On the meaning and measurement of affective instability: clues from chaos theory.

BACKGROUND: "Affective instability" describes affective shifts occurring over hours to days that are associated with clinically significant impairment or distress. Since patients with this condition are clinically "chaotic," we undertook to study affective instability relative to normal affective variability using the tools of chaos theory. METHODS: Patients and controls generated time series data over 90 days using a visual analog mood scale to capture daily affective means and extremes. The series were analyzed using the Mean Squared Successive Difference (MSSD), Power Spectral Density (PSD), and Fractal Dimension (FD). RESULTS: Patients demonstrated substantially more variability than controls on the MSSD, but less complexity as measured by the FD. The PSD revealed that power varied with frequency (f) in a 1 [corrected] alpha relationship, wherein the alpha for patients was double that for controls. CONCLUSIONS: Despite the "chaotic" clinical presentation of affective instability patients, affective instability itself was found to be less complex from a chaos-theoretic perspective than normal affective variability. Of particular interest is the alpha ratio of order 2 between patients and controls seen in both our study and a similar but much longer study of mood in rapid-cycling bipolar disorder; an observation suggesting that pathological affect may be distinguishable from normal affective variability by a scale-invariant parameter.

Clozapine for treatment-refractory mania.

OBJECTIVE: The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder. METHOD: The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score. CONCLUSIONS: These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.

Predictors of response to mood stabilizers.

Although lithium remains the preferred treatment of bipolar disorder, only 60 to 80% of patients with the classic presentation have an adequate response to this drug. When the response rate to lithium is considered across the entire spectrum of bipolar disorders, this rate probably decreases to 50%. Natural history, illness subtype, and comorbidity are all important general predictors of response to treatment. At present, the only predictors that seem to differentially favor divalproex, and possible, carbamazepine over lithium are mixed states and rapid cycling. An overview of clinical presentations that predict general and differential response to mood stabilizers is provided.

Lithium therapy: limitations and alternatives in the treatment of bipolar disorders.

As clinical experience with lithium treatment of bipolar disorders accumulates, factors predictive of nonresponse are emerging. Prominent among these are conditions such as comorbid substance abuse and the presence of the malignant variants rapid cycling and mixed states. Lithium therapy is further complicated by noncompliance, attributable in large measure to burdensome side effects such as memory impairment and cognitive slowing. The issues of lithium nonresponse and noncompliance have driven the search for alternative agents, such as the anticonvulsants carbamazepine and valproic acid. While preliminary evidence suggests that these agents may provide improvements over lithium in terms of tolerability and response (especially in rapid cycling and mixed states), methodologic limitations temper the conclusiveness of these findings. The natural history of bipolar disorders is defined by characteristic symptom clusters which evolve in intensity and duration over long time scales, resulting in a high morbidity and mortality. These features raise critical concerns for research design, especially concerning the ethics of placebo controls and the need to generate long-term observational data upon which to predicate meaningful treatment recommendations. With the apparent increase in lithium nonresponse in recent years, the need to identify and definitively evaluate alternative agents is becoming imperative.

A medication algorithm for treatment of bipolar rapid cycling?

Individuals with the rapid cycling form of bipolar disorder represent 13% to 20% of the bipolar population. Although lithium remains the treatment of choice for classic bipolar disorder, failure rates as high as 72% to 82% have been reported for lithium among those who have the rapid cycling variant. Treatment alternatives, including the use of divalproex sodium and carbamazepine, have shown promise for this often treatment-refractory group of patients. Predictors of positive outcome for the acute and prophylactic management of mania with divalproex sodium have emerged; they include nonpsychotic mania, the occurrence of decreasing or stable episode frequencies, mild mania, and mixed states. Predictors for positive acute and prophylactic antidepressant responses to divalproex sodium include nonpsychotic mania, increasingly severe mania, and the absence of borderline personality. Mixed results have been reported for studies using carbamazepine therapy for the treatment of rapid cycling bipolar disorder. Some investigators have reported success with carbamazepine in conjunction with other medications, while others have not. A psychopharmacologic algorithm for the treatment of rapid cycling bipolar disorder is proposed. There is a growing opinion among psychiatrists that patients who rapidly cycle should be treated with an anticonvulsant prior to lithium. However, until homogeneous cohorts of rapid cyclers undergo at least random assignment to different open treatments, these recommendations remain controversial.

Clozapine in treatment-refractory mood disorders.

Lithium remains the mainstay of treatment for patients with bipolar affective disorder; however, nearly half of patients with bipolar disorder fail to respond to lithium. Recently, there have been an increasing number of preliminary clinical reports that clozapine, an atypical antipsychotic agent, has potential efficacy in patients with mood disorders. We review the available clinical data supporting the potential use of clozapine in these psychiatric disorders and report our preliminary data from a study that used clozapine in the acute treatment of mania in treatment-refractory patients. Twenty-five patients meeting the DSM-III-R criteria for the manic phase of either bipolar or schizoaffective disorder entered a 13-week open prospective trial of clozapine. These patients either had failed to respond to or had been intolerant to treatment with lithium, an anticonvulsant, and at least two typical neuroleptics. Eighteen of 25 patients demonstrated a greater than 50% decrease in the Young Mania Rating Scale score. These preliminary data as well as the clinical reports reviewed indicate that the efficacy of clozapine in treatment-resistant patients is not limited to patients with schizophrenia.

Quantification of occipital EEG changes in Alzheimer's disease utilizing a new metric: the fractal dimension.

In a retrospective preliminary investigation, the occipital electroencephalogram (EEG) changes associated with Alzheimer's disease (AD) were examined using a novel quantification metric: the fractal dimension. The mean occipital EEG fractal dimension was determined for each of three patient groups representing a spectrum of clinical and EEG pathology: controls, probable AD, and autopsy-confirmed AD. The fractal dimension was significantly reduced in each of the AD groups with respect to controls (p < 0.001); and within the AD groups, it was significantly reduced in autopsy-confirmed AD relative to probable AD (p < 0.01). The fractal dimension findings paralleled the manifest EEG abnormalities in a way that suggests it has potential clinical utility in metric studies on the EEG, especially when applied to the dementias. Additionally, the EEG pathology studied here was particularly well-described by the fractal dimension, providing further support for a nonlinear approach to the background activity of the EEG.

Predictors of valproate response in bipolar rapid cycling.

Multiple regression/discriminant analyses were separately conducted to generate predictors of acute and prophylactic antimanic and depressive outcome in 101 valproate-treated bipolar rapid cyclers. Predictors of good antimanic response included decreasing or stable episode frequencies and nonpsychotic mania. Predictors of good antidepressant response included nonpsychotic mania worsening over the years of the illness and absence of borderline personality disorder comorbidity. This report confirms prior findings that indicate that valproate possesses marked acute and prophylactic antimanic and antimixed effects with only poor to moderate antidepressant properties.

Rapid cycling bipolar disorder and its treatment with valproate.

A large subgroup of lithium-resistant manic patients are rapid cyclers and as many as 82% of them exhibit poor responses to lithium. Thus, a substantial percentage of poor responses to lithium is accounted for on the basis of rapid cycling. Although controlled trials have demonstrated the efficacy of carbamazepine for the treatment of rapid cycling bipolar disorder, the response to carbamazepine frequently deteriorates. Furthermore, its ability to auto-induce and hetero-induce drug metabolism complicates its routine use. These findings suggest that substantial numbers of rapid cyclers do not respond to either carbamazepine or lithium and that additional mood stabilizers are needed. Our recent findings on 101 rapid cycling bipolar patients continue to support the impression that valproate has marked antimanic efficacy and poor to moderate antidepressant properties. Most patients with mixed states exhibited good antimixed state responses but then became depressed. Predictors of a good antimanic response included decreasing or stable episode frequencies and non psychotic mania. Predictors of a good antidepressant response were non psychotic mania worsening over the years of the illness and absence of borderline personality disorder comorbidity. These open prospective trials, as well as other positive reports of valproate's efficacy in bipolar rapid cycling, await replication with ongoing, controlled maintenance trials.