Antidepressant-associated mania and psychosis resulting in psychiatric admissions.

BACKGROUND: The safety and tolerability of the selective serotonin reuptake inhibitors and the newer atypical agents have led to a significant increase in antidepressant use. These changes raise concern as to the likelihood of a corresponding increase in adverse behavioral reactions attributable to these drugs. METHOD: All admissions to a university-based general hospital psychiatric unit during a 14-month period were reviewed. RESULTS: Forty-three (8.1%) of 533 patients were found to have been admitted owing to antidepressant-associated mania or psychosis. CONCLUSION: Despite the positive changes in the side effect profile of antidepressant drugs, the rate of admissions due to antidepressant-associated adverse behavioral effects remains significant.

Rab27a enables myosin Va-dependent melanosome capture by recruiting the myosin to the organelle.

The peripheral accumulation of melanosomes characteristic of wild-type mouse melanocytes is driven by a cooperative process involving long-range, bidirectional, microtubule-dependent movements coupled to capture and local movement in the actin-rich periphery by myosin Va, the product of the dilute locus. Genetic evidence suggests that Rab27a, the product of the ashen locus, functions with myosin Va in this process. Here we show that ashen melanocytes, like dilute melanocytes, exhibit normal dendritic morphology and melanosome biogenesis, an abnormal accumulation of end-stage melanosomes in the cell center, and rapid, bidirectional, microtubule-dependent melanosome movements between the cell center and the periphery. This phenotype suggests that ashen melanocytes, like dilute melanocytes, are defective in peripheral melanosome capture. Consistent with this, introduction into ashen melanocytes of cDNAs encoding wild-type and GTP-bound versions of Rab27a restores the peripheral accumulation of melanosomes in a microtubule-dependent manner. Conversely, introduction into wild-type melanocytes of the GDP-bound version of Rab27a generates an ashen/dilute phenotype. Rab27a colocalizes with end-stage melanosomes in wild-type cells, and is most concentrated in melanosome-rich dendritic tips, where it also colocalizes with myosin Va. Finally, neither endogenous myosin Va nor an expressed, GFP-tagged, myosin Va tail domain fusion protein colocalize with melanosomes in ashen melanocytes, in contrast to that seen previously in wild-type cells. These results argue that Rab27a serves to enable the myosinVa-dependent capture of melanosomes delivered to the periphery by bidirectional, microtubule-dependent transport, and that it does so by recruiting the myosin to the melanosome surface. We suggest that Rab27a, in its GTP-bound and melanosome-associated form, predominates in the periphery, and that it is this form that recruits the myosin, enabling capture. These results argue that Rab27a serves as a myosin Va 'receptor', and add to the growing evidence that Rab GTPases regulate vesicle motors as well as SNARE pairing.

Interactive effects of subanesthetic ketamine and haloperidol in healthy humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with prominent psychoactive effects in humans. This study evaluated whether the oral administration of haloperidol 5 mg would block the effects of an intravenous ketamine infusion (bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour). Twenty healthy subjects completed 4 test days involving the oral administration of haloperidol or matched placebo 2 h prior to the intravenous infusion of ketamine or saline. Ketamine produced cognitive, behavioral, neuroendocrine, and physiologic effects in the healthy subjects that were similar to previous reports. Haloperidol pretreatment reduced impairments in executive cognitive functions produced by ketamine as measured by proverb interpretations and the Wisconsin Card Sorting Test. However, it failed to block the capacity of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria in healthy subjects. These data outline an important, but functionally delineated modulation of ketamine effects by dopamine2 receptors and other sites of haloperidol action.

Management of the adverse effects of clozapine.

Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Acute neuroleptic treatment in elderly patients without dementia.

Low doses of neuroleptics are the standard for treating psychosis in elderly patients because of concern about inducing adverse effects. The authors found that fixed, low-dose neuroleptic treatment (0.15 mg/kg/day) for 10 days resulted in low perphenazine levels and low rates of acute response (25%) in elderly patients with primary psychotic illness (without dementia). Increase in initial dose did not speed acute response and induced adverse effects that were absent or minimal with low-dose treatment. With higher-dose treatment, drug blood levels rose disproportionately, and level-to-dose ratios were higher than those observed in non-elderly adults. Naturalistic follow-up suggested that response may take longer to develop than in non-elderly adults and that low doses for a longer duration may provide effective treatment.

Chronological association between increases in drug abuse and psychosis in Connecticut state hospitals.

Disagreement remains as to whether drug use can result in an autonomous psychotic disorder. If drug use can create new psychosis cases, an increase in the number of psychosis patients ought to be observable following periods of increased drug use by the general population. First admissions data for the categories of drug abuse and schizophrenia/paranoid disorders from all Connecticut state hospitals from 1965 to 1983 were examined to determine the prevalence of psychotic disorders before, during, and after a period of increased drug use by the general population. Affective disorders first admissions were examined for comparison. A rapid increase in new schizophrenia admissions coincided with a peak period for drug-related admissions. The data suggest that increased drug use of the late 1960s may have contributed to the increase noted 3 to 5 years later in first admissions of patients diagnosed with psychotic disorders.

Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

Pretreatment plasma HVA predicts neuroleptic response in manic psychosis.

Elevated pretreatment plasma free homovanillic acid (HVA) predicted acute response to neuroleptic treatment in patients with manic psychosis. These findings suggest that plasma HVA may be a useful predictor of a successful short-term response in manic as well as schizophrenic psychoses, and that elevated pre-synaptic dopaminergic release may play a role in more than one group of psychotic disorders.

Plasma homovanillic acid and the dopamine transporter during cocaine withdrawal.

BACKGROUND: Plasma homovanillic acid (HVA) has been used as a measure of central dopaminergic activity but the validity of this method continues to be investigated. We used single photon emission tomography (SPECT) assessment of the dopamine (DA) transporter for comparison with plasma HVA in subjects at varying stages of abstinence from cocaine. METHODS: Nineteen subjects were studied in two separate treatment sites. Plasma HVA and methoxyhydroxyphenethyleneglycol (MHPG) were measured by gas chromatography-mass spectroscopy (GC-MS). The DA transporter was quantified using the SPECT ligand [123I]B-CIT. RESULTS: At 2 weeks of abstinence and beyond there was an increasing positive correlation between plasma HVA and the SPECT measurement of the DA transporter (V3"). CONCLUSIONS: Plasma HVA may be more likely to reflect DA transporter density in the striatum when there is not a major drug-related change in the DA system.

Imaging D2 receptor occupancy by endogenous dopamine in humans.

The impact of endogenous dopamine on in vivo measurement of D2 receptors in humans was evaluated with single photon emission computerized tomography (SPECT) by comparing the binding potential (BP) of the selective D2 radiotracer [123I]IBZM before and after acute dopamine depletion. Dopamine depletion was achieved by administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT), given orally at a dose of 1 g every six hours for two days. AMPT increased [123I]IBZM BP by 28 +/- 16% (+/- SD, n = 9). Experiments in rodents suggested that this effect was due to removal of endogenous dopamine rather than D2 receptor upregulation. Synaptic dopamine concentration was estimated as 45 +/- 25 nM, in agreement with values reported in rodents. The amplitude and the variability of the AMPT effect suggested that competition by endogenous dopamine introduces a significant error in measurement of D2 receptors in vivo with positron emission tomography (PET) or SPECT. However, these results also imply that D2 receptor imaging coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration in the living human brain.

The expanding indications for clozapine.

Clozapine is increasingly being used for clinical indications in addition to treatment-resistant schizophrenia; this article reviews the relevant literature. The first section reassesses the risks associated with clozapine treatment, particularly agranulocytosis. The next section discusses its use for schizophrenia in patients who are treatment resistant, not treatment resistant, and intolerant of traditional drug treatments. Subsequent sections address its use in mood disorders, neurologic conditions, comorbid substance abuse, aggressive behavior, and childhood schizophrenia. Each includes the initial rationale for the use of clozapine in the disorder, a critical evaluation of the relevant literature, and theories as to why clozapine's unique pharmacodynamic profile may be efficacious for the specific condition. This body of literature suggests clozapine may be an effective treatment for a wide range of disorders.

Delta 9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: blockade of dopaminergic effects with HA966.

The present study examined delta 9-tetrahydrocannabinol (THC)-induced alterations in monoamine transmission in the rat forebrain as well as the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on the monoamine response to THC. Activation of dopamine (DA) and norepinephrine (NE) but not serotonin (5-HT) turnover in the prefrontal cortex (PFC) was observed after THC (5 mg/kg i.p.) administration. Both enantiomers of HA966 completely prevented the effects of THC on PFC DA turnover and partially blocked the THC-induced rise in NE metabolism. The cognitive consequences of THC exposure were also examined. THC significantly impaired spatial working, but not reference, memory in rats, and this effect was ameliorated by HA966. Thus, HA966 prevents the THC-induced increases in PFC DA turnover and impairments of prefrontal cortical working memory function. Furthermore, these data suggest that cognitive impairments displayed by marijuana self-administering humans may be related to PFC DA hyperactivity and that HA966 may prevent this effect.

Recent life stressors and biological markers in newly admitted psychotic patients.

The association of recent life stressor severity to putative biological markers of stress was examined in 34 newly admitted patients with acute psychosis. Of the biological variables examined, only pretreatment admission serum cortisol was correlated with stressor severity. Pretreatment serum prolactin, plasma homovanillic acid (HVA), and methoxyhydroxyphen-ethylglycol were not associated with severity of recent life stressors. We controlled for clinical and psychosocial variables that might affect the relationship of stressor severity to biological markers, and found that duration of psychotic symptoms was negatively correlated with stressor severity; however, when both cortisol and duration were entered in a stepwise multiple regression analysis, only pretreatment admission cortisol remained significantly and positively correlated with stressor severity. These findings suggest that serum cortisol may be a useful biological marker when investigating the relationship of life stress to episode onset. In addition, pretreatment HVA was correlated with early neuroleptic response but not with stressor severity, suggesting that HVA has value as a predictor of response independent of recent life stressors.