Abnormal involuntary movements in patients on long-acting neuroleptics

1. 1. Two hundred and thirty eight patients (144 males, 94 females) on long-acting neuroleptics; mainly fluphenazine decanoate, were surveyed and evaluated for abnormal involuntary movements and associated risk factors.

2. 2. A highly significant correlation was found between the three scales used in the evaluation.

3. 3. The prevalence rate for the transient, acute extrapyramidal syndrome was 37.38%, while that of tardive dyskinesia was 57%. Half of the tardive dyskinesia cases were of minimal severity. Most of these were located in orofacial region.

4. 4. Tardive dyskinesia was more frequent in younger patients but more severe in older age groups. Other associated risk factors were tremors and rigidity, and use of antiparkinsonien drugs.

5. 5. Tardive dyskinesia is a common abnormal involuntary movement in patients on long-acting neuroleptic. Early recognition of TD in this population could help in planning for its prevention by the use of minimum effective dose of medication.

Noradrenergic effects in tardive dyskinesia, akathisia and pseudoparkinsonism via the limbic system and basal ganglia

1. 1. This paper proposes that the neuropsychiatric symptoms of tardive dyskinesia, akathisia and pseudoparkinsonian tremor are modulated by a noradrenergic pathway that projects from the locus coeruleus to the linbic system.

2. 2. The proposed pathway is found to be consistent with neuroanatomical and neurochemical data in the literature.

3. 3. The proposed pathway is found to be clinically consistent with observations by ourselves and others on the efficacy of clonidine and beta-adrenoreceptor blockers like propranolol for treating akathisia and pseudoparkinsonian tremor. It is also consistent with reports by ourselves and others that some patients with tardive dyskinesia benefit from treatment with propranolol or clonidine.

4. 4. Noradrenergic modulation of the limbic system by way of the locus coeruleus accounts for a number of clinical observations, such as the worsening of tardive dyskinesia by stress, the greater risk for tardive dyskinesia in patients with affective disorder, the time-of-onset of tardive dyskinesia, and the coexistence of tardive dyskinesia and pseudoparkinsonism.

5. 5. The functional significance of beta-adrenoreceptors in the basal ganglia is considered from an evolutionary perspective.

6. 6. The model proposed in this article appears to have considerable heuristic value because it may further our understanding of Gilles de la Tourette syndrome and attention deficit disorder (hyperkinesis).

Modulation of CNS dopamine receptors by peptides

1. 1. L-prolyl-L-leucyl-glycinamide (PLG), when administered concurrently with neuroleptic drug, blocked the development of dopamine receptor supersensitivity both at the behavioral and biochemical level.

2. 2. Chronic administration of haloperidol resulted in development of cholecystokinin (CCK) receptor supersensitivity in the mesolimbic regions of the brain. There was no change in equilibrium dissociation constant (KD) for CCK binding.

3. 3. The results are discussed in relation to modulation of dopamine receptor by peptides and possible models of Interaction of peptides with dopamine receptors are proposed.

An experimental antidepressant increases rem sleep

1. 1. An experimental antidepressant was studied through sleep laboratory recordings, psychoendocrinological tests and clinical measurements in terms of its efficacy, side effects and effects on sleep.

2. 2. The design included a four-week drug administration period, proceeded and followed by a one week placebo period.

3. 3. In the presence of antidepressant efficacy, the drug did not disturb sleep induction and maintainance.

4. 4. The only effect on sleep stages was an increase of REM sleep during the short-term drug administration period which is contrary to the REM supressant effect of most antidepressants.

5. 5. This finding suggests that REM supression and antidepressant efficacy are not necessarily related.

6. 6. Further, given that the only known action of the drug is its inhibitory effect on GABA-ergic transmission, one can speculate that GABA mechanisms may be involved in REM sleep modulation.

CGP 11.952: An experimental benzodiazepine derivative. Effects on cognitive functioning in patients with epilepsy

1. 1. In two open studies using patients with intractable epilepsy, the effects of CGP 11.952, a triazolyl benzophenone, on cognitive functioning were assessed by means of a computerized neuropsychological battery.

2. 2. In the first study CGP 11.952 turned out to have a positive effect on information processing speed, perceptual sensitivity and precisaness of responses.

3. 3. Negative effects were found on reaction time.

4. 4. In the second study this latter effect was less clear.

5. 5. A striking result was the less negative effect on memory consolidation under influence of CGP 11.952 in comparison with other benzodiazepines.

A follow-up study of a population of schizophrenic patients treated with clozapine

1. Clozapine is a dibenzodiazepine neuroleptic which presents the advantage of not having undesirable neurological side-effects. Its efficacy for the treatment of the symptoms of schizophrenia is known, but the use of clozapine is limited to treatment-resistant schizophrenic patients as it induces agranulocytosis with a higher incidence than that of other neuroleptic drugs.

2. The present study was designed in order to evaluate the benefit/risk of chronic treatment. The analysis was performed using the files of schizophrenic patients. These patients were not stabilized by a classical neuroleptic treatment and/or presented individual secondary effects.

3. Clozapine induced neutropenia and 1 case of agranulocytosis in 3 females. Analysis of leukocyte expression highlighted some premonitory symptoms in patients who presented neutropenia. The observation of 2 to 3 early successive peaks in leukocyte expression (between the third and tenth week of treatment) could be predictive of neutropenia in the 3 to 4 months of treatment.

4. The patients who presented a lower leukocyte base-line following a peak had a higher risk, of developing neutropenia. This might explain some late accidents beyond the first six months of treatment.

5. The present study confirmed the advantages of clozapine treatment and demonstrated that the risk of neutropenia may be diminished by the detection of premonitory symptoms and the early monitoring of patients at risk i.e. female patients and subjects with a lower leukocyte base-line.

Dexamethasone effects on numbers of cells in lymphocyte subpopulations: Changes associated with major depression and DST nonsuppression

1. 1. The authors studied the effects of administration of 1 mg of dexamethasone on the number of cells in discrete subpopulations of lymphocytes in major depressed and psychiatric control patients with depressive symptoms.

2. 2. Dexamethasone significantly decreased the total lymphocyte count and numbers of T and helper T lymphocytes in control patients.

3. 3. In contrast, dexamethasone failed to significantly decrease the numbers of cells in any of the subpopulations of lymphocytes studied in major depressed patients.

4. 4. Among major depressed patients both DST suppressors and nonsuppressors were insensitive to the suppressive effects of dexamethasone on lymphocyte numbers.

5. 5. However, in DST nonsuppressors, but not in DST suppressors, dexamethasone administration significantly the number of cytotoxic/suppressor T lymphocytes and natural killer cells.

6. 6. The authors conclude that insensitivity to the suppressive effects of dexamethasone on lymphocyte numbers is specific to major depression and is not associated with DST status. However, DST nonsuppression is associated with a facilitating effect of dexamethasone on the number of cells in some subpopulations of lymphocytes.

Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment

Wiesel, Frits-Axel: Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 871–881.

1. 1. Determination of regional glucose metabolism has been considered to be a tool to elucidate the mechanisms of action of neuroleptics.

2. 2. D₂-dopamine antagonists seem to increase glucose consumption in dopamine innervated areas.

3. 3. Studies in humans do not give results in complete accordance with animal findings.

4. 4. In patients neuroleptic compounds and dopamin agonists probably increase and decrease striatal metabolism respectively.

5. 5. Changes in metabolism, especially in the right hemisphere may be coupled with improvement of the patients.

6. 6. Future research must be based on protocols specially designed for the study of drug effects.

Assessment of agoraphobia and panic disorder

1. 1. Phobia and panic are defined by the measures used.

2. 2. Rating scales, diaries, global measures, physiological measures, behavioural assessment.

3. 3. Three fear systems: physiological, cognitive and behavioral

4. 4. Concordance and discordance.

5. 5. Synchrony and desynchrony

6. 6. The Behavioural Approach Test at the Calgary General Hospital.

Biphasic actions of pentobarbital on synaptic transmission

1. 1. The effects of pentobarbital were studied on synaptic transmission in the rat hippocampal slice preparation.

2. 2. Low concentrations of pentobarbital (0.04–0.1 mM) produced an increase in the Schaffer collateral to CA 1 evoked EPSP and population field potential amplitudes.

3. 3. Higher concentrations of pentobarbital (0.2–1.0 mM) produced depression of field potential amplitudes.

4. 4. Pentobarbital altered synaptic transmission by affecting both pre- and post-synaptic functions.

5. 5. Analysis of input/output curves suggest the presynaptic site is most sensitive.

A simple and efficient method for solubilization of the dopamine receptor

1. 1. The solubilization of dopamine receptors from bovine caudates was carried out with different detergents and detergent-salt combination.

2. 2. 0.25 M cholic acid: 1 M NaCl combination solubilized more effectively than the other detergents used.

3. 3. Solubilized receptors demonstrated the similar affinity and specificity as the membrane receptors.

4. 4. Solubilized receptors satisfied all the criteria of solubilization.

5. 5. Solubilized receptors were highly stable at 4°C and freezing at −70°C.

Escape from dexamethasone suppression: Possible role of an impaired inhibitory opioid mechanism

1. 1. Several lines of evidence indicate that the activity of the hypothalamus-pituitary-adrenal (HPA) axis in depression is disinhibited.

2. 2. Escape from dexamethasone suppression, although not limited to is more frequent in patients with endogenous depression compared to normals or patients with other psychiatric diagnoses.

3. 3. Norepinephrine, serotonin and acetylcholine have been implicated in the pathophysiology of this neuroendocrine abnormality.

4. 4. Morphine, 5 mg intravenously, suppressed Cortisol secretion in healthy volunteers (n = 4) and the majority of 32 psychiatric inpatients.

5. 5. However, patients with endogenous depression abnormal dexamethasone suppression test results show early resumption (escape) of cortisol secretion following the initial suppression induced by morphine.

6. 6. It is concluded that the pathophysiology of this neuroendocrine abnormality is not limited to classical neurotransmitter-HPA axis interaction but that it also involves opioid inhibitory mechanisms.

The effects of β-phenylethylamine and phenylethanolamine on water intake in rats: A temporal analysis

1. 1. Hale Wistar rats were adapted to a restricted access schedule of water intake.

2. 2. For each animal overall water intake (m1) and number of licks per minute were measured over the period of access to water.

3. 3. The effects of various doses of β-phenylethylamine and of phenylethanolamine were assessed in separate groups of animals.

4. 4. In terms of effects on overall consumption the two amines were equipotent in suppressing water intake. The local analysis revealed, however, that β-phenylethylamine was more potent, but had a much shorter duration of action than phenylethanolamine.

New concepts in benzodiazepine therapy: Rebound anxiety and new indications for the more potent benzodiazepines

1. 1. Abrupt withdrawal of benzodiazepine treatment in generalized anxiety patients was found to induce a rebound anxiety state in addition to minor physical symptoms.

2. 2. Controlled clinical trials suggest that the newer high potency benzodiazepines (alprazolam, clonazepam and bromazepam) have novel psychiatric indications and greater anxiolytic effect than the classical benzodiazepines.

3. 3. Alprazolam, a triazolobenzodiazepine, was superior to placebo in the treatment of panic disorder, for which medium or low potency benzodiazepines are generally inefficacious.

4. 4. Clonazepam, an anticonvulsant which increases 5HT synthesis, was more efficacious than lithium in reducing manic symptoms.

5. 5. Bromazepam, a new potent benzodiazepine, was superior to diazepam in the treatment of generalized anxiety disorder.

Buspirone: An anxioselective alternative for the management of anxiety disorders

1. 1. Buspirone HCl (Buspar ) is a novel anxiolytic agent unrelated to the benzodiazepines or other psychotherapeutic agents.

2. 2. Animal studies support an anxioselective profile, relief of anxiety without sedation, muscle relaxation or anticonvulsant activity.

3. 3. Double-blind clinical studies show buspirone to be effective in the treatment of anxiety and anxiety in the presence of depression.

4. 4. The effects of buspirone on psychomotor function, physical dependence and abuse potential tests are similar to those seen with placebo treatments.

5. 5. Mechanism of action studies indicate activity in a variety of neuronal systems.

Opioid receptor affinities of kappa agonists, agonist/antagonists and antagonists in vitro and in vivo

1. 1. The CMS opioid receptors consist of a major triad: μ, δ and κ.

2. 2. The κ agonists presently available act as κ agonists, δ antagonists and μ₂ isoreceptor antagonists.

3. 3. Pure opiate antagonists possess a broad spectrum of activity at all 3 opioid receptor populations.

4. 4. The Ag/Ant analgesics also possess a broad spectrum of receptor affinities which awaits the definition of complex species differences in their actions.

5. 5. The design of more specific opioid agonists and antagonists will lead to a greater understanding of the many possible roles opioids serve within the CNS.

The relationships of neukoendocrine tests in endogenous depression

1. 1. Amphetamine induced growth hormone (GH) response (Study 1) and TRH Induced TSH response (Study 2) were assessed in patients with endogenous depression (n = 20 and n = 22, respectively), who underwent a dexamethasone suppression test (DST) on the following day.

2. 2. The GH response to the amphetamine was significantly lower in the group of depressed patients than in the healthy controls (n = 13).

3. 3. There was no difference between the DST nonsuppressors (n = 12) and suppressors (n = 8) in the GH peak values. This data strongly suggests that the two tests are independent from each other.

4. 4. There was no significant relationship between the DST and TRH-TSH results.

5. 5. Patients with blunted TSH response to TRH have had significantly higher cerebrospinal fluid 5-HIAA levels.

Fluoxetine in borderline personality disorder

1. 1. Twelve patients with borderline personality disorder and not suffering a major depression were treated with fluoxetine, a selective serotonin reuptake inhibitor, in an open label trial. All of the patients improved, and 75% were rated as much or very much improved.

2. 2. Treatment was generally very well tolerated, but careful dosage titration was important in some patients, especially to manage agitation.

3. 3. Improvement has been maintained with continued treatment throughout the follow-up period which ranged up to six months.

4. 4. Incidental findings suggest fluoxetine may also be of use in treating substance abuse, attention deficit hyperactivity disorder, late luteal phase dysphoria disorder, dysthymic and cyclothymic disorders, and seasonal pattern depression.

5. 5. These preliminary results support the hypothesis that borderline personality disorder may be related to a central scrotonergic deficit.

The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives).

Mitsukuni Murasaki and Sadanori Miura: The Future of 5-HT_1A Receptor Agonists. (Aryl-Piperazine Derivatives) Prog. Neuro- Psychopharmacol-& Biol Psychiat, 1992, 16(6): 833–845.

1. 1. At present the dominant position among anti-anxiety medications has changed from meprobamate to the benzodiazepine derivatives.

2. 2. In order to avoid benzodiazepine's (BZ) undesirable side effects such as impairment of psycho-motor function, memory impairment, low dose dependence and withdrawal symptoms, a third generation anxiolytic agent, buspirone, the focus of the aryl-piperazine group of anti-anxiety agents, has been introduced recently.

3. 3. Aryl-piperazine derivatives work as 5-HT_1A receptor partial agonists and are known as serotonin normalizers.

4. 4. Therefore, they are expected to have not only an anxiolytic function but also an anti-depressant effect as well.

5. 5. A characteristic of the aryl-piperazine derivatives is that they have no sedative and muscle relaxant effects, and they do not have BZ's undesirable side-effects, especially in regard to withdrawal symptoms. However they have a rather weak anxiolytic action and a slow onset of action.

6. 6. Aryl-piperazine derivatives will not take the place of BZ, but the use of BZ and buspirone as bridge medications, making the most of the strong points of both, can be proposed as a way to compensate for their respective disadvantages.

Treatment of alcohol organic mental disorder with piracetam

1. 1. The paper presents an investigation of the efficiency of piracetam in alcohol organic mental disorder.

2. 2. A double blind placebo controlled study design was used to compare two dosages of the substance (2 × 3g versus 2 × 12g).

3. 3. The cognitive functions of the patients, especially short term memory and concentration, were assessed on the days 0, 7, 14, 28 and 42 using various psychological instruments.

4. 4. An analysis of 39 patients showed an improvement of cognitive functions in all three groups.

5. 5. Patients receiving drug treatment showed earlier responses than patients receiving placebo; differences between the three investigational groups were not statistically significant.

6. 6. The results achieved make the effect of piracetam appear somewhat questionable.