Joseph F. Lipinski

In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action.

In addition to being dopamine antagonists, all antipsychotic drugs are potent antagonists of alpha-1 noradrenergic receptors. Nevertheless, the contribution of alpha blockade to the clinical therapeutic effects of the antipsychotic drugs has never attracted extensive study. In particular, the relative alpha-1 noradrenergic antagonist potency of antipsychotic drugs has rarely been determined in vivo during extended treatment, although such treatment would provide a better model of clinical drug effects than the determination of potencies in in vitro systems, such as assays of competition for binding sites in tissue homogenates, as is most often done. To estimate the physiological efficacy of antipsychotic drugs as dopamine and alpha adrenergic antagonists, we treated rats for four weeks with daily IP injections of the following antipsychotic drugs: Fluphenazine, 1 mg/kg; haloperidol, 1 mg/kg; chlorpromazine, 25 mg/kg; thioridazine, 25 mg/kg; and clozapine, 25 mg/kg. Effective antagonism should lead to an increase in density of the relevant receptors. After two drug-free days, rats were sacrificed and the affinity and density of dopamine D2 and alpha-1 noradrenergic receptors were determined in striatum and brain exclusive of striatum, respectively. Alpha 1 noradrenergic receptor density but not dopamine receptor density was increased after all treatments. Thus, preliminary experiments with this in vivo model suggest that all antipsychotic drugs are effective antagonists at alpha 1 noradrenergic receptors, while not all are effective antagonists at dopamine D2 receptors.

Effects of amantadine hydrochloride on catecholamine metabolism in the brain of the rat

Abstract We have examined the effects of the cyclic amine, amantadine, on the metabolism of catecholamines in the rat. Large doses of the drug had minimal effects on cardiac norepinephrine stores, but produced small decreases in concentrations of norepinephrine in the brain, while having less effect on dopamine and no effect on serotonin. The drug altered the metabolism of previously intrathecally administered [ 3 H]norepinephrine: there were small decreases of [ 3 H]norepinephrine, but clear decreases of [ 3 H]deaminated catechol metabolites and marked increases of [ 3 H]normetanephrine for 1–6 hr, at times paralleling decreases in endogenous norepinephrine levels. Later, smaller increases of [ 3 H ] deaminated -O- methylated products appeared. These metabolic changes were not due to inhibition of monoamine oxidase by this drug, as amantadine had no effect on the deamination of [ 14 C]serotonin or [ 3 H]norepinephrine even at high concentrations in vitro or doses in vivo . Amantadine decreased the retention by isolated nerve endings in vitro of previously intrathecally injected [ 3 H]norepinephrine by a very small amount and competitively inhibited the initial uptake of [ 3 H ]d,l- norepinephrine by nerve endings of whole brain, with a K i of approximately 1.5 × 10 −5 M. This inhibition of uptake was somewhat greater in the cerebral cortex than in the corpus striatum. There was much less inhibition of the uptake of [ 3 H]dopamine in both regions. Thus, part of the action of this drug in Parkinsons disease may be due to inhibition of uptake and retention of catecholamines at central nerve terminals. However, since the doses required to produce changes in vivo were much higher than those used clinically, these findings may reflect non-specific or toxic effects of the drug.

Comparison of metoprolol and propranolol in the treatment of akathisia

Metoprolol was compared to propranolol in the treatment of neuroleptic-induced akathisia by means of an on-drug/off-drug crossover study. Both beta-blockers were effective, but the usefulness of metoprolol was limited by side effects due to the high dose of this medication required to produce a therapeutic effect. The mechanism of action of beta-blockers in the treatment of akathisia is discussed in light of the different pharmacologic properties of metoprolol and propranolol. The study results suggest that these agents are effective in reducing akathisia through a central mechanism of action requiring beta-2 blockade.

Antidepressant-related akathisia

Five neuroleptic-free patients exhibited syndromes that were indistinguishable from idiopathic or neuroleptic-induced akathisia in association with antidepressant administration. While antidepressant-related akathisia may be produced by any of a variety of antidepressants, the susceptibility of each individual patient to the development of this disorder may be limited to only one or a few of these agents. A considerably rarer syndrome than neuroleptic-induced akathisia, antidepressant-related akathisia appears to respond to established pharmacologic treatments for neuroleptic-induced akathisia.

Long-term response to carbamazepine: a retrospective study

Carbamazepine is now used by many clinicians in the treatment of bipolar disorder (BD) refractory to standard treatments, including lithium and neuroleptics. Little information is yet available about the utility and efficacy of this novel treatment during long-term use. We carried out a retrospective study of 50 patients (34 with BD) who had received carbamazepine for the treatment of a psychotic disorder. Two-thirds (22) of the BD patients and two of the 16 patients with other diagnoses appeared to respond to carbamazepine acutely. However, follow-up 3 to 4 years later revealed that only eight patients (seven with BD) were still receiving the drug. In only two cases was the treating psychiatrist convinced that carbamazepine was clearly beneficial. Side effects, particularly hematological abnormalities, during both short- and long-term treatment were troublesome. Carbamazepine may only infrequently be useful in the long-term care of patients who fail to respond to standard treatment.

Use of clonidine in treating neuroleptic-induced akathisia

Six patients with akathisia were treated with clonidine in an open, on-drug/off-drug trial. All six patients demonstrated substantial improvement of their akathisia, with four of the six obtaining complete remission. The dose of clonidine used to treat the remaining two patients was limited by the development of symptomatic hypotension. Daily doses ranged from 0.2 to 0.8 mg, and maximal response to a particular dose occurred within 24 to 48 hours. Although no effects on lithium tremor, parkinsonism, or tardive dyskinesia were observed, two bipolar patients exhibited considerable improvement in their manic and psychotic symptoms during treatment with clonidine.

Polysomnographic characteristics of schizophrenia in comparison with mania and depression.

Despite the recognized importance of the study of sleep in schizophrenic patients~ there is little consensus as to the pattern of polysomnographic abnormalities displayed by schizophrenic patients and even less regarding how thc.~e ,d~normalitics compare with patients with other disorders. Earlier studies of schizophrenia are difficult to interpret because of the effects of medication and use of broad diagnostic criteria (Hiatt et al 1985; Keshavan et al 1990). More recently, six polysomnographic studies (Hiatt et al 1985; Ganguli et al 1987; Zarcone et al 1987; Kempenaers et al 1988; Riemann et al 1991; Tandon et al 1992) have evaluated the characteristics of unmedicated schizophrenic patients versus healthy control subjects, with three of these studies (Ganguli et al 1987; Kempenaers et al 1988; Riemann et al 199 I) also comparing schizophrenic patients with age-matched patients with major depression. These studies have yielded somewhat inconsistent findings: whereas schizophrenic and depressed patients have displayed disturbances in sleep continuity, abnormalities of sleep architecture and rapid eye movement (REM) measures have been found variably in both groups. Furthermore, no study has compared schizophrenia with mania--a disorder important in the differential diagnosis of schizophrenia. To evaluate further the characteristics of sleep in schizophrenia, we performed a polysomnographic study of eight patients with schizophrenia, compared with age-matched patients with mania, patients with major depression, and healthy individuals studied previously at our center (Hudson et ai 1992a).

Clinical use of the radioreceptor assay for neuroleptics

The potential clinical utility of the radioreceptor assay for neuroleptics (NRRA) was examined. The NRRA was able to detect neuroleptic activity in blood specimens from patients receiving a variety of neuroleptic medications. For each medication, mean plasma neuroleptic activity was lower in patients showing a poor response to treatment than in those showing a good response. Because the range of plasma neuroleptic activities found was quite different from drug to drug, it appears that results obtained by the NRRA must be standarized for each drug.

Neuroleptic blood levels and therapeutic effect.

Studies attempting to delineate a therapeutic range of blood levels for neuroleptics have yielded conflicting results. The reasons for this are briefly reviewed and a study is described in which a correlation is sought between blood levels of thioridazine and clinical efficacy. The study employs the radioreceptor assay for neuroleptics to detect both parent drug and active metabolites in blood. The results of the study indicate that while dose is a poor predictor of blood levels of medication, blood levels of neuroleptic activity in patients on thioridazine may be very highly correlated with antipsychotic effect.

Serotonin-uptake inhibitors in obsessive-compulsive disorder: a case report.

Abstract The authors describe a patient with severe obsessive-compulsive disorder (OCD) refractory to treatment with a tricyclic antidepressant, a monoamine oxidase inhibitor, lithium carbonate, carbamazepine, neuroleptics and various combinations of these drugs, whose OCD responded dramatically and repeatedly to treatment with two potent serotonin-uptake inhibitors, clomipramine and citalopram. Response to these agents was complicated by the induction of mania, but the amelioration of obsessive-compulsive symptoms in this patient argues for further trials of selective serotonin-uptake blockers in the treatment of this and other obsessive-compulsive patients, and may offer some support to the hypothesis of a disturbance in serotonergic transmission, at least in this case of this disorder.