The evolution of the concept of bipolar disorder

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Effects of naltrexone on the intake of ethanol and flavored solutions in rats.

It has been suggested that the endogenous opioid system may mediate the intake of preferred fluids, perhaps through an attenuation of reinforcement properties causing a subsequent shift in palatability. The purpose of the present study was to investigate the effects of the nonspecific opiate antagonist naltrexone on the intake of 10% ethanol, 0.1% saccharin, 0.0006% quinine, 0.4% saccharin + 10% ethanol, and 0.4% saccharin + 0.04% quinine solutions. Fluid intake was measured in male Long-Evans and Wistar rats under 24-h continuous and 30-min limited-fluid-access drinking paradigms. All rats received injections of naltrexone hydrochloride (10 mg/kg, i.p.) for 5 days after baseline intake measures and were monitored for a further 5 days (after-treatment phase). Results indicated that naltrexone did not affect intake of any solution when fluids were available over 24 h. However, under limited-access conditions, naltrexone caused a decrease in the intake of all fluids except quinine in both rat strains. On the basis of these findings, it is possible that the effects of this dose of naltrexone were not due to any true conditioning effect on the reinforcement properties of ethanol, but perhaps to some nonspecific effect of the drug, such as an alteration in palatability or an attenuation of locomotor activity. As well, due to the inconsistent results in fluid intake across drinking paradigms, the present findings do not provide evidence for an effective role for opiate mediation in ethanol intake as well as any ethanol-sweet fluid intake interactions.

Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use.

OBJECTIVE: Risks have been associated with the long-term use of antidepressant in the treatment of bipolar disorder. We review our naturalistic experience with divalproex versus lithium in treating depressive symptoms of bipolar illness. METHOD: All patients with bipolar disorder treated with lithium or divalproex were identified in a university outpatient psychiatry clinic sample over one year (n=38 patients, 41 treatment trials). Treatment response was based on standard prospective symptom rating scales. Mean duration of follow-up was 90 weeks. RESULTS: Lithium and divalproex were equally effective and tolerated in the total sample. Antidepressant effects were noted despite sparing use of standard antidepressant agents (19% received them). Lithium non-responders responded well to divalproex (50%), and vice versa (44%). Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, P=0.07) and was notably effective in treating depressive symptoms, with a 7/10 response on the CGI-BP and improvement on the HDRS (14.8+/-9.2 to 7.6+/-7.8, P=0.003, duration of prospective follow up 26.7 weeks). CONCLUSIONS: Lithium and divalproex were equally effective and tolerated in this naturalistic sample, but responders may represent distinct subgroups. Both agents, but particularly divalproex, demonstrated long-term antidepressant effects, with limited adjunctive standard antidepressant use.

Gabapentin treatment of the non-refractory bipolar spectrum: an open case series.

OBJECTIVE: To determine if gabapentin is effective in monotherapy or add-on treatment of non-refractory bipolar disorder in open prospective treatment. METHODS: Charts of 21 outpatients meeting DSM-IV criteria for bipolar spectrum disorder (type I, type II, NOS, and cyclothymia) and who were treated with gabapentin were reviewed and clinical response was assessed based on prospective application of the Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS), the Clinical Global Impression scale (CGI), and the Global Assessment of Functioning scale (GAF). Also, response was rated retrospectively using the Clinical Global Impression scale for Bipolar Disorder (CGI-BP). RESULTS: Eight patients received gabapentin monotherapy and 13 received adjunctive therapy. Similar improvement in depression was noted in the monotherapy group, without induction of mania. Gabapentin was associated with a 43.8% improvement in manic symptoms and a 27.6% improvement in depressive symptoms in the overall sample. In the depressed subsample (n=10), there was a 57.5% improvement in depressive symptoms (P=0.10). Using the CGI-BP, gabapentin was moderately to markedly effective in 43% of patients for overall bipolar illness, 38% for depressive symptoms, and 25% for manic symptoms. Of those in the study, 62% reported side effects, mainly sedation and nausea, with 14% of the total sample discontinuing treatment due to adverse events. CONCLUSIONS: Gabapentin, either alone or as an adjunct, appeared moderately effective in treating depression in this small, uncontrolled, heterogeneous sample of non-refractory bipolar spectrum illness. Coupled with the earlier clinical literature, these data suggest the need for prospective double-blind studies of depressive illness in the bipolar spectrum.

The bipolar spectrum and the antidepressant view of the world.

Whereas much progress has been made in the diagnosis and treatment of schizophrenia and depression in recent years, bipolar disorder continues to be frequently misunderstood, leading to its inconsistent diagnosis and treatment. In this article, we seek to identify the causes of this problem and suggest possible solutions, based on a critical review of studies concerning the nosology of bipolar disorder and the effects of antidepressant agents. Bipolar disorder appears to be underdiagnosed as well as frequently misdiagnosed as unipolar major depressive disorder. Underdiagnosis can stem from patients' impaired insight into mania and failure to involve family members in the diagnostic process and also from clinicians' inadequate understanding of manic symptoms. Underdiagnosis may also reflect disagreement about the breadth of the bipolar spectrum. We therefore propose a heuristic definition of "bipolar spectrum disorder," a diagnosis that gives greater weight to family history and antidepressant-induced manic symptoms. This diagnosis would include all forms of bipolar illness that are not type I or II . The evidence also suggests that antidepressants are probably overused and mood stabilizers underused. We consequently recommend aggressive use of mood stabilizers and less emphasis on antidepressants. In summary, the state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to the criteria for mania is necessary. In addition, the current pattern of antidepressant use in bipolar disorder does not appear to be evidence-based.

Topiramate treatment of bipolar spectrum disorders: a retrospective chart review.

The objective of this paper was to determine if topiramate is effective as treatment for bipolar spectrum disorders in a naturalistic setting. All charts of outpatients treated with topiramate (n = 76) were reviewed, and clinical response was assessed retrospectively using the Clinical Global Impressions Scale for Improvement. Mild improvement was seen in 47% (n = 36) and moderate-to-marked improvement in 13% (n = 10). Responders received a higher mean dose (180 mg/day) than did nonresponders (83.2 mg/day, p = 0.002). Topiramate dose was also higher in those who lost weight (138.3 mg/day) than in those who did not (70 mg/day, p = 0.007). Weight loss was experienced by 50% of the sample, with a mean loss of 14.2 lbs. Side effects were reported by 82% (n = 62) of the population, including cognitive effects, sedation, parasthesias, nausea, insomnia, headache, and dizziness. Adverse effects led 36% (n = 27) of the total sample to discontinue treatment with topiramate. Topiramate led to significant weight loss in about half of this bipolar population, while also improving mood symptoms at least mildly in most patients. Topiramate response and weight loss were both dose-related, with efficacy, in particular, associated with higher doses (mean = 180 mg/day) than frequently used in current clinical practice.

Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study.

OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings.

Relative taste thresholds for ethanol, saccharin, and quinine solutions in three strains of rats nonselected for ethanol: a comparative study.

C. P. Richter and K. H. Campbell (1940b) originally defined taste threshold as "the point at which the rats first indicated that they recognized a difference between the distilled water and the solutions" (p. 34). The present study sought to apply this simple behavioral measure to the investigation of strain differences in taste sensitivities, particularly with respect to predictive relationships in ethanol, saccharin, and quinine preference. Fawn-Hooded, Lewis, and Wistar rats were presented with gradual increments in concentration of ethanol (0.01-15%; C. P. Richter & K. H. Campbell, 1940a), saccharin (0.002-3%) or quinine (0.0001-0.0055). Results showed that although intake for saccharin was similar in all strains, consumption of ethanol and quinine differed among the groups. Although previous research has proposed that sweet preference is a promising behavioral marker for ethanol preference, these results suggested that bitter preference may be a more reliable predictor of ethanol preference in rats.

Insight and outcome in bipolar, unipolar, and anxiety disorders.

We performed a study to assess the relationship between impairment of insight and the long-term outcome in affective and anxiety disorders. Standardized insight assessments were made using the Scale to Assess Unawareness of Mental Disorder (SUMD) in 101 outpatients with psychiatric disorders, mostly affective and anxiety disorders, treated over 1 year in a university-based clinic. Outcome was prospectively assessed with the Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) rating scales. The mean follow-up period was 3.9 months. Initial impairment of insight did not correlate with poor outcome. However, improvement in insight correlated with good outcome, particularly in bipolar disorder type I (r = .56 to .67, P = .0005). Insight was similarly impaired in bipolar and unipolar major depressive disorders, and more so than in anxiety disorders (P = .002). An association between a lack of improvement in insight and a poor outcome, most significantly in bipolar disorder type I, was observed in this sample. We found a greater relative impairment of insight in mood versus anxiety disorders.

Diaphragmatic spinal muscular atrophy with bulbar weakness.

We present the clinical and histopathological features of a child affected by diaphragmatic spinal muscular atrophy. The child was born with mild distal arthrogryposis, mild hypotonia and developed marked diaphragmatic and bulbar muscle weakness in the first week of life. Electrophysiological and pathological investigations performed at presentation were not conclusive, while the investigations performed at 3 months showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that this syndrome represents a different entity from typical proximal spinal muscular atrophy.

Differences in the consumption of ethanol and flavored solutions in three strains of rats.

Several studies have shown a correlation between ethanol consumption and the intake of flavored solutions in rats, particularly sweet solutions. This observation, however, has not been shown in all strains of rats. The present study examined whether the intake of ethanol and that of flavored solutions would be related in Lewis (LEW), Wistar (WIS), and Wistar Kyoto (WKY) rats. During phase I, all rats were presented with water and a flavored solution following a continuous access paradigm as developed by Overstreet et al.: quinine (0.25% wt/vol), saccharin (0.1% wt/vol), ethanol (ETOH) (10% vol/vol), and saccharin-quinine (SQ) solutions (0.4% wt/vol-0.04% wt/vol). During phase II, fluid presentations were reduced to a 10-min limited access schedule and were presented in the same order. Results showed strain differences in intake and preference for ETOH and SQ during both phases, but not in quinine or saccharin intake. ETOH and saccharin intake were only correlated in the LEW strain during limited access drinking, while ETOH and SQ intake were correlated in the LEW strain as well as when all strains were collapsed during continuous drinking. These findings suggested that any association between ETOH and sweet intake may not be generalizable to all rat strains. The animals used in this study may have differed in taste sensitivity, as low ETOH-consuming LEW rats were sensitive to the bitter taste of quinine alone, as well as when mixed with saccharin. Sensitivity to bitter tastes may be an important predictor of low ETOH consumption and/or preference. These data provide further evidence for the role of taste factors in the mediation of voluntary ETOH consumption in rats.

Cholesterol levels in mood disorders: high or low?

OBJECTIVES: To assess cholesterol levels in patients with mood disorders. METHODS: All consecutively admitted patients meeting inclusion criteria (n = 50) who were hospitalized in an affective disorders unit received assessments of cholesterol levels. Correlations were made with diagnosis using DSM-IV criteria, current mood states, and other clinical and demographic features of illness. Exclusion criteria included current alcohol abuse, medical illnesses that could influence cholesterol levels, eating disorders, and age greater than 70 years. RESULTS: Cholesterol levels did not differ based on diagnostic status of unipolar depression or bipolar disorder. In the total sample, cholesterol levels were lower in patients with current manic (170.2 +/- 38.9, p = 0.05) and depressive (182.0 +/- 42.0) than in mixed (226.4 +/- 43.3) episodes (p = 0.05). In subgroups of patients with bipolar disorder, manic episodes (169.9 +/- 38.8, n = 9) were associated with lower cholesterol levels than depressive (201.0 +/- 49.4) or mixed (226.4 +/- 44.4) episodes (p = 0.02 for comparison of manic and mixed episodes). Body mass index (BMI), age, alcohol use, and gender did not account for these findings. CONCLUSIONS: Cholesterol levels were lower in manic and depressive than in mixed episodes. No differences were found between diagnoses of unipolar or bipolar mood disorders. Cholesterol may be a state rather than a trait function, and may be influenced by the acute mood state.

Does olanzapine have antidepressant properties? A retrospective preliminary study.

OBJECTIVE: Mood-stabilizing agents are ideally conceptualized as possessing antimanic and antidepressant properties. While research on olanzapine's antimanic effects is growing, data on its possible antidepressant properties are limited. We sought to determine if olanzapine is effective in the add-on treatment of major affective disorders, particularly depressive symptoms, in a naturalistic setting. METHODS: All charts of patients meeting DSM-IV criteria for bipolar disorder or unipolar major depressive disorder treated with olanzapine in a private psychiatric practice were reviewed and clinical response was assessed retrospectively using the Clinical Global Impression Scale for Improvement (CGI-I). RESULTS: Olanzapine was moderately effective in 6/10 (60%) patients. Side-effects were present in 8/10 (80%), most commonly weight gain. CONCLUSIONS: Olanzapine appears to be moderately effective in open add-on treatment in patients with mainly depressive symptoms. Accumulating evidence suggests that olanzapine, and atypical antipsychotics in general, possess mild to moderate adjunctive antidepressant properties.

What is to be done? Controversies in the diagnosis and treatment of manic-depressive illness.

BACKGROUND: In recent years, much progress has been made in the diagnosis and treatment of schizophrenia and depression. Bipolar disorder, however, remains frequently misunderstood, leading to inconsistent diagnosis and treatment. Why is the case? What is to be done about it? METHODS: We critically review studies in the nosology of bipolar disorder and the effects of antidepressant agents. RESULTS: Bipolar disorder is underdiagnosed and frequently misdiagnosed as unipolar major depressive disorder. Antidepressants are probably overused and mood stabilisers underused. Reasons for underdiagnosis include patients' impaired insight into mania, failure to involve family members in the diagnostic process, and inadequate understanding by clinicians of manic symptoms. We propose using a mnemonic to aid in diagnosis, obtaining family report, and utilising careful clinical interviewing techniques given the limitations of patients' self-report. We recommend aggressive use of mood stabilisers, and less emphasis on antidepressants. CONCLUSIONS: The state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to manic criteria is necessary and the current pattern of use of antidepressant use in bipolar disorder needs to change.

Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1.

We present the clinical and histopathological features and the diagnostic difficulties encountered in five children affected by a motor neuron disorder other than spinal muscular atrophy. Investigations performed suggested the diagnosis of ponto-cerebellar hypoplasia type 1 (PCH-1). Severe respiratory difficulty was present at birth in two of these children; hypotonia, arthrogryposis, microcephaly and nystagmus were present in all. Early and progressive bulbar involvement with swallowing difficulties and stridor was also a common feature in these infants. Severe cognitive delay was invariably present. Brain magnetic resonance imaging showed ponto-cerebellar hypoplasia in four children while striking atrophy of the cerebellar vermis and cerebellar hemispheres were present in the fifth child. Electrophysiological and pathological investigations of proximal muscles performed at presentation in all these children were not conclusive, while the post-mortem studies, or the study of distal muscles during life, showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that ponto-cerebellar hypoplasia type 1 is a different entity from typical proximal spinal muscular atrophy.

Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: review of the empirical literature.

Atypical antipsychotic agents seem to be effective treatments for bipolar disorder, especially as adjunctive treatments. They may be a safer and more effective alternative to the common practice of maintenance adjunctive treatment with traditional antipsychotic agents in patients with bipolar disorder. However, currently available research studies are limited methodologically mainly to open-label, uncontrolled designs. Further research is required before the definitive efficacy of these agents in bipolar disorder is established. If randomized or double-blind data support the open-label data reviewed here, atypical antipsychotic agents may possess an important role in the adjunctive treatment of bipolar disorder.

Cognitive-behavioral group therapy with medication for depressed gay men with AIDS or symptomatic HIV infection.

OBJECTIVE: The feasibility and effectiveness of a combination of group cognitive-behavioral therapy and medication for the treatment of depression among gay men with AIDS or symptomatic HIV infection were evaluated. METHODS: Fifteen patients diagnosed with DSM-IV major depressive disorder or dysthymia were treated in one of two weekly therapy groups in which cognitive-behavioral therapy had been specially modified for the target population. The majority of these patients, including two who had been on medication before joining the groups, also received antidepressant medication. Thirteen of the 15 patients completed therapy, attending an average of 15 of the 20 therapy sessions. RESULTS: The group cognitive-behavioral therapy used in this project appeared to be attractive to most patients; retention, attendance, and therapy compliance were good. Depression scores showed substantial decreases from pre- to posttherapy, with further decreases at one-year follow-up. Patients' self-reports indicated that some aspects of the intervention, particularly the focus on cognitive restructuring, were especially valuable in alleviating their depression. CONCLUSIONS: The modified group cognitive-behavioral therapy described in this study report offers a reasonable option for treatment of this clinically challenging group of patients.

Environmental lighting has a selective influence on ethanol intake in rats.

The effect of lighting condition on levels of absolute ethanol intake were systematically examined in the present study. Wistar rats were exposed to one of three lighting conditions: constant light, constant dark, and a standard 12/12 light/dark cycle. The animals were acclimatized to lighting conditions for 2 weeks prior to ethanol (EtOH) acquisition with water and food available ad lib. EtOH was then presented in increasing concentrations from 2% (v/v; 95% with tap water) to 10% on alternate days in free choice with water. Immediately following the acquisition phase, a maintenance period was initiated that began with everyday presentations of 10% EtOH solution in free choice with water. After 10 days, lighting conditions for the constant light and dark groups were switched to normal lighting (12/12 light/ dark). EtOH and water intake were recorded for an additional 10 days. Rats exposed to constant light during EtOH acquisition and maintenance consumed less EtOH during the maintenance period than rats exposed to normal lighting conditions. When lighting conditions were switched to a normal cycle, water consumption increased significantly but EtOH intake did not change. Rats living in constant dark during EtOH acquisition and maintenance consumed less EtOH during the acquisition period when compared with rats living in normal lighting conditions. Unlike animals trained under constant lighting, switching to normal lighting conditions had no effect on EtOH or water intake. There were no differences in water consumption levels among the groups during acquisition and maintenance, suggesting a specificity of the effects of lighting condition on EtOH intake. The present study, therefore, has attempted to show that an environmental variable such as lighting may exert a selective influence on EtOH self-selection in rats.