Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Reduced catechol-O-methyltransferase activity in red blood cells of women with primary affective disorder.

Red blood cell catechol-O-methyltransferase, histamine-N-methyltransferase, and a methanol-forming enzyme were examined in a number of subjects with mental diseases. Catechol-O-methyltransferase activity was significantly reduced in female subjects with primary affective disorder (depression) as compared to normal women and men, men with primary affective disorder, and schizophrenic men and women. In depressed women, histamine-N-methyltransferase activity was elevated and the methanol-forming enzyme was unchanged.

Psychiatric illness in fathers of men with bipolar primary affective disorder.

A systematic interview regarding family history was administered to 48 men with bipolar affective illness who were attending a lithium clinic. Several families were found in which both the patient and father had affective disorders, but the mother and maternal second-degree relatives were well. Of 30 men who had histories of hospitalization for mania, three had fathers with affective disorder (all bipolar). Of 18 men who had depression and hypomania, one father had unipolar depressive disorder. The hypothesis that bipolar manic-depressive illness may be transmitted by a single dominant genetic factor on the X chromosome is discussed in relation to these ill father-ill son pairs.

Lithium carbonate and affective disorders. V: A double-blind study of prophylaxis of depression in bipolar illness.

The efficacy of lithium carbonate as a prophylactic drug against depression in bipolar manic depressive patients was assessed through a double-blind, placebo-controlled study of patients who had histories of recurrent depressions and hypomanias ("bipolar II"). The results revealed that treatment with lithium carbonate resulted in a reduction in the frequency of depressive attacks was observed with lithium carbonate treatment during the study (mean length of study, approximately 16 months), although there was a suggestion that the depressive attacks that occurred during treatment with lithium carbonate might be less severe than with placebo treatment.

Lithium carbonate in affective disorders. IV. A double-blind study of prophylaxis in unipolar recurrent depression.

The prophylactic efficacy of lithium carbonate vs placebo was examined in a double-blind study in a carefully delineated group of 28 unipolar recurrent depressed patients followed up from three months to four years. Indexes of prophylactic efficacy revealed a statistically significant decrease in episode frequency, depth of global depression scores, and increased clinic attendance rate in the lithium carbonate group compared with the placebo group. Planned studies are now needed to determine which unipolar patients do best on a maintenance regimen of lithium carbonate alone, lithium carbonate plus tricyclic drugs, or tricyclic drugs alone.

The life table. A method for analyzing longitudinal studies.

The life table is presented as the method of choice for analyzing data from longitudinal studies in which the outcome under study occurs randomly and in which patients are followed up varying lengths of time. We discuss the superiority of the life table to methods typically used, the calculation of its entries, and some of the clinical uses that can be made of its results. The method is applied to follow-up data on manic-depressive patients maintained with prophylactic lithium carbonate or with control regimens, and it is shown to disclose mathematical regularities in the parameters of longitudinal course.

Prostaglandins. A review of neurophysiology and psychiatric implications.

This article reviews the function of prostaglandins (PGs) in the nervous system and discusses the possible alterations in PG metabolism as relating to mental illness. The PGs are a unique group of cyclic fatty acids whose immediate precursors are thought to function postsynaptically by inhibition or facillitation of neurotransmission through cyclase inhibition or activation, and by means of a negative feedback loop to inhibit further release of neurotransmitter from the presynaptic nerve. A review of PGs in psychiatric conditions is presented as well as a discussion of the interaction of psychoactive drugs with the PGs. The concluding section of this review discusses possible future strategies to provide insight into PG physiology as it relates to synaptic transmission in normal and pathological conditions in man.

Toward the validation of RDC schizoaffective disorder.

The Research Diagnostic Criteria (RDC) for schizoaffective disorder were applied to a clinic population of 71 patients with bipolar I disorder. Twenty-five patients were found to meet RDC criteria for schizoaffective disorder. The RDC-positive group were found to be the most psychotic patients and had a younger age at onset and admission to the clinic that the RDC-negative group. They had also had their conditions diagnosed more frequently as schizophrenic by referring physicians. There was no difference, however, between the two groups on many other variables, including clinical, family history, drug response, and laboratory studies. We conclude that our bipolar I population cannot be further subdivided into meaningful clinical entities using the RDC criteria for schizoaffective disorder.

Body composition in affective disorder before, during, and after lithium carbonate therapy.

The body composition of three unipolar and 17 bipolar patients, studied during the depressive state, was compared with that of 48 controls. The ratio of extracellular to intracellular water content was significantly less in male patients than in male controls: the difference between female patients and female controls was not statistically significant. In patients of both sexes, residual sodium concentration was greater in patients than in controls. The intracellular content of potassium was the same in patients as in controls. In six patients, body composition was studied prior to lithium carbonate therapy, after 17 days of treatment, and 17 days after discontinuing administration of the drug. The significant changes were a decrease in body weight during therapy, and a decrease in body water content and an increase in residual sodium concentration after drug treatment was discontinued.

L-tryptophan in depression.

L-tryptophan, the amino acid precursor of serotonin, was administered to 16 depressive patients in a double-blind study of its potential antidepressant efficacy. Antidepressant responses were observed in one of ten unipolar patients and in three of six bipolar patients. These results are discussed in the context of possible interactions of amines with electrolyte systems in the etiology of affective illness.

Erythrocyte catechol-o-methyltransferase activity in primary affective disorder.

Previous studies have suggested that the activity of erythrocyte catechol-O-methyltransferase (COMT) may be reduced in women with bipolar and particularly unipolar affective illness. More recently, increased COMT activity in both men and women with affective disorder was reported. The activity of COMT in erythrocytes was determined in 184 outpatients with primary affective disorder at the Lithium Clinic of the New York State Psychiatric Institute. COMT activity was determined by a modification of the Axelrod and Cohn method with dopamine as substrate. This change resulted in an apparent threefold increase in the values for COMT activity; however, when both methods were compared, the results correlated (r = 0.97, p less than 0.001, N = 37). We found that the values for women were not significantly lower than those for men. In addition, there was no difference between patients with affective disorder and controls. Further, no difference was demonstrated between patients diagnosed as bipolar or uni-polar. Parameters such as mood, medication, and inpatient or outpatient status had no effect on COMT activity. The results of previous studies are discussed in an attempt to reconcile the different results.

Biological markers in panic states: lactate-induced panic and mitral valve prolapse.

Anxious patients, and more specifically, patients experiencing panic attacks, are thought to have a significant biological component to their illness. This study looks at two promising biological markers associated with this patient population-mitral valve prolapse and lactate-induced panic. We present our findings, which further characterize clinical and biological aspects of these two markers.

Heritable factors in the severity of affective illness.

A review of clinical experience with 163 patients with primary affective disorder indicates that patients with a history characterized by recurrent depression interspersed with periods of hypomania (bipolar II) may have clinical courses that are distinguishable from bipolar I (depression with histories of mania) or unipolar patients. A prior history of suicide attempt and suicide after discharge from the research unit were most frequent among bipolar II patients. The family histories of bipolar I and bipolar II patients revealed similarly increased morbid risks for bipolar illness, whereas no bipolar illness was found in the first-degree relatives of unipolar patients. The suggestion that patients classified as bipolar II be separately considered in future studies of affective disorder is discussed.

Assortative mating in primary affective disorder.

Psychiatric illness in spouses of patients with primary affective disorder was determined and compared to psychiatric illness in spouses of a nonpsychiatrically ill control group. An increase in affective illness in wives of bipolar male patients with affective disorder was found. There was no increase in affective illness among husbands of female patients. Marital status of these patients was evaluated and the percentages of patients who had never married or who had married but had ever been divorced or separated were similar to control data. Several of the marriages were quite stable over long time periods in spite of the severe recurrent affective illness experienced by these patients.

Prostaglandin F in patients with primary affective disorder.

Two aspects of prostaglandin F (PGF) metabolism were assessed in patients with primary affective disorder. For a group of hospitalized patients cerebrospinal fluid PGF was measured by radioimmunoassay and the effects of probenecid and L-tryptophan were determined. For outpatients attending our Lithium Clinic, plasma PGF was measured and the acute and chronic effects of lithium were determined. The results of the studies reveal apparently normal concentrations of PGF in cerebrospinal fluid. These concentrations increase twofold after probenecid, indicating that PGF is transported out of the central nervous system by a probenecid-sensitive active transport system. Evidence for inhibition of PGF synthesis during L-tryptophan treatment was found. The results for outpatient plasma studies suggest no effect on PGF with 12 weeks of lithium treatment, although a slight elevation of plasma PGF with chronic lithium treatment may occur. Specificity of the assay technique as applied to plasma is discussed. This is the first report of the direct measurement of PGF in a psychiatric disorder.

The importance of dietary control in metabolic studies of manic-depressive patients.

Diet control of electrolyte intake appears to diminish day to day variation of urinary electrolyte output. Urine sodium concentration is more affected by diet control than potassium, possibly due to the greater variation in sodium ingestion on uncontrolled diets. The coefficient of variation of urinary sodium excretion on the controlled diet was not significantly greater than the variation in sodium ingestion. These experimental results suggest that controlled diets reduce random variation in sodium and potassium excretion and therefore enhance the possibility of observing illness-related biological changes.

Response to lactate infusion in generalized anxiety disorder.

Intravenous sodium lactate infusion provokes symptoms of panic in patients with panic disorder at a significantly higher rate than in normal controls. Lactate sensitivity has been postulated to be specific for patients with panic attacks regardless of frequency of attacks or coexisting diagnoses. The authors present results of a pilot study of lactate infusions in patients with generalized anxiety disorder (GAD) without any history of panic attacks. Patients with GAD reacted more like panic disorder patients than like normal controls in anxiety and symptom scores during lactate infusion and in the rate of positive responses to lactate. Although preliminary, these findings raise questions regarding the specificity of lactate sensitivity and the relationship of GAD to panic disorder.

Lactate vulnerability after alprazolam versus placebo treatment of panic disorder.

Thirty-six patients with panic disorder underwent sodium lactate infusion before and after 8 weeks of treatment with alprazolam or placebo. With reinfusion, those patients panic-free with chronic alprazolam treatment displayed significantly decreased reactivity to lactate, as measured by subjective symptom ratings, duration of infusion before developing peak lactate-induced symptoms, and the proportion of patients experiencing lactate-induced anxiety or panic. Patients panic-free on placebo, as well as nonresponders to alprazolam treatment, displayed some, although less striking, decreases in reactivity to lactate with reinfusion. As a group, patients clinically unchanged with placebo treatment showed no systematic change in lactate response with reinfusion. Although the small numbers of patients in each treatment outcome group prohibit drawing definitive conclusions, these findings suggest that decreases in lactate-induced panic after successful alprazolam treatment of panic may result from a combination of changes in clinical state and direct effects of the medication.

Morning or evening bright light treatment of winter depression? The significance of hypersomnia.

In a randomized crossover design 19 patients with winter depression were treated with 7 days of bright morning light (6:00 to 8:00 AM) and 7 days of evening light (7:00 to 9:00 PM). Bright light in the morning reduced the Hamilton Depression Rating Scale score from 22.3 to 5.5; bright light in the evening decreased the Hamilton score from 21.0 to 12.2. Improvement in the depression as measured by the Hamilton Depression Rating scores was greater with morning light compared with evening lights. Hypersomnia was associated (p less than 0.05) with a superior response to morning light.

Amino acid concentrations in cerebrospinal fluid: effects of aging, depression, and probenecid.

Cerebrospinal fluid (CSF) amino acid concentrations were measured in six Bipolar I, eight Bipolar II, eight Unipolar, and four other and control patients. All but four were also studied after administration of probenecid. Fourteen amino acids showed significant correlations of concentrations with age of subjects. Significant diagnostic group differences were found for five amino acids; only that of tyrosine persisted after taking subject's age into account. Following probenecid administration, there were statistically significant changes in CSF concentration of several amino acids, but these changes were small and likely indicative of diurnal changes.