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.

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.

Long term treatment with oxaprotiline in patients with major depression

1. 1) Four hundred thirty-seven patients with depressive illness were treated for up to 11 months with oxaprotiline (Ba-49802B)in a continuation study.

2. 2) Results of this study suggest that oxaprotiline continued to be effective in alleviating depressive symptoms.

3. 3) Additionally, evaluation of safety parameters failed to reveal any significant risk to patients who were treated with oxaprotiline over this extended period of time.

Increments in plasma homovanillic acid concentrations after neuroleptic discontinuation are associated with worsening of schizophrenic symptoms

Khan, René s., Farooq Amin, Peter Powchik, Peter Knott, Marvin Goldstein, Seth Apter, Ben Kerman, Stacey Jaff and Michael Davidson: Increments in Plasma Homovanillic Acid Concentrations after Neuroleptic Discontinuation are Associated with Worsening of Schizophrenic Symptoms. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1990, : 879–884.

1. 1. Thirty-two male schizophrenic patients participated in this study.

2. 2. Plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA) were assessed once on neuroleptic medication and twice a week for a maximum of six weeks after its discontinuation.

3. 3. Psychiatric symptomatology was assessed once on neuroleptic medication and once a week for a maximum of six weeks after its discontinuation, using the brief psychiatric rating scale (BPRS).

4. 4. pHVA and total BPRS score increased significantly after discontinuation of neuroleptic as compared to baseline.

5. 5. The magnitude of pHVA and BPRS increments after discontinuation of neuroleptic correlated significantly.

6. 6. Results of this study suggest that worsening of schizophrenic symptoms after discontinuation of neuroleptic treatment is associated with increased pHVA concentrations.

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.

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.

Biogenic amine metabolites in delusional (psychotic) depression and melancholia subtypes of major depression

1. 1. The levels of the urinary main metabolites of norepinephrine 3-methoxy-4-hydroxyphenylglycol (MHPG), of dopamine homovanillic acid (HVA) and of serotonin 5-hydroxyindoleacetic acid (5-HIAA) were measured in 84 patients with major depressive disorder, 34 delusional and 50 nondelusional. Melancholia subtype was also defined (N=62).

2. 2. MHPG was significantly higher in the delusional depressed group (p=0.023). Female patients with delusional major depression also had significantly higher HVA excretion than female patients with non delusional major depression (p=0.036). 5-HIAA excretion was similar in the two patient subgroups.

3. 3. No significant differences in the three monoamine metabolites were found between the melancholic and nonmelancholic depressed patients.

Pharmacologic Perturbation Strategies in the Study of the Neurobiology of Depression

1. 1. Psychological, behavioral, physiological, biochemical, and receptor binding measurements are useful as dependent variables when studying the biology of depression and mania.

2. 2. Pharmacological perturbations of cholinergic mechanisms can produce changes mimicking aspects of the neurobiology of affective disorders.

3. 3. These changes can be quantitated by measuring their impact on variables in each of these classes.

4. 4. Pharmacological methods for inducing these changes in cholinergic systems and their application to clinical and basic research in the field of affective disorders are highlighted.

Fever and leukocytosis: Physical manifestations of bipolar affective disorder?

1. 1. Fever and leukocytosis are occasionally observed in patients with psychiatric disorders. A thorough medical evaluation does not always reveal the origin of these abnormalities.

2. 2. We report the case histories of three patients with bipolar affective disorder and an abnormal DST who had fever and leukocytosis during the acute phase of their illness. No organic etiology could be found.

3. 3. All three patients responded to ECT with resolution of the depression, the fever, and the leukocytosis, and normalization of the DST.

4. 4. We propose that fever and leukocytosis may be rare physical manifestations of bipolar affective disorder, particularly in patients with abnormal DST.

Diagnosis and pharmacotherapy of conduct disorder

Lavin Michael R. and Arthur Rifkin: Diagnosis and Pharmacotherapy of Conduct Disorders. Prog. Neuro- Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 875–885.

1. 1. There are few double-blind, placebo-controlled studies of the drug treatment of conduct disorders in children and adolescents.

2. 2. The diagnosis of conduct disorders involves a persistent pattern of behavior in which the basic rights of others and standards of society are violated.

3. 3. There is frequent comorbidity associated with conduct disorders including attention-deficit hyperactivity disorder, oppositional defiant disorder, mood disorders and substance abuse.

4. 4. Childhood Conduct disorder is associated with a significant risk for adult psychopathology.

5. 5. A variety of treatment approaches may be employed to combat conduct disorders.

6. 6. The use of neuroleptics, lithium carbonate, stimulants and other agents is reviewed.

Preclinical and clinical studies with cysteamine and pantethine related to the central nervous system

Vécsei, László and Erik Widerlöv: Preclinical and Clinical Studies with Cysteamine and Pantethine Related to the Central Nervous System. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, : 835–862.

1. 1. Cysteamine is formed by degradation of coenzyme A (CoA) and causes somatostatin (SS), prolactin and noradrenaline depletion in the brain and peripheral tissues.

2. 2. Cysteamine influences several behavioral processes, like active and passive avoidance behavior, open-field activity, kindled seizures, pain perception and SS-induced barrel rotation.

3. 3. Cysteamine has several established (cystinosis, radioprotection, acetaminophen poisoning) and theoretical (Huntington's disease, prolactinsecreting adenomas) indications in clinical practice.

4. 4. Pantethine is a naturally occurring compound which is metabolized to cysteamine.

5. 5. Pantethine depletes SS, prolactin and noradrenaline with lower efficacy compared to that of cysteamine.

6. 6. Pantethine is well tolerated by patients and has been suggested to treatment of atherosclerosis. The other possible clinical indications (alcoholism, Parkinson's disease, instead of cysteamine) are discussed.

Neurotransmitter functions in depression

The understanding and management of depression has now progressed beyond the limitations imposed by clinical examination. Biochemical and pharmacological studies based on the biogenic amine hypothesis have investigated neurotransmitter mechanisms to varying degrees.

1. Subgroups of depressions may be identified and treated based on MHPG execution.

2. HVA correlates more with activity than with mood.

3. CSF-5HIAA may be helpful in categorising some depressions.

4. Acetylcholine has some effect on mood most probably through indirect action on other neurotransmitters.

5. GABA is still not adequately investigated.

6. Desensitization of presynaptic adrenergic autoreceptors may explain some of the mechanisms of antidepressant action of drugs.

7. Decreased post-synaptic adrenergic activity is a common effect of most antidepressants and of ECT.

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.

GABA-Transaminase in brain and blood platelets: Basic and clinical aspects

1. 1. Several lines of evidence suggest that the major inhibitory neuro-transmitter, gamma-aminobutyric acid (GABA) is involved, both directly and indirectly, in the pathogensis of certain neurological and psychiatric disorders.

2. 2. The main enzyme responsible for GABA catabolism is gamma-aminobutyrate aminotransferase (GABA-T). Inhibition of this enzyme produces a considerable elevation of brain GABA concentrations, and such elevation has been correlated with many pharmacological effects.

3. 3. There seems to be that, as is discussed below, GABA-T activity in the brain and/or blood platelets is related to some neuro-psychiatric disorders such as alcoholism, epilepsy and Alzheimer's disease.

4. 4. GABA-T has been identified in the blood platelets with similar characteristics to those of brain GABA-T. In this way, studies on GABA-T activity in neuro-psychiatric disorders could be performed to understand, diagnosis and treat GABA-related disorders of the central nervous system (CNS).

Determination of plasma haloperidol concentrations by radioreceptor assay in schizophrenia: Clinical utility

1. 1. Haloperidol concentrations were determined by radioreceptor assay (RRA) and prolactin concentrations were measured in 20 patients diagnosed as schizophrenia (DSM-III).

2. 2. The patients were treated with a fixed dose of haloperidol for 21 days.

3. 3. Our results suggest the existence of a curvilinear relationship, in the form of an inverted U, between stable haloperidol levels and clinical improvement assessed by total BPRS score.

4. 4. We also found a curvilinear relationship between the improvement observed in positive symptoms and state steady levels.

5. 5. No relationship was seen between improvement in negative symptoms and state steady levels.

6. 6. An interval of optimal haloperidol concentration was found: 8.1 ng/ml to 19.6 ng/ml.

7. 7. No relation was found between the dose of haloperidol administered and plasmatic concentration, nor between haloperidol and prolactin levels.

8. 8. Our findings suggest that haloperidol concentrations determined by RRA have clinical utility as predictors of response in schizophrenia.

Evidence for distinct benzodiazepine receptors for anticonvulsant and sedative actions: Implications for the treatment of temporal lobe epilepsy

1. 1. An imidazobenzodiazepine, Ro15-1788, has anticonvulsant effects in the kindling model for epilepsy.

2. 2. Ro15-1788 reverses the sedative actions of diazepam (3 mg/kg i.p.) but does not reverse the anticonvulsant effects.

3. 3. The anticonvulsant effects of Ro15-1788 are prevented by the pyrazoloquinolinone CGS-8216 which interacts with benzodiazepine receptors but has no anticonvulsant actions itself.

4. 4. It is suggested that Ro15-1788 is a partial agonist at the BZ₂ (anticonvulsant) receptor but is an antagonist at the BZ₁ (sedative, anxiolytic) receptor. CGS-8216 is an antagonist at both receptors.

5. 5. Ro15-1788 or related compounds may be effective anticonvulsants without the sedative side-effects usually found with the benzodiazepines.

Different effects of antidepressants on dissociation of H-imipramine from solubilized binding sites of rat brain

1. 1. The effects of several antidepressants and 5-hydroxytryptamine on dissociation of ³H-imipramine from solubilized binding sites were investigated.

2. 2. Binding sites were solubilized from rat brain membranes and gelfiltrated on a column of Sephacryl S-300.

3. 3. Most of the agents used allowed biphasic dissociation with 1mM of displacing agent and without using dilution-induced dissociation. This biphasic dissociation without nonspecific effects of membranes may be due to the existence of low-affinity binding sites.

4. 4. Dissociation of up to 40 min followed first-order kinetics. The dissociation half-life of ³H-imipramine with the various displacing agents was calculated at from 15.0 to 25.0 min, and the differences among the agents were not so significant as the attenuation or the acceleration of the dissociation was indicated. The lower concentration of the displacing agents may obscure the modulation of the dissociation.

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.

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.

A preliminary study of serotonergic antidepressants in treatment of dysthymia

Rosenthal, Jesse et al. A Preliminary Study of Serotonergic Antidepressants in the Treatment of Dysthymia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 933–941.

1. 1. There is increasing evidence that antidepressants may alleviate symptoms of dysthymia, but few prior studies on selective serotonergic agents.

2. 2. Twenty patients meeting criteria for dysthymia, but not meeting criteria for major depression, received open label trials of a serotonergic antidepressant, either fluoxetine or trazodone.

3. 3. Seventeen (85%) completed three-month medication trials, and of these, twelve (70.6% of completers) responded to treatment. Seven (41.2% of completers) were still in remission on followup at five months.

4. 4. Both fluoxetine and trazodone were well tolerated in dysthymics, and showed similar short-term effectiveness in treating dysthymic symptoms.