Precursor amino acid concentrations in normal weight bulimics and normal controls

1. 1. CNS serotonergic neurotransmission has been implicated in the control of appetitive behavior. The ratio of plasma tryptophan (TRP) to other large neutral amino acids (LNAA) is believed to regulate CNS serotonin (5-HT) synthesis.

2. 2. After an overnight fast, plasma TRP ratios were determined in 23 normal weight bulimics and 7 normal controls.

3. 3. All subjects were assessed for mood disorder using a SADS interview and Beck Depression ratings.

4. 4. There was no significant difference in TRP ratios between bulimics and normal controls. TRP ratios in depressed bulimics were not significantly different from those of nondepressed bulimics.

5. 5. Potential abnormalities in CNS serotonergic function in bulimics are not reflected in decreased baseline TRP ratios. Further investigation of the dynamic serotonergic system may prove fruitful.

6. 6. Reduced availability of tryptophan for conversion to serotonin is not likely to be the postulated biological abnormality common to both depression and bulimia.

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.

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.

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.

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).

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.

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.

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.

The association of tardive dyskinesia and pseudoparkinsonism

1. 1. A survey of 315 chronic inpatients for the presence of extrapyramidal side effects indicates that 58.7% of the patients had no evidence of extrapyramidal side effects, 28.6% had tardive dyskinesia (TD) alone, 8.9% had pseudoparkinsonism and 3.8% had a combination of both.

2. 2. Women seemed to exhibit more side effects.

3. 3. Aging was another factor associated with a higher risk for the appearance of extrapyramidal side effects.

4. 4. Affective disorder patients carried more risk than patients with schizophrenia.

5. 5. The low prevalence of the combined TD and pseudoparkinsonism may be related to several factors. The possible explanations are explored and discussed. These patients present a therapeutic dilemna.

Antidepressant binding: Implications for the mode of action and the biology of depression

1. 1. (³H)Imipramine binding sites in the brain are localized mainly on serotonergic nerve terminals. In the hippocampus of rats with a lesion of serotonergic nerve terminals produced by neonatal administration of 5,7-DHT the depletion of serotonin was paralleled by a decrease in (³H)imipramine recognition sites.

2. 2. (³H)Imipramine recognition sites in brain tissue or platelets are associated with serotonin uptake sites. A significant correlation exists between the potency of a series of antidepressants and other compounds to displace high affinity (³H)imipramine binding and to inhibit the neuronal uptake of serotonin but not of norepinephrine.

3. 3. There is a significant correlation between the ability of drugs to displace (³H)desipramine binding and to inhibit norepinephrine but not serotonin reuptake. (³H)Desipramine recognition sites are located at least in part at noradrenergic nerve terminals since destruction of these terminals by 6-OH-DA results in parallel decrease in (³H)desipramine but not in (³H)imipramine Binding.

4. 4. The high affinity recognition sites of (³H)imipramine and (³H)desipramine in the brain could be physiologically And Pharmacologically relevant regulatory sites associated with neuronal uptake of serotonin and norepinephrine respectively. Treatments which clinically lead to improvement of depression (eg. antidepressants ECT REM sleep deprivation) were shown to “down-regulate” (³H)imipramine binding sites in brain of experimental animals.

5. 5. The density of (³H)imipramine binding sites was shown to be lower in platelets from depressive patients and in brains of suicide victims. It appears that decreased binding of (³H)imipramine to platelets of depressed patients is a promising biological marker of depression although there is no conclusive evidence to indicate whether it is a state- or trait-dependent phenomenon.

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.

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.

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.

Consequences of decreased brain serotonin in the pyridoxine-deficient young rat

1. 1. The concentrations of serotonin in various brain areas were significantly decreased in the pyridoxine-deficient young rat.

2. 2. There was no change in the concentration of dopamine.

3. 3. Both Bmax and Kd of [³H] serotonin binding to membrane preparations from cerebral cortex were increased in deficiency and were restored to normal upon pyridoxine supplementation.

4. 4. There was no change in [³H] spiroperidol binding to corpus striatal membrane preparations in pyridoxine-deficient rats.

Topographic evoked potentials during backward masking in schizophrenics, patient controls and normal controls

1. 1. A backward masking task with simultaneous measurement of topographically mapped evoked potentials was performed by normal, schizophrenic, and patient control subjects.

2. 2. Behavioral results replicated previous studies demonstrating schizophrenic deficit and to a lesser extent patient control deficit in this task.

3. 3. Two competing theories of (A) defects in “gating” mechanisms or (B) failure in early stimulus “registration” processes were tested.

4. 4. Topographical evoked response maps Indicated a significant absence of a negative going wave in the 70–100 msec epoch in the schizophrenic group relative to both control groups.

5. 5. As the 70–100 msec negativitity attenuation occurred during target presentation, and well before mask onset, it was concluded that schizophrenic deficit in this task consists of a failure in Initial stimulus “registration” processes within the time allowed for stimulus availability.

6. 6. Such defective mechanisms may be significant in the pathogenesis of schizophrenia.

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.

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.

Effect of nicotine on human blood platelet serotonin uptake and efflux

1. 1. Physostigmine administration has been previously shown to decrease the uptake of serotonin in human platelets. In order to test whether uptake could be inhibited as a nicotinic-cholinergic effect, the in vitro effects of nicotine on platelet 5HT uptake and efflux were examined.

2. 2. Nicotine stimulated release of serotonin from human blood platelets, and competitively inhibited human platelet serotonin uptake in a concentration-dependent fashion at in vitro concentrations as low as 20 μM for uptake.

3. 3. The kinetics of the nicotine effects on uptake were different from those of physostigmine. Unlike the effects of physostigmine, nicotine produced different kinetic changes, with an increase in Km and no consistent change in Vmax.

4. 4. The efflux and inhibition of uptake paralleled that previously reported in rat brain in vitro, and was likewise similar to concentrations found previously to augment extracellular amine in other tissue preparations. However, the effects of nicotine in human platelets were not reversible by nicotinic antagonism with hexamethonium.

5. 5. The results distinguish human platelet from rat brain with respect to nicotinic antagonism, and suggest that, at similar concentrations, nicotine may increase extracellular serotonin through differing mechanisms.

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.