The social and economic effects of manic depressive illness and of its treatment in lithium clinics. (1/3659)

Advising about the employment of those who have had manic depressive episodes requires Occupational Health Physicians to obtain, with consent, an objective account of previous episodes and to appreciate the enormous range of manic and depressive manifestations. Familiarity is needed with the likely effects of treatment of episodes and the benefits and problems of prophylaxis--not just in general but in individual cases, for example, where driving is required. This article summarizes research into the effects of lithium preparations on the course of the illness, thyroid and renal function and the risk of suicide. The author found that changing from treatment of episodes to continuous prophylaxis benefited employment and personal relationships without causing body weight problems. Many patients do well in life if supported by an experienced professional team, with 61% requiring no further admissions once on lithium, and with an 86% reduction in admissions achieved in our local clinic.  (+info)

S-16924 [(R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]- pyrrolidin-3yl]-1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic with marked serotonin1A agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol. (2/3659)

S-16924 is a potential antipsychotic that displays agonist and antagonist properties at serotonin (5-HT)1A and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increased punished responses, an action mimicked by S-16924, whereas the atypical antipsychotic clozapine and the neuroleptic haloperidol were inactive. Similarly, in a Vogel conflict paradigm in rats, CLZ increased punished responses, an action shared by S-16924 but not by clozapine or haloperidol. This action of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultrasonic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and haloperidol. However, although WAY-100,635 abolished the action of S-16924, it did not affect clozapine and haloperidol. In a rat elevated plus-maze, CLZ, but not S-16924, clozapine, and haloperidol, increased open-arm entries. Like CLZ, S-16924 increased social interaction in rats, whereas clozapine and haloperidol were inactive. WAY-100,635 abolished this action of S-16924. CLZ, S-16924, clozapine, and haloperidol decreased aggressive interactions in isolated mice, but this effect of S-16924 was not blocked by WAY-100, 635. All drugs inhibited motor behavior, but the separation to anxiolytic doses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialysis levels of 5-HT in the nucleus accumbens: this action of S-16924 was blocked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine, S-16924 possessed a broad-based profile of anxiolytic activity at doses lower than those provoking motor disruption. Its principal mechanism of action was activation of 5-HT1A (auto)receptors.  (+info)

Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: interaction with bromocriptine. (3/3659)

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate] is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D1 receptor antagonist SCH-23390. The treatment with D1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D2 and D1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D2 receptors. We propose that the D2 and 5HT2 receptor-blocking and D1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.  (+info)

Mixed agonist-antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells. (4/3659)

We recently reported that clozapine behaves as a partial agonist at the cloned human m4 muscarinic receptor subtype. In the present study, we investigated whether the drug could elicit similar effects at the cloned human m1, m2, and m3 muscarinic receptor subtypes expressed in the Chinese hamster ovary (CHO) cells. Clozapine elicited a concentration-dependent stimulation of [3H]inositol phosphates accumulation in CHO cells expressing either the m1 or the m3 receptor subtype. Moreover, clozapine inhibited forskolin-stimulated cyclic AMP accumulation and enhanced [35S] GTP gamma S binding to membrane G proteins in CHO cells expressing the m2 receptor. These agonist effects of clozapine were antagonized by atropine. The intrinsic activity of clozapine was lower than that of the full cholinergic agonist carbachol, and, when the compounds were combined, clozapine potently reduced the receptor responses to carbachol. These data indicate that clozapine behaves as a partial agonist at different muscarinic receptor subtypes and may provide new hints for understanding the receptor mechanisms underlying the antipsychotic efficacy of the drug.  (+info)

Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. The Parkinson Study Group. (5/3659)

BACKGROUND: Drug-induced psychosis is a difficult problem to manage in patients with Parkinson's disease. Multiple open-label studies have reported that treatment with clozapine at low doses ameliorates psychosis without worsening parkinsonism. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of low doses of clozapine (6.25 to 50 mg per day) in 60 patients at six sites over a period of 14 months. The patients (mean age, 72 years) had idiopathic Parkinson's disease and drug-induced psychosis of at least four weeks' duration. All the patients continued to receive fixed doses of antiparkinsonian drugs during the four weeks of the trial. Blood counts were monitored weekly in all the patients. RESULTS: The mean dose of clozapine was 24.7 mg per day. The patients in the clozapine group had significantly more improvement than those in the placebo group in all three of the measures used to determine the severity of psychosis. The mean (+/-SE) scores on the Clinical Global Impression Scale improved by 1.6+/-0.3 points for the patients receiving clozapine, as compared with 0.5+/-0.2 point for those receiving placebo (P<0.001). The score on the Brief Psychiatric Rating Scale improved by 9.3+/-1.5 points for the patients receiving clozapine, as compared with 2.6+/-1.3 points for those receiving placebo (P=0.002). The score on the Scale for the Assessment of Positive Symptoms improved by 11.8+/-2.0 points for the patients receiving clozapine, as compared with 3.8+/-1.9 points for those receiving placebo (P=0.01). Seven patients treated with clozapine had an improvement of at least three on the seven-point Clinical Global Impression Scale, as compared with only one patient given placebo. Clozapine treatment improved tremor and had no deleterious effect on the severity of parkinsonism. In one patient, clozapine was discontinued because of leukopenia. CONCLUSIONS: Clozapine, at daily doses of 50 mg or less, is safe and significantly improves drug-induced psychosis without worsening parkinsonism.  (+info)

Antagonistic effects of trifluoperazine, imipramine, and chlorpromazine against acetylcholine-induced contractions in isolated rat uterus. (6/3659)

AIM: To examine the effects and affinity of some phenothizines (trifluoperazine, Tri and chlorpromazine, Chl) and antidepressant (imipramine, Imi) drugs on acetylcholine (ACh)-induced uterine contraction. METHODS: Isotonic contractions of rat uterine strips were recorded. ACh was administrated to induce maximal contraction before exchange of nutrient solution. ACh was added 5 min after the testing drugs. The nutrient solution was exchanged 4 times after each agonist (ACh or other agents) to produce maximal contraction. RESULTS: Atropine (Atr, 0.029-2.9 mumol.L-1), 4-DAMP (3.6-360 nmol.L-1), pirenzepine (Pir, 0.23-23.5 mumol.L-1), and AF-DX 116 (0.7-35.6 mumol.L-1) competitively antagonized the muscular uterine concentration induced by ACh (0.068-36068 mumol.L-1). The Schild plot was linear (r = 1.00). The pKB and slopes values (95% confidence limits) were 9.28 +/- 0.12 and 1.00 +/- 0.10 to Atr, 9.06 +/- 0.10 and 1.10 +/- 0.08 to 4-DAMP, 7.03 +/- 0.15 and 0.99 +/- 0.12 to Pir, and 5.60 +/- 0.08 and 1.00 +/- 0.19 to AF-DX 116. Tri 0.01-2 mumol.L-1 (pKB = 8.39 +/- 0.04) and Imi 94-940 nmol.L-1 (pKB = 7.21 +/- 0.10) produced also a competitive antagonism of the muscular uterine contraction induced by ACh (r = 1.00), but the slope was only 0.60 +/- 0.03 to Tri or 0.83 +/- 0.16 to Imi. Chl 2.8-5.6 mumol.L-1 produced a weak antagonism on amplitude of muscular contraction induced by the cholinomimetic. CONCLUSION: The muscarinic receptors on uterus behaved as M3 subtype. Tri and Imi, but not Chl, were competitive antagonist of muscarinic receptors of uterus. Imi behaved a simple competitive antagonist at a single site on myometrium, but Tri was not a simple competitive agent at a single site.  (+info)

The use of atypical antipsychotics in the management of schizophrenia. (7/3659)

Long-term drug treatment of schizophrenia with conventional antipsychotics has limitations: an estimated quarter to one third of patients are treatment-resistant; conventional antipsychotics have only a modest impact upon negative symptoms (poverty of thought, social withdrawal and loss of affect); and adverse effects, particularly extrapyramidal symptoms (EPS). Newer, so-called atypical, antipsychotics such as olanzapine, risperidone, sertindole and clozapine (an old drug which was re-introduced in 1990) are claimed to address these limitations. Atypical agents are, at a minimum, at least as effective as conventional drugs such as haloperidol. They also cause substantially fewer extrapyramidal symptoms. However, some other adverse effects are more common than with conventional drugs. For example, clozapine carries a significant risk of serious blood disorders, for which special monitoring is mandatory; it also causes troublesome drowsiness and increased salivation more often than conventional agents. Some atypical agents cause more weight gain or QT prolongation than older agents. The choice of therapy is, therefore, not straightforward. At present, atypical agents represent an advance for patients with severe or intolerable EPS. Most published evidence exists to support the use of clozapine, which has also been shown to be effective in schizophrenia refractory to conventional agents. However, the need for compliance with blood count monitoring and its sedative properties make careful patient selection important. The extent of any additional direct benefit offered by atypical agents on negative symptoms is not yet clear. The lack of a depot formulation for atypical drugs may pose a significant practical problem. To date, only two double-blind studies in which atypical agents were compared directly have been published. Neither provides compelling evidence for the choice of one agent over another. Atypical agents are many times more expensive than conventional drugs. Although drug treatment constitutes only a small proportion of the costs of managing schizophrenia, the additional annual cost of the use of atypical agents in, say, a quarter of the likely U.K. schizophrenic population would be about 56 M pound sterling. There is only limited evidence of cost-effectiveness. Atypical antipsychotics are not currently licensed for other conditions where conventional antipsychotics are commonly used, such as behaviour disturbance or dementia in the elderly. Their dose, and place in treatment in such cases have yet to be determined.  (+info)

Synergistic interactions between ampakines and antipsychotic drugs. (8/3659)

Tests were made for interactions between antipsychotic drugs and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors ("ampakines"). Typical and atypical antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the effects of near or even subthreshold doses of the antipsychotics were greatly enhanced by the ampakines. Interactions between the ampakine CX516 and low doses of different antipsychotics were generally additive and often synergistic. The ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the interaction between the different pharmacological classes was selective. These results suggest that positive modulators of cortical glutamatergic systems may be useful adjuncts in treating schizophrenia.  (+info)