Differential diagnosis of anxiety disorders

1. 1. The literature comparing panic disorder with natural fear, hypoglycemia, hyperthyroidism, pheochromocytoma, the hyperventilation syndrome, the mitral valve prolapse syndrome and partial complex seizures is briefly reviewed.

2. 2. Some features of each of these syndromes may clinically resemble panic disorder.

3. 3. It is concluded that: a) patients with panic disorder should be medically evaluated. b) the diagnosis of panic disorder should be based on a broad system, rather than on symptoms alone, c) diagnostic systems should include a category for “organic anxiety syndromes”.

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.

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.

Are the pharmacological effects of L-prolyl-L-leucylglycinamide (PLG) mediated through specific receptor mechanisms?

1. 1. In an attempt to delineate the mechanism subserving the demonstrated central effects of the tripeptide, L-prolyl-L-leucyl-glycinamide (PLG) in mammals including humans, we developed a radioligand binding assay to characterize the binding of ³H-PLG to rat brain membranes.

2. 2. Equilibrium binding studies indicated that PLG binds to rat striatum with high affinity (K_D = 4.69 ± 0.50 nM), saturability (B_max = 9.20 ± 0.30 fmoles mg⁻¹protein) and reversibility. Kinetic data yielded a K_D = 1.42 ± 0.21 nM for rat striatum.

3. 3. Regional distribution profile of specific H-PLG binding revealed that the striatum has the highest density of PLG binding sites, followed by the hypothalamus and the cerebral cortex.

4. 4. Analogues of PLG compete for specific PLG binding in rat striatum with potencies parallelling their activities in behavioural systems.

5. 5. Our results support the existence of a unique class of putative peptide receptor sites specific for PLG mediating a spectrum of pharmacological effects.

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.

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.

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.

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).

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.

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.

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.

Activation of brain function by S-135, a benzodiazepine receptor inverse agonist

1. 1. S-135, 2-(5-methylthien-3-y1)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one, binds to benzodiazepine receptors with a high affinity and shows pharmacological actions opposite to those of conventional benzodiazepine drugs.

2. 2. S-135 induced no convulsion in mice by itself, but selectively potentiated the effect of subconvulsive dose of pentylenetetrazole.

3. 3. S-135 potentiated rat crossed extensor reflex and Ro 15-1788 completely antagonized this potentiation.

4. 4. S-135 antagonized pentobarbital-induced anesthesia, tetrabenazine-induced ptosis and reserpine-induced hypoactivity and shortened immobilization time in the despair test in mice, indicating that this compound possesses antidepressive properties.

5. 5. S-135 antagonized amnesia in mice and rats in passive avoidance tasks.

6. 6. Glucose utilization in brain areas relating to memory and arousal functions was enhanced following S-135 treatment.

7. 7. These results indicate that S-135 can be a useful drug for activating depressed brain function.

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.

Strategies for studying the neurochemical substrates of drug reinforcement in rodents

1. 1. Results from three different experimental paradigms for studying drug reinforcement are reviewed.

2. 2. Rate-increasing effects of amphetamine on intracranial self-stimulation are abolished by lesions to ascending dopamine neurons.

3. 3. Rate-increasing effects of intracranial microinjection of opioids on self-stimulation are localized to the vicinity of dopamine cell bodies in the ventral tegmentum.

4. 4. Conditioned reinforcement produced with intracranial microinjection of opioids into the ventral tegmental area is blocked by the dopamine antagonist haloperidol and lesions to ascending dopamine pathways.

5. 5. Intravenous self-administration of cocaine is blocked by intracerebral microinjection of spiroperidol into the nucleus accumbens but not into the caudate nucleus.

6. 6. Ascending dopamine neurons appear to mediate some of the reinforcing properties of both psychomotor stimulants and opioids.

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.

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.

Time course of physostigmine effects on neuroendocrine responding at varying environmental temperatures

1. 1. Hypothermia was found to be related to both the dose of physostigmine and the environmental temperature.

2. 2. Plasma corticosterone levels were elevated above controls regardless of dose of physostigmine or environmental temperature.

3. 3. Plasma free fatty acid levels appeared to be inversely related to physostigmine-induced hypothermia.

4. 4. A hyperglycemic response was observed under all experimental conditions at 0.5 hours and 1.0 hour post injection.

5. 5. Significant inhibition of brain acetylcholinesterase was observed, whereas, plasma and erythrocyte acetylcholinesterase activity was inconsistent.

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.

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.