients with cocaine dependence (COC; n=20), schizophrenic patients comorbid for cocaine dependence (COC+SZ; n=23), as well as two other comparison groups using a modified version of the Stroop test to include cocaine-relevant words. Results revealed that only the COC patients demonstrated Stroop interference on the cocaine-related words. Moreover, COC patients attentional processing biases were significantly associated with their cocaine craving severity ratings. COC+SZ patients, in contrast, did not demonstrate Stroop interference and manifested significantly fewer craving symptoms than their COC counterparts. These results suggest that COC+SZ patients inability to selectively encode their drug-use experience may limit and shape their subjective experience of craving cocaine and motivation for cocaine use.

The InterSePT scale for suicidal thinking reliability and validity

BACKGROUNDnThe InterSePT Scale for Suicidal Thinking (ISST) is a 12-item instrument for the assessment of current suicidal ideation in patients with schizophrenia and schizoaffective disorders. We report the psychometric characteristics of this new scale based on two studies.nnnMETHODnIn Study 1, 22 inpatients with schizophrenia and schizoaffective disorders, who had recently attempted suicide or engaged in suicidal ideation, were rated by three trained independent raters to examine interrater reliability. In Study 2, a total of 980 patients with schizophrenia or schizoaffective disorder with a history of suicidal ideation in the past 36 months were enrolled in a 2-year industry-sponsored suicide prevention study. At baseline, these patients were administered the ISST and the Clinical Global Impression Scale for Severity of Suicidality (CGI-SS) by the Principal Investigator (PI) and by a blinded rater (BR), who also administered the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDS), and the Scale of Functioning (SOF). Indices of internal reliability, construct and discriminant validity were examined.nnnRESULTSnThe intraclass correlation coefficient (ICC) for the total ISST score for the 22 subjects in Study 1 was 0.90 and mean weighted item kappa coefficients ranged from 0.66 to 0.92. In Study 2, internal reliability (Cronbach alpha) was high, ranging from 0.86 to 0.89 for the individual items, and the overall Cronbach alpha coefficient for all items was 0.88. The ISST (PI) total score was highly correlated with the CGI-SS by the blind rater (r = 0.61, p < 0.0001). ISST total scores significantly differentiated the different levels of CGI-SS (F = 519.2; p < 0.0001). Results of construct and discriminant validity analyses are also presented.nnnCONCLUSIONnThe ISST is a reliable and valid instrument for the assessment of current suicidal thinking in patients with schizophrenia and schizoaffective disorder by both clinicians and researchers.

Recent Advances in Treatment of Acute Mania

Standard and more recent advances in treatment of acute mania are reviewed with special emphasis on controlled studies. Lithium is still the drug of choice and the most common treatment for mania, but some of its limitations have become more apparent, and specific indications for its use are defined. Alternatives to lithium are recommended for psychotic, rapid cycling, severely manic, and lithium-refractory patients. Neuroleptics are effective and used commonly but carry risks of long term side effects. Substantial reduction in neuroleptic dose and duration of exposure is probably feasible in many patients. Neuroleptic-lithium combinations are popular but do not have clear advantages over treatment with a single drug in the initial treatment of acute mania. These combinations have also been associated with increased neurotoxicity. Carbamazepine, both alone and in combination with lithium, has been used increasingly over recent years. Its efficacy is comparable to lithium, but clinical features predicting responsiveness may be different for these two drugs. Carbamazepine-neuroleptic combinations offer little advantage over neuroleptics alone. Valproic acid, verapamil, clonazepam, lorazepam, benzodiazepine-neuroleptic combinations, clonidine, tryptophan, propranolol, and electroconvulsive therapy are also popular, but their effectiveness has not yet been adequately confirmed by controlled studies.

Learning and memory impairment in cocaine-dependent and comorbid schizophrenic patients

Impairments in verbal learning and memory functioning have been found to be cardinal features among individuals with schizophrenia as well as among non-schizophrenic cocaine abusers. Cognitive deficits in these areas, moreover, have been associated with poor treatment response and short-term outcome. Little is known, however, about the acute effects of cocaine abuse on schizophrenic patients learning and memory functioning. Consequently, a potentially reversible and treatable source of cognitive impairment has been virtually ignored. The present study examined the extent of verbal learning and memory impairment in a group of cocaine-dependent schizophrenic patients (n=42) and a group of non-schizophrenic cocaine-dependent patients (n=21) within 72 h of the last cocaine use using the California Verbal Learning Test (CVLT). Schizophrenic patients (n=34) without any substance-use disorders were also tested in an identical time frame and served as a comparison group. Results revealed that all groups demonstrated significant learning and memory impairment relative to CVLT published age and gender corrected norms. Both cocaine-dependent and non-substance abusing schizophrenic groups presented a very similar pattern of impaired learning and recall performance across all CVLT task domains. Comorbid patients, in contrast, presented with marked deficits in their ability to learn and recall verbal information relative to either schizophrenic or cocaine-only groups. Moreover, the cocaine-abusing schizophrenic patients showed significant forgetfulness of the information that they did acquire during delayed recall conditions. The performance deficits exhibited by cocaine-abusing schizophrenic patients differed not only in relative severity of impairment, but also qualitatively in their increased rates of forgetfulness of acquired information. These results are interpreted in terms of the neurobiological substrates of learning and memory and the neurobiological impact of cocaine on schizophrenic patients cognition during the early phase of inpatient hospitalization. These results suggest that comorbid patients should be targeted for specialized remediation efforts at the beginning phases of inpatient treatment.

Acute mania : Haloperidol dose and augmentation with lithium or lorazepam

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.

Neuroleptics in Acute Mania: A Pharmacoepidemiologic Study

OBJECTIVE: To provide an epidemiologic descriptive analysis of the acute drug treatment of inpatients with bipolar mania in state psychiatric facilities in 1990. METHODS: We surveyed the first 3 weeks of drug treatment of all inpatients with bipolar mania who were admitted to 22 New York State adult psychiatric facilities during a 6-month period (n = 528). RESULTS: Almost all patients with mania were treated with neuroleptics. The mean ± SD neuroleptic dosage was 684 ± 543 mg/d chlorpromazine equivalents. Sixty-one percent of the patients received lithium and 12% received carbamazepine or valproate. Neuroleptic dosage was related to age, with older patients receiving lower dosages. Patients receiving combination treatment of a neuroleptic with either lithium, an anticonvulsant, or a benzodiazepine received a mean neuroleptic dosage similar to that of patients treated with a neuroleptic alone. CONCLUSIONS: Although their use has been widely discouraged for mood disorders, neuroleptics have been the standard treatment for acute mania.

Convergent validity and neuropsychological correlates of the schedule for the assessment of negative symptoms (SANS) attention subscale.

Cognitive deficits have come to be viewed as a hallmark feature of schizophrenic illness. Although laboratory based assessment of patients cognitive deficits has been well investigated, few studies to date have examined the utility of clinical ratings of cognitive symptoms using the Schedule for the Assessment of Negative Symptoms (SANS) attention subscale. In this report, we examined the convergence between clinical ratings of cognitive impairment using the SANS attention subscale and performance on a variety of neurocognitive tests designed to measure attentional impairment, as well as other cognitive constructs such as working memory and executive functioning. A total of 56 acute schizophrenic inpatients were clinically rated with the SANS and completed the Continuous Performance Test, Digit Span Distraction Test, Wisconsin Card Sorting Task, and the Trailmaking Test. A series of correlational and regression analyses were conducted to test the concurrent and discriminant validity of the SANS attention subscale. Performance measures of attention, but not working memory or executive functioning, were significantly correlated with and moderately predicted the severity of SANS rated inattention. Additionally, the attention subscale was discriminated from the other SANS negative symptom subscales in predicting a laboratory measure of attentional functioning. The SANS attention subscale demonstrated both concurrent and discriminant validity. These data indicate that attentional dysfunction in schizophrenia can be meaningfully rated and interpreted using the SANS.