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Treatment of acute mania requires attention to both specific and nonspecific antimanic medications. The choice of specific agents now includes lithium, carbamazepine, and valproate; and nonspecific agents include benzodiazepines, calcium channel blockers, alpha adrenergic agonists, as well as neuroleptic drugs. Treatment-resistant manic states are best treated by careful sequential strategies that may include polypharmacy and electroconvulsive therapy.

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Lithium remains the mainstay of pharmacologic therapy for the majority of patients with bipolar disorder; however, significant numbers of patients with both classical bipolar disorder and syndromal variants fail to respond to lithium therapy. The discussion that follows outlines subgroups of patients who are likely to be nonresponsive to or have poor tolerance for lithium therapy either because of disease type (rapid cyclers and schizoaffectives) or patient characteristics (the elderly or those with psoriasis or organic brain syndrome). Alternate therapy with valproate and carbamazepine is discussed. The relative efficacy of lithium versus valproate is briefly evaluated through a retrospective review of current case material. Algorithms for patient management are presented based on experience in our center for mood disorders. Valproate and carbamazepine were found to have an important clinical role for the treatment of bipolar spectrum disorders with the initial preference for treatment based on broad clinical phenomena.

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Eight women with prospectively documented premenstrual syndrome (PMS) underwent multiple samplings for estradiol, progesterone, prolactin, cortisol, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) during an asymptomatic midcycle (late follicular) and a symptomatic premenstrual (late luteal) phase of the menstrual cycle. Cerebrospinal fluid (CSF) was collected for analysis of MHPG, norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), gamma-aminobutyric acid (GABA), homovanillic acid (HVA), tyrosine, tryptophan, beta-endorphin, prostaglandins, adrenocorticotropic hormone (ACTH), and arginine vasopressin (AVP). In subsequent months, a dexamethasone suppression test (DST) and a thyrotropin-releasing hormone (TRH) stimulation test were performed during midcycle and premenstrual phases. Significant results included increased CSF concentrations of MHPG in the premenstrual, as compared with the midcycle, phase of the cycle, and increased plasma cortisol concentrations during the midcycle phase. The DST showed a 62% overall rate of nonsuppression, irrespective of menstrual cycle phase. Though there were no abnormalities of thyrotropin-stimulating hormone (TSH) after TRH stimulation, the mean delta maximum prolactin values after TRH stimulation were higher than reported normal values both at midcycle and premenstrually. These pilot data suggest hormonal axes that might be worthy of further systematic investigation in future studies of PMS.

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Seasonal cycles of platelet 3H-imipramine binding were compared in 49 endogenous unipolar depressed patients and 20 normal volunteers. A significant sinusoidal component was detected in the Bmax of binding in both patients and controls with similar amplitudes and seasonal peaks. However, the yearly average (mesor) of the patient group was significantly lower (20.0%) than that of the normal controls. The results support earlier claims of a diminished platelet binding in endogenous depression and indicate that this decrease was still evident in the presence of a 48.2% (controls) to 65.8% (patients) seasonal variation. Control Bmax values were normally distributed about a best-fit mean (cosinor fit). In contrast, patient values appeared to be bimodally distributed with one mode that was similar to controls and one mode that was substantially lower. In general, psychiatric symptoms failed to distinguish between patients with high and low platelet binding and no correlation was found between Bmax and severity of illness (HAM-D).

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A decreased density of platelet 3H-imipramine (3H-IMI) binding sites has been proposed as a putative trait marker of major depressive illness. However, subsequent studies have demonstrated that the number of such sites is increased so as to be more like normal controls upon chronic treatment with antidepressant drugs. In addition, there is some evidence to suggest that altered 3H-IMI binding may be secondary to elevated plasma cortisol levels which are common in depressed patients and which normalize with remission. The present study compares platelet 3H-imipramine binding, plasma cortisol levels, and clinical improvement of 10 endogenous depressed patients before and after 6 weeks of treatment with imipramine-HCl. Total high affinity 3H-IMI binding sites were further differentiated into two subclasses on the basis of their relative sensitivities to cyanoimipramine (CNIMI) inhibition. Treatment was associated with a significant increase (134%) in CNIMI resistant binding but a decrease (45.2%) in CNIMI sensitive binding. While the former was significantly correlated with posttreatment cortisol levels, no significant correlation was found between cortisol and CNIMI specific binding. Neither site appeared to be directly related to mood state. The significance of these findings to the evaluation of platelet binding as a trait dependent marker is discussed.

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Seasonal variations in cyanoimipramine (CNIMI) sensitive and CNIMI resistant subclasses of platelet 3H-imipramine (3H-IMI) binding sites were studied in depressed patients and normal volunteers. Sinusoidal rhythms of the binding of both subclasses were found in patients and controls with peak levels in mid-February. Patient values of CNIMI sensitive binding fluctuated about a yearly average that was 32% lower than the average of controls. Patient deviations from the normal pattern were apparently bimodally distributed, whereas those of controls were normally distributed. CNIMI resistant binding was also normally distributed in controls, but not in depressed patients, although patient mesor values were not lower than those of controls. Platelet binding was not correlated with the severity of illness as measured by the Hamilton Rating Scale for Depression, and individual symptoms failed to discriminate between patients with high and low Bmax values.

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Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trial for 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patient with no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.

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One month of imipramine treatment increased both the Kd and Bmax of platelet 3H-imipramine binding in 11 endogenous unipolar depressed patients. Continued treatment (13 weeks) of 5 patients subsequently lowered the Bmax values of 2 patients who had initially shown the largest increases, so that binding was no longer significantly elevated after 13 weeks. The observed changes in Kd but not in Bmax, could be explained by the carryover of tightly bound drug to the binding assay, although neither of the measures were correlated with plasma imipramine levels. Posttreatment Bmax (4 weeks) values were inversely related to plasma cortisol levels, although a weak but positive correlation was found before treatment. No significant change was found in plasma cortisol with treatment. Clinical responses were not related to cortisol or Bmax changes, although optimal improvement was associated with extreme values (high and low) of pretreatment Bmax. The present results, obtained with imipramine, and similar results obtained after nortriptyline and electroconvulsive shock by others, suggest that at least some antidepressants may induce transient changes in the Bmax of platelet binding that are independent of affective state.

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Using positron emission tomography, we studied cerebral glucose metabolism in drug-free, age- and sex-matched, right-handed patients with unipolar depression (n = 10), bipolar depression (n = 10), obsessive-compulsive disorder (OCD) with secondary depression (n = 10), OCD without major depression (n = 14), and normal controls (n = 12). Depressed patients were matched for depression on the Hamilton Depression Rating Scale, and subjects with OCD without depression and OCD with depression had similar levels of OCD without depression and OCD with depression had similar levels of OCD pathology. We also studied six non-sex-matched patients with mania. Mean (+/- SD) glucose metabolic rates for the left dorsal anterolateral prefrontal cortex, divided by the rate for the ipsilateral hemisphere as a whole (ALPFC/hem), were similar in the primary depressions (unipolar depression = 1.05 +/- 0.05; bipolar depression = 1.04 +/- 0.05), and were significantly lower than those in normal controls (1.12 +/- 0.06) or OCD without depression (1.15 +/- 0.05). Results for the right hemisphere were similar. Values in subjects with OCD with depression (1.10 +/- 0.05) were also significantly lower than in subjects with OCD without depression, and values in subjects with bipolar depression were lower than those in manic subjects (1.12 +/- 0.03) on this measure in the left hemisphere, although results were not significant in the right hemisphere. There was a significant correlation between the HAM-D score and the left ALPFC/hem. With medication for depression (n = 12), the left ALPFC/hem increased significantly and the percentage change in the Hamilton scale score correlated with the percentage change in the left ALPFC/hem.(ABSTRACT TRUNCATED AT 250 WORDS)

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With the growing number of Americans over the age of 65 years, the high incidence of geriatric depression has become a major concern in the United States. Age-related circumstances--increased incidence of illness, bereavement, financial difficulties, and institutionalization--may contribute to an increased rate of depression in this age group. The signs and symptoms of depression in elderly patients are similar to those seen in younger individuals; therefore, standard Diagnostic and Statistic Manual III (DSM-III) criteria are reliable for making a diagnosis. However, symptoms such as insomnia, obsessional thought, and hypochondriasis may be relatively increased in the elderly patient; and the diagnosis of geriatric depression can be complicated by signs and symptoms of depression that may overlap with those of dementia. In the geriatric group, the mainstay of pharmacotherapy has been the reuptake antidepressant agents. Choice of antidepressant therapy is largely based on the side-effect profile. Thus, the fewer and less severe side effects associated with trazodone make it a suitable drug choice in these patients. Trazodone has been shown to demonstrate comparable efficacy to the other reuptake and monoamine oxidase inhibitors, but has the advantages of a low cardiovascular-risk profile, extremely low suicide toxicity, absence of anticholinergic side effects, and minimal effects on cognition.

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The dexamethasone suppression test (DST) has been primarily investigated as an aid in diagnosing endogenous depression; yet, its major clinical use has been as a predictor of treatment response. It is commonly held that 1) an abnormal DST predicts response to somatic (and not psychologic) therapies, 2) an abnormal DST predicts response to noradrenergic antidepressants, and 3) a normal DST predicts response to serotonergic agents. The DST predicted response to somatic therapies in only 6 of 16 published studies. No single methodologic factor, such as population variables, DST technique, or study design, can explain the marked discrepancy in study results. Only two of seven studies examining the DST and response to neurotransmitter-specific antidepressant groups found a positive relationship. The evidence that the DST predicts response to noradrenergic agents is weak. The DST does not predict acute response to somatic treatment in general or response to specific antidepressants. The selection of the appropriate treatment for depressed patients is still best made using clinical criteria.

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Blunted TSH response to TRH and elevation of reverse T3 (rT3) have been reported in depression, though the relationship between these two abnormalities has not been clear. The authors measured basal levels of T4, T3, rT3 and the TSH response to TRH in a group of 28 depressed men and women, unipolar and bipolar subtypes. No significant difference was found between these two subtypes of depression with respect to mean basal hormonal levels or magnitude of the TSH response to TRH. Two males had slight, but significant elevations of rT3 though only one of them had a blunted TSH response to TRH levels and the TSH response to TRH. Finally no significant correlation was found between rT3 levels and the TSH response to TRH.

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Cerebral metabolic rates for glucose were examined in patients with unipolar depression (N = 11), bipolar depression (N = 5), mania (N = 5), bipolar mixed states (N = 3), and in normal controls (N = 9) using positron emission tomography and fluorodeoxyglucose F 18. All subjects were studied supine under ambient room conditions with eyes open. Bipolar depressed and mixed patients had supratentorial whole brain glucose metabolic rates that were significantly lower than those of the other comparison groups. The whole brain metabolic rates for patients with bipolar depression increased going from depression or a mixed state to a euthymic or manic state. Patients with unipolar depression showed a significantly lower ratio of the metabolic rate of the caudate nucleus, divided by that of the hemisphere as a whole, when compared with normal controls and patients with bipolar depression.

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The increasing proportion of elderly to the general population and the relatively high prevalence rate of depression in this age group justifies concern for specific clinical indications for antidepressant selection. Of the numerous agents that possess antidepressant activity, some have a more narrow therapeutic window for the old (lithium), while others may be more efficacious for the old than traditional tricyclics (stimulants and monoamine oxidase inhibitors). Stimulants and monoamine oxidase inhibitors require close monitoring to obviate complications, and this limits their use in this population. Prescription of the more common reuptake inhibitors in this age group can be based on consideration of efficacy and especially predictable incidence of side effects. Efficacy of all the reuptake inhibitors is essentially equivalent over 4 weeks, if the patient can tolerate treatment. Antidepressants with many side effects are, thus, less efficacious if we consider only whether the patient will be better 4 weeks after we start treatment since drop outs must be considered treatment failures for that particular treatment. Side effects are more clearly different among the antidepressants with demonstrably fewer cardiac effects (i.e. ECG changes, orthostatic hypotension) for buproprion, mianserin, nomifensine, and trazodone in the geriatric group compared to older agents such as amitriptyline and imipramine. Further, anticholinergic effects in the periphery (dry mouth, constipation, blurred vision, and urinary hesitancy) and centrally (confusion, sedation, decreased memory recall) are substantially less with several of the newer antidepressants: buproprion, maprotiline, nomifensine and trazodone.

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Cerebrospinal fluid from 31 normals and two groups of phenomenologically similar schizophrenics (n = 72) were collected by identical methods. Radioimmunoassay of CSF was carried out for somatostatin, bombesin, and cholecystokinin. One group of schizophrenics had increased baseline somatostatin and cholecystokinin, and decreased bombesin. No CSF gradient effect was found for the peptides nor were their levels affected by probenecid or pimozide treatment. An inverse correlation was found between bombesin and psychosis rating. Intercorrelation between the peptides and HVA, 5-HIAA, and MHPG were not significant.

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The few studies reported to date suggest that CSF cortisol is increased in depression and mania compared to normal subjects but that this increase is not specific to these disorders, since increased levels occur in other psychiatric and neurologic disorders. The CSF elevation is probably secondary to cortisol changes in the blood, but CSF levels appear to be more stable. The diurnal change in CSF may also be greater than that in blood. The significant correlation between CSF and blood levels observed in monkeys has not been found in humans. Future studies must control for time of day, as well as diagnostic factors, and ideally should include other measures of cortisol function, such as urinary excretion or the DST. Regulation of CSF cortisol is not well understood, and its relationship to other brain chemistries is unclear.

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A total of 114 subjects (41 depressed, 20 schizophrenic, 15 manic, and 38 normal controls) underwent lumbar puncture and their CSF was analyzed for levels of tyrosine, tryptophan, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), choline, gamma-aminobutyric acid (GABA), and calcium. Results showed that depressed patients, particularly those over 40 years of age, had lower levels of GABA than did controls, and that their level of HVA increased with age, while controls' decreased. Schizophrenic subjects tended to have higher levels of 5-HIAA and manic subjects tended to have higher levels of HVA and MHPG. Age-associated changes were found in HVA, 5-HIAA, MHPG, GABA, and choline concentrations.

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