Electrophysiological and behavioral correlates of psychomotor responsivity in depression.

Psychomotor retardation is a frequently observed clinical feature of depressive states. This study attempted to assess the relationship between response slowness and central nervous system (CNS) activity by examining cortical evoked potentials (EPs) during psychomotor task performance. Patients consisted of 21 women who met Research Diagnostic Criteria (RDC) and exhibited a minimum Hamilton Rating Scale for Depression score of 18 at the end of a drug washout period, the scheduled time of testing. The same number of normal women with no history of psychiatric illness were employed as controls. Cortical EPs from Cz and integrated electromyogram (EMG) from the dominant forearm extensor were recorded and time-locked to warning and imperative stimuli of a standard, two-choice, fixed foreperiod reaction time (RT) task, which yielded behavioral measures of decision time (DT) and movement time (MT). Analysis focused on behavioral RTs, latency and amplitudes of EMG, sensory and slow cortical (CNV) EPs, and measures of input time (IPT), central processing time (CPT), and motor execution time (MET), derived from combinations of EP and EMG peak latencies. Patients exhibited slower DT and MT response times, delayed EMG latencies, and attenuated EP amplitudes. The derived CPT measure was also significantly longer in patients. These findings support the view that a central dysfunction is implicated in psychomotor retardation, and the results are discussed in relation to information processing theory.

Erythrocyte membrane sodium-potassium and magnesium ATPase in primary affective disorder.

Erythrocyte membrane Mg2+ ATPase and Na+-K+ ATPase were measured in patients with affective disorder, their well relatives, and normal controls during euthymic moods. On the average, the Mg2+ ATPase activity was high in subjects belonging to affective disorder families. However, the difference between normal and affective disordered individuals was not statistically significant. Only the well individuals from affective disorder pedigrees as a group had significantly higher than normal Mg2+ ATPase activity (p less than 0.05). The Na+-K+ ATPase activity was similar for all the groups, including normal, bipolar manic-depressive (with or without lithium), unipolar depressive, and well individuals. Lithium treatment did not seem to have any effect on Mg2+ ATPase. Even though the values of Na+-K+ ATPase in the lithium-treated group were high, it is not certain that this was due to lithium per se.

Effects of cholinergic and GABAergic drugs on apomorphine-induced gnawing behavior in rats.

The effects of cholinergic and GABAergic agonist and antagonist were studied on the apomorphine-induced gnawing behavior in rats. Physostigmine (0.5 mg/kg) decreased the biting scores, whereas atropine (5 mg/kg) had an opposite effect. Picrotoxin potentiated the physostigmine inhibitory action on gnawing responses. This inhibitory gnawing effect was antagonized by prior treatment with atropine. Pretreatment with amino-oxyacetic acid (25 mg/kg) also potentiated the inhibitory effect of physostigmine on gnawing behavior in animals. Such an additive inhibitory response could be antagonized by simultaneous pretreatment with cholinergic and GABAergic blockers such as atropine and picrotoxin, respectively. These findings indicate that the modulatory action of cholinergic neurons on DA system is probably influenced by changes in the GABAergic system.

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.

Mianserin kinetics in depressed patients.

We studied mianserin kinetics after a single (60 mg) dose in eight inpatients suffering from depression. There was a considerable interpatient variability in plasma levels. Mean peak plasma levels (+/- SEM) were 114 +/- 26 ng/ml and were reached between 1 and 3 hr. The decline of mianserin levels in plasma was biphasic. The mean elimination t 1/2 was 21.6 +/- 3.1 hr and ranged from 10.7 to 40.8 hr. The estimated first-pass loss ranged from 26% to 48% (mean, 37%) and was lower than that reported for tertiary amine tricyclic antidepressants. The mean apparent volume of distribution (15.7 +/- 2.2 l/kg; 9.7 to 28.8 l/kg) was in the range of that for imipramine but somewhat lower than for maprotiline. Apparent total body clearance ranged from 0.33 to 0.81 l/hr/kg (mean +/- SEM, 0.52 +/- 0.05 l/hr/kg) and was of the order of that after maprotiline. Our results indicate that mianserin kinetics are in most respects similar to those of tertiary amine tricyclic antidepressants (e.g., imipramine) and the tetracyclic maprotiline.

A controlled study of penfluridol in the treatment of chronic schizophrenia.

Twenty patients were treated with penfluridol and 21 with fluphenazine for a period of up to 1 year. Penfluridol, an oral neuroleptic administered weekly was as efficacious as fluphenazine administered twice daily and appeared to be superior to fluphenazine in improving emotional withdrawal and anergia. The low incidence of side effects and other signs of toxicity, coupled with an effective prophylactic activity, suggests that penfluridol is an important addition to our therapeutic armamentarium for the treatment of chronic schizophrenia.

Platelet serotonin measures in primary dysthymia.

Serotonergic function in 22 patients with primary dysthymia and 22 normal volunteers was evaluated by measuring [3H]serotonin uptake and [3H]paroxetine binding in platelets. A significantly lower maximum rate of serotonin uptake was noted in the dysthymic patients than in the normal subjects, indicating a possible serotonergic dysfunction in dysthymia. However, the values for parameters of paroxetine binding were similar in the two groups.

Alterations in brain 5-hydroxytryptamine metabolism during the 'withdrawal' phase after chronic treatment with diazepam and bromazepam.

1 Daily administration of diazepam or bromazepam (10 mg/kg) for 22 days significantly increased the activity of mid-brain tryptophan hydroxylase by 36% and 39%, respectively. The concentration of tryptophan was also enhanced in the mid-brain region of rats subjected to benzodiazepine treatment.2 Chronic therapy with either of the two anti-anxiety agents enhanced the endogenous levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in cerebral cortex, hypothalamus, pons-medulla, mid-brain and striatum.3 Whereas diazepam treatment decreased (13%) the activity of monoamine oxidase in mid-brain, bromazepam failed to exert any effect, suggesting that the observed elevation in 5-hydroxy-indoleacetic acid levels is not associated with enhanced deamination of 5-hydroxytryptamine.4 Discontinuation of treatment for 48 h significantly decreased the activity of mid-brain tryptophan hydroxylase to levels that were significantly lower than those seen for benzodiazepine-treated and normal rats. The concentrations of mid-brain tryptophan and 5-hydroxytryptamine were also reduced in various brain regions examined.5 Withdrawal from diazepam or bromazepam therapy further augmented the levels of brain 5-hydroxyindoleacetic acid.6 The results demonstrate that the depressant effects on behaviour of these agents are accompanied by increased metabolism of 5-hydroxytryptamine in the brain. Withdrawal from these minor tranquillizers, on the other hand, reduces the synthesis of this indoleamine.

A review of trimipramine. 30 years of clinical use.

The hybrid chemical structure of trimipramine incorporates an imipramine nucleus and levomepromazine side chain. This structure predicts much of the clinical profile of trimipramine. The initial studies on trimipramine date back nearly 30 years. It now has a well-recognised clinical profile with some characteristics akin to other tricyclic antidepressants (TCA) and others which are quite distinct. It is well established as a highly effective antidepressant with an efficacy profile similar to the other TCAs. Clinically, its anxiolytic and sedative properties distinguish it from most other TCAs. Its effects on sleep architecture are unique and explain some of its unique properties. The side effect profile of trimipramine is in some ways similar to those of the tertiary amine TCAs with a preponderance of anticholinergic and sedative effects. Its cardiotoxic properties are minimal, with some findings suggesting a very favourable profile. Interactions with other drugs, psychotropic or non-psychotropic, are compatible with its pharmacological profile. These are reviewed with its clinical applications in mind. The pharmacokinetic characteristics of trimipramine differ from those of many of the other TCAs. The application of this to clinical situations is addressed. Based on experience using trimipramine, a profile of 'ideal' patient characteristics has been built up. Finally, the use of trimipramine in selected patient populations is reviewed.

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

New antidepressant drugs.

Antidepressants recently marketed, under development, or in clinical trials are reviewed in terms of the neurotransmitter systems they preferentially affect, dosage ranges, side effect profiles, and comparative efficacy. The development of these agents contributes not only to treatment efforts but to our understanding of the mechanisms underlying depression.

A therapeutic and discontinuation study of clobazam and diazepam in anxiety neurosis.

The efficacy and safety of clobazam and diazepam were compared in 40 patients with generalized anxiety disorder in a 28 day non-placebo-controlled trial followed by a 3-day single-blind placebo washout. The two drugs were equally anxiolytic, and the anxiety symptoms of most patients were brought under control within 1 week. Both drugs were found to be nontoxic. Diazepam had slightly greater sedative properties than clobazam, which was the patients' preferred drug after 28 days of treatment. During placebo washout, anxiety returned to pretreatment levels. Abrupt withdrawal did not result in rebound phenomena.

Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression.

A double-blind, placebo- and amitriptyline-controlled comparison study was performed to evaluate the antidepressant efficacy of sertraline, a specific serotonin uptake inhibitor. Patients with DSM-III-defined major depression randomly received either sertraline (N = 149), amitriptyline (N = 149), or placebo (N = 150) once daily for the 8-week study period. The mean final daily medication dose for the all-patients group was 145 mg and 104 mg for the sertraline- and amitriptyline-treatment groups, respectively. As measured by the Hamilton Rating Scale for Depression and the Clinical Global Impressions Scale, both the sertraline and amitriptyline treatment groups showed a significantly greater improvement from baseline (p less than or equal to .001) than the placebo group. The sertraline group had a higher proportion of gastrointestinal complaints and male sexual dysfunction than either the amitriptyline or the placebo group. The amitriptyline group showed a higher proportion of anticholinergic and sedative side effects and dizziness compared with patients who received either sertraline or placebo.

Treatment of major affective disorder with fluvoxamine.

A placebo-controlled, double-blind study of 63 inpatients with major affective disorder was performed to compare the safety and efficacy of fluvoxamine and imipramine. Results indicate that fluvoxamine and imipramine are superior to placebo and demonstrate a trend toward superiority of fluvoxamine over imipramine. Fluvoxamine was generally well tolerated in most patients.

Cholinesterases in primary affective disorders.

Cholinesterase activities were measured in plasma (ChE) and in intact erythrocytes (AChE) in patients suffering from manic-depressive illness, their first degree relatives who were well, and unrelated normal volunteers. All the subjects were in a normal mood state at the time of testing. Plasma cholinesterase activity was found to be significantly lower than normal in bipolar (BP), unipolar (UP), other affective disorder (OA) and well subjects belonging to manic-depressive families. Intact erythrocyte cholinesterase (true cholinesterase) activity was also found to be significantly lower than normal in all the above mentioned patients and their relatives. Half of the BP subjects were on lithium treatment and their cholinesterase activities were similar to those patients not on lithium treatment. The data suggest a significant role of cholinergic mechanisms in the etiology of manic-depressive illness.

Course of clinical response to antidepressants.

The postulated pharmacological mechanisms of antidepressant effect are reviewed. The clinical profile of response to antidepressants are linked to the pharmacological mechanisms. The limitations of presently available instruments for diagnosis and measurement of change in depression are discussed.

Neurotransmitter functions in depression.

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.

Are all benzodiazepines clinically equivalent?

Clinical observations are not always consistent with laboratory findings where half-life or pharmacokinetics do not always correlate with pharmacodynamics, ie. clinically effective duration of action. The parent compound, chlordiazepoxide, was observed to have anticonvulsant, anxiolytic, muscle relaxant properties to varying degrees. Subsequently, diazepam seemed to exert a greater potency in these three areas. The final metabolite, oxazepam, has been observed to have a different therapeutic profile. The advent of the triazolo compounds brought a new dimension to benzodiazepine treatment both in primary and side effects. The relationship between blood levels and clinical efficacy is considered in the light of clinical observations as well as in the perspective of clinical management. Problems of tolerance and escalation of dosage must be addressed in the administration of these drugs where the confluence of pharmacokinetic and pharmacodynamic findings may serve as a guide in the management of anxious patients.

Clinical and biological correlates of panic states.

Panic states may be a presenting symptom in medical or psychiatric conditions. It is also a discrete diagnostic entity with distinct genetic, clinical and biological profiles. This paper reviews the salient features of the condition and its clinical presentation including its biological characteristics.

Neuropsychophysiological correlates of lactate-induced panic.

1. One of the simplest and most direct applications of neuropsychophysiological techniques is to anxiety disorders. 2. The physiological changes accompanying the lactate induction of panic appear, for most response systems, to be similar to those found spontaneously in anxious patients and are characteristic of a state of hyperarousal. 3. Patients vulnerable to lactate-induced panic exhibit higher than normal pre-panic autonomic activity, elevated autonomic-somatic activity during lactate-induced panic and an EEG response to provoked panic which appears to be comprised of a "paradoxical" shift towards slow wave delta activity and an altered brainstem evoked response. 4. Additional studies are warranted to determine the relationship of these physiological changes to the triggering of panic and preliminary attempts in this direction are discussed.