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.

On the significance of cholecystokinin receptors in panic disorder

1. 1.Interest in the biological aspects of panic disorder has been focussed mainly on the noradrenergic and serotonergic systems in the brain.

2. 2. Recently evidence has been found that Cholecystokinin (CCK) receptors in the Central Nervous System (CNS) may be involved in panic disorders. This hypothesis is based on the results of animal electrophysiological studies, animal models of anxiety and on challenge test using CCK fragments in humans.

3. 3. In this review, the studies evaluating the putative involvement of CCK, and especially CCK-B receptors, in panic disorder will be discussed.

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.

Effects of light on human melatonin production and the human circadian system

1. 1. Bright artificial light appears to have similar effects in humans as in other species.

2. 2. Bright light may therefore be used as a clinical research tool and as a therapeutic modality for treating certain biological rhythm disorders.

3. 3. Melatonin production appears to be a particularly useful “biological marker” for the human endogenous circadian pacemaker and the effects of light.

Suriclone: A new anxiolytic drug

1. 1. Suriclone, a new psychotherapeutic agent chemically unrelated to benzodiazepines or phenothiazines was assessed in a single-blind dose-ranging study to determine its efficacy and safety in out-patients with generalized anxiety disorder.

2. 2. Suriclone was an effective anxiolytic drug at a dose range between 1.2 mg. and 3.6 mg. per day. The drug, when effective, has a duration of action between 6 and 8 hours. There was no evidence of a rebound phenomenon. There was, however, a rapid return to pre-treatment level of anxiety. Side effects were few, mild and transient.

3. 3. This new molecule may herald an advance in the treatment of these disorders and should be investigated more fully.

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.

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).

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.

Neurobehavioral studies of forced swimming: The role of learning and memory in the forced swim test

West A. Preston: Neurobehavioral studies of forced swimming: The role of learning and memory in the forced swim test. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, 863–877.

1. 1. Immobility in the forced swim test (“behavioral despair test”) has often been regarded as an animal model of despair or depression.

2. 2. Behavioral studies of forced swimming (“behavioral despair”) are reviewed and compared with certain behavioral effects of exposure to inescapable shock (i.e., “learned helplessness”).

3. 3. Exposure to inescapable shock clearly impairs subsequent coping responses. However, detailed behavioral studies of forced swimming indicate that immobility during forced swimming is not a failure of coping but instead reflects a relatively successful coping strategy that employs energy conserving behaviors.

4. 4. Certain neurobiological studies of forced swimming are reinterpreted in light of the behavioral evidence that immobility during forced swimming reflects effects of learning and memory rather than effects of despair or depression.

5. 5. Some implications for future neurobehavioral studies of forced swimming and uncontrollable shock are discussed.

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.

Behavioural modifications in relation to hypothyroidisim and hyperthyroidism in adult rats

1. 1. Behavioural experiments were carried out on adult rats made hypothyroid and hyperthyroid. The hypothyroid rats in an “open field” situation reduced the number of squares crossed and boluses defecated, the hyperthyroid rats reduced the number of squares crossed. A swimming endurance was conducted to evaluate the physical resistence of the rats: only hypothyroidism affected the performance.

2. 2. Two operant tests were studied: a) an “extinction” trial (60 min), in which the rats trained in a fixed ratio schedule (FR 1:10), were no longer rewarded with pellets of food and b) the “reversal” test in which the contingency for food delivery was switched four times from one lever, where responses were previously reinforced, to the other lever where responses had no programmed consequences.

3. 3. Both hypo and hyperthyroid conditions caused a lower rate of responses during the “extinction” trial, while in the “reversal” test only hyperthyroid rats showed improved performances.

4. 4. Our data clearly demonstrate behavioural changes in adult hypothyroid and hyperthyroid rats.

The diagnosis and drug treatment of anxiety disorders

1. 1. Anxiety, phobic and related neurotic disorders lend themselves to diagnostic confusion because of the large and variable array of symptoms associated with them. This has complicated attempts at coherent classification.

2. 2. This paper examines the problems in diagnosis and classification and the diversity of causal models of these disorders. It offers an alternative Integrated perspective that may have heurestic merit in guiding clinicians to a practical choice of treatment and in delineating a useful starting point for the biological investigation of these disorders.

A study of the catabolism of trace amines in mentally disordered individuals with particular reference to agoraphobic patients with panic attacks

1. 1. Platelet MAO activity toward several trace amine substrates and the plasma levels of some trace acids have been investigated. Compared to controls, the agoraphobic patients were found to have significantly increased MAO activity.

2. 2. The substrate specificity in some of the patients appeared to be altered.

3. 3. The plasma levels of -HPA and -HPA were significantly lower than those of the control groups.

Clonidine immediately after immobilization stress prevents long-lasting locomotion reduction in the rat

1. Stress-induced behavioral change in the rat has been utilized as an animal model of anxiety disorder. The authors examined the effect of early intervention by noradrenergic inhibition on stress-induced long-lasting locomotion reduction.

2. Clonidine, an alpha2 agonist, was administered immediately after a single session of 8 min immobilization stress in a restraining box, followed by locomotion measurement on day 1, day 7, and day 14 after the stress session.

3. In the saline-treated control group, locomotion on day 1, day 7, and day 14 after the 8 min stress session was significantly reduced to about 80 % in comparison with that before the stress. This finding confirmed the previous report that a single stressful event could lead to long-lasting behavioral changes. When clonidine was administered, locomotion reduction was not observed on any post-stress day.

4. The results suggest that early intervention by noradrenergic inhibition to stressful events may have a preventive effect on subsequent behavioral change which may be considered as an animal model of post-traumatic stress disorder.

Schizophrenia and the D1 receptor: Focus on negative symptoms

Lynch, Minda R.: Schizophrenia and the Dl receptor: Focus on negative symptoms. Prog. Meuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 797–832.

1. 1. Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate.

2. 2. Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS.

3. 3. Lesions of ascending DA forebrain projections “uncouple” the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output.

4. 4. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC Dl receptors may induce hyperinhibition of descending corticofugal efferents to the NAS.

5. 5. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC Dl stimulation.

6. 6. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC Dl receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.

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.

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.

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.

Effects of repeated trazodone administrations on serotonergic neurotransmission: Biochemical studies

1. 1. Repeated administrations of trazodone as well as imipramine or mianserin(10 mg/kg i.p. twice daily for 3 weeks) attenuated the norepinephrine (NE) stimulation of adenylate cyclase studied in brain minces. Therefore trazodone shares with “tricyclic” (imipramine) and “atypic” (mianserin) antidepressants the capability to modulate the beta-adrenergic function.

2. 2. Daily treatments with imipramine or trazodone enhanced the Vmax of neural uptake of serotonin (5HT) in minces prepared from rat frontal cortex; in contrast mianserin failed to modify the [³H]-5HT uptake.

3. 3. Repeated administrations of imipramine but not of trazodone or mianserin reduced the maximum number of [³H]-imipramine recognition sites which are located on serotonergic axon terminals.

4. 4. Differently, only repeated administration of trazodone decreased Bmax values of [³H]-mianserin binding sites which are located on membranes innervated by serotonergic neurons. Moreover trazodone did not change the number or affinity of 5HT₂ receptors either after single or repeated administrations; in contrast even a single administration with mianserin or repeated administrations with imipramine down-regulated [³H]-ketanserin specific binding in membranes prepared from the frontal cortex.

5. 5. Our observations therefore suggest that trazodone, imipramine or mianserin exerts similar effects on the adenylate cyclase system, by acting on a interneuronal loop which links serotonergic and noradrenergic transmission function. However, its exact mechanism of action, in part resembling both tricyclic and atypic antidepressants, requires further exhamination.

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.