Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder: randomised, placebo-controlled trial.

BACKGROUND: Although serotonin reuptake inhibitors are effective in panic disorder, questions concerning whether doses associated with antidepressant efficacy are also effective for panic disorder remain. AIMS: To assess the efficacy of the usual antidepressant dose of fluoxetine in treating full panic attacks. METHOD: Patients with panic disorder were randomised to placebo or to fluoxetine initiated at 10 mg daily for 1 week and then increased to 20 mg daily. The trial lasted 12 weeks, but after 6 weeks patients who had failed to achieve a satisfactory response were eligible for dose escalation to a maximum of 60 mg of fluoxetine daily. RESULTS: Fluoxetine was associated with a statistically significantly greater proportion of panic-free patients compared with placebo after 6 weeks and at end-point. CONCLUSIONS: Fluoxetine at a dose of 20 mg daily is safe and efficacious in reducing symptoms of panic disorder. Patients who fail to obtain a satisfactory response at 20 mg daily may benefit from further dose increases.

Comparison of two approaches to amitriptyline dose individualisation.

Individualisation of an amitriptyline dose regimen offers substantial advantages over non-individualised treatment. In our study, we have compared both clinical effects, adverse effects and plasma steady-state concentrations of amitriptyline in 15 patients with major depressive disorder divided in three groups; (i) patients in group A were taking non-individualised doses of amitriptyline; (ii) patients in group B were taking doses of amitriptyline individualised by modified Bayesian method; and (3) patients in group C were taking doses of amitriptyline individualised by the multiple point method. The treatment course was 8 weeks long, in the setting of a psychiatric clinic. The patients in group A were taking significantly higher doses throughout the treatment course; the initial doses for the patients in group B were higher than doses for the patients in group C, but after corrections based on measured steady-state plasma concentrations they became similar. While Hamilton score descended uniformly in all three groups, both adverse effects and steady-state plasma concentrations of amitriptyline were higher in non-individualised group during the whole treatment course. The results of our study suggest that the multiple points method is the most precise, but tedious and not practical. The modified Bayesian method with correction based on first measured plasma steady-state concentration of amitriptyline offers similar therapeutic outcome and adverse effects score combined with low cost and being easy-to-use.

The influence of lithium on fluvoxamine therapeutic efficacy and pharmacokinetics in depressed patients on combined fluvoxamine-lithium therapy.

The influence of lithium on fluvoxamine therapeutic efficacy, plasma concentrations and pharmacokinetics was studied in 12 depressed inpatients. Six patients were on fluvoxamine monotherapy and six were on combined fluvoxamine-lithium therapy. The treatment response was determined using 17-item Hamilton Rating Scale for Depression. Blood samples were collected during 48 h after a single dose administration of 100 mg fluvoxamine, and five times at steady state after repeated doses of 100 mg fluvoxamine per day. The evaluation of 17-item Hamilton Rating Scale for Depression Scores showed a significant clinical improvement 2 and 4 weeks after the beginning of the therapy in both groups (p < 0.01). However, 2 weeks after the administration of the drug(s) had started, significant differences (p < 0.05) in efficacy between the two treatments in favour of the fluvoxamine-lithium combination were found. Plasma concentrations of fluvoxamine were measured by high-performance liquid chromatography. The comparison of the measured concentrations of fluvoxamine showed a similar course of the plasma concentration-time curves in both groups of patients. Pharmacokinetic parameters of fluvoxamine did not show any significant difference on the comparison between the groups. According to the results from this study, it is evident that lithium does not affect plasma concentrations and pharmacokinetics of fluvoxamine in depressed patients on concomitant treatment with these two drugs. However, the effect achieved with the combination was better.

Clinical response and plasma concentrations of amitriptyline and its metabolite-nortriptyline in depressive patients.

Although many attempts have been made, to date no convincing evidence exists of a relationship between plasma concentrations of amitriptyline (AT), its active metabolite nortriptyline (NT) and clinical response. Fifteen patients with primary depression (according to DSM-IV) were divided in two groups according to given doses: (I) 6 patients received 3 x 50 mg of AT daily; and (II) 9 patients received 3 x 25 mg of AT daily, for 6 weeks. The clinical status was determined with Hamilton Depression Rating Scale. Both investigated doses were therapeutically effective. AT and NT plasma concentrations were assayed by high performance liquid chromatography. Following administration of 3 x 50 mg of AT daily, the correlation of concentrations of AT, NT, total AT + NT and clinical response were rAT = -0.702 (P < 0.1), rNT = -0.761 (P < 0.1), rAT + NT = -0.741 (P < 0.1). The linear and very high correlation were also present with concentrations of AT, NT, total AT + NT and clinical response in depressive patients on 3 x 25 mg AT daily: rAT = -0.785 (P < 0.02), rNT = -0.811 (P < 0.01), rAT + NT = -0.848 (P < 0.01). Our results support a high correlation between AT/NT plasma concentrations and clinical response indicating that therapeutic monitoring of AT and its metabolite, NT, can provide eventual clinical response.

The side-effects of clozapine: a four year follow-up study.

Clozapine, as the model agent for the atypical antipsychotic drugs, is currently recommended as effective regarding negative symptoms of schizophrenia and treatment-resistant schizophrenic patients. This study focuses on the clozapine-induced side-effects in 100 hospitalized schizophrenic patients (negative and therapy-resistant forms), followed-up for a four year period. Clinically relevant side-effects occurred in 73% of all patients. Tachycardia (67%), the increase of liver enzymes (36%), hypotension (29%) and sedation (27%) were most frequent. Tachycardia, hypotension and sedation disappeared during the initial phase of treatment (i.e. 4-6 weeks), as tolerance developed with continuation of therapy. The increase of liver enzymes appeared to be dose related, since the reduction of daily clozapine dose led to the normalization of transaminases values. The other side-effects (constipation, nausea and vertigo) were rare and transient. Leucopenia was not registered in any patient during the follow-up period. Therefore, clozapine is efficient and, with some precautions concerning hepatotoxicity, is safe for in- and outpatient long-term treatment in appropriately selected patients.

Correlation of mono and combined amitriptyline/lithium therapy with therapeutic and side effects.

The role of lithium in combination with tricyclic antidepressants (TCA) used in the treatment of unipolar depression has been much less studied than in the case of bipolar disorders. The aim of this study was to compare the therapeutic and side effects with doses and plasma concentrations in the patients with major (unipolar) depression (DSM-III-R criteria) treated by amitriptyline combine (At+Li) and mono-therapy. All three, of these regimens, were therapeutically effective, but after 6 weeks combined (At+Li) therapy showed the absence of the increased number of side effects.

Lithium ion influence on N-acetyl-beta-glucosaminidase isoenzymes serum level.

N-acetyl-beta-glucosaminidase (NAG) is a lysosomal enzyme found in most human cells, including those from the nervous system and kidneys. There are several different NAG forms in human tissues and fluids, but isoenzymes A and B are the most abundant, presenting about 98% of the whole NAG activity in normal serum. The paper is dealing with the total NAG serum level, main isoenzymes (A and B) activity, their ratio and possible lithium ion influence in affectively disordered patients. The sample consisted of thirteen bipolar-euthymic patients who had been receiving lithium for more than two years. The results pointed out reduction in total serum NAG activity, the lithium ion influence absence on total serum NAG activity, but at the same time the important modifying effects on isoenzyme NAG activities.

Neuroleptic actions on the thyroid axis: different effects of clozapine and haloperidol.

Twenty-six in-patients treated for schizophrenia, were divided in two groups. The first group received haloperidol, 20-40 mg p.d., and the second, clozapine, 150-250 mg p.d. TRH-TSH test was performed by injecting 0.2 mg TRH. Four drug-free schizophrenic patients gave normal TSH response to TRH, as well as the group of patients treated with haloperidol. Contrary to that, the clozapine-treated group showed a blunted TSH response. The results obtained are discussed in terms of the different pharmacological profiles of haloperidol and clozapine, especially regarding their dopaminergic actions, alpha-adrenergic and serotonergic control upon thyroid axis.

[Life events in correlation with the intensity and entity of depressive disorder]. / Zivotni dogadjaji u korelaciji sa intenzitetom i entitetom depresivnog poremcaja.

The article deals with types of life events preceding the onset or repeated episodes of endogenous (major) depression, as well as their influence on the intensity of depressive symptoms in hospitalized patients. It was found that events with intensive long-term contextual threat more often precede the first episode than the repeated depressive episodes (4 cases), although the difference was not statistically significante (F=0.12 F>0.05). Loss (death or separation from a close person) is an event. Recent in closeds relation with the onset of depressive disorder and far more often procedes the first than the repeated (1 case) episode. The difference was statistically significant (F=0.018 P<0.05). It seems that, due to the exhaustion of defensive mechanisms, a mild stress is sufficient to provoke a repeated episode of depression. The intensity of depressive symptoms was not indicated by the stress impact of the experienced life events both in the onset (t=0.039 P>0.05) and the repeated episode of illness.