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The effects of chronic administration (28 days s.c. via osmotic minipumps) of the antidepressants phenelzine sulphate, desipramine hydrochloride and clomipramine hydrochloride (each at 10 mg/kg per day) on dopamine function have been measured in rats. Both phenelzine and desipramine attenuated the suppression of locomotor activity induced by apomorphine hydrochloride (0.05 mg/kg s.c. 15 min). Clomipramine did not affect the behavioural response to apomorphine. Analyses of brain tissue from these animals using the radioligand [3H]GBR 12935 revealed that there were no changes in dopamine uptake site density or affinity following the administration of phenelzine, desipramine or clomipramine. Analyses of brain monoamine oxidase activity and tricyclic levels were used to confirm the efficacy of the drug administration protocol. These data indicate that changes in dopamine uptake site density do not mediate antidepressant-induced changes in behavioural responses to apomorphine.
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We report the clinical and therapeutic features of three patients with an obsessive-compulsive syndrome that emerged during the course of panic disorder. The DSM-IV criteria for panic disorder places central attention on the patient's phobic responses to the panic attacks and their perceived consequences. These phobic responses may develop into a syndrome that closely resembles obsessive-compulsive disorder (OCD) but typically responds to conventional anti-panic approaches. Our cases suggest that patients with OCD should be probed for an underlying panic disorder. This 'panic disorder-related subtype of OCD' may be associated with an excellent treatment response and increased rates of remission.
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Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.
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We found no strong evidence that fluvoxamine was either superior or inferior to any other antidepressants in terms of efficacy and tolerability in the acute phase treatment of depression. However, differing side effect profiles were evident. Based on these findings, we conclude that clinicians should focus on practical or clinically relevant considerations, including these differences in side effect profiles.
The serotonin syndrome is frequently characterized by minor neurologic manifestations that regress rapidly (such as confusion, tremor, ...). Many medications including tricyclic antidepressants, serotonin reuptake inhibitors, tryptophan and the association of monoamine oxidase inhibitors together with a serotoninergic agent have been implicated in this syndrome. In certain cases, and for poorly understood reasons, clinical manifestations can include circulatory collapse, malignant hyperthermia, convulsions and rhabdomyolysis. These forms are often fatal. Treatment, other than the withdrawal of the offending drug, is symptomatic. Dialysis may be of value in withdrawing the drug from the circulatory system. We report a patient with the serotonin syndrome of favorable outcome due to an overdose of moclobemide and clomipramine.
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In platelets of normal volunteers taking chlorimipramine (50 mg/day) for one week, the saturable uptake of [3H]5HT was fully inhibited at day 8, but returned to control values at day 15. The Bmax of [3H]imipramine binding was decreased by 65% at day 8 and remained significantly below control values at day 15. If the present findings can be extrapolated to other antidepressants, the reported decreases in [3H]imipramine binding in depression may partly reflect residual treatment effects. It cannot be excluded that, in depression, the platelet [3H]imipramine receptor already is down-regulated maximally which would preclude a further down-regulation due to antidepressant drug therapy.
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In recent years, there has been rapid progress in the pathophysiology, diagnostic methods and therapeutics of sleep apnea syndrome (SAS). In this article, we present our findings in these fields for the past several years. Recently, we have been able to use ultralow-field magnetic resonance (MR) fluoroscopy to visualize the upper airway for extended periods of time. The severity of SAS should be evaluated by precise history taking, physical and laboratory examination and polysomnography together with SpO2 and esophageal pressure monitoring. Treatment strategy includes multidisciplinary approaches, life style modification and suitable treatment choice, such as CPAP, dental appliance, upper airway surgery, pharmacological agents.
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To compare the efficacy of clomipramine hydrochloride (CMI), a serotonin reuptake inhibitor with the noradrenergic tricyclic antidepressant agent, and desipramine hydrochloride (DMI) for patients with panic disorder (PD).
The tricyclic antidepressants have previously been shown to exert activity against glioma cells in vitro. Initial studies in cell lines suggested that this might extend to melanoma cells. We have therefore conducted a study in primary cell cultures from metastatic cutaneous melanoma deposits using a well established ATP-based tumour chemosensitivity assay to confirm and extend these findings. Two cell lines and eight primary cell cultures from metastatic melanoma deposits were exposed to three tricyclic drugs, amitriptyline, nortriptyline and clomipramine, at concentrations ranging from 200 to 6.25 µmol/l in the ATP-based tumour chemosensitivity assay. All three drugs showed activity, although nortriptyline was more active than clomipramine or amitriptyline in both cell lines and primary cell cultures, with an IC50 of 9, 27 and 33 µmol/l, respectively. Tricyclic agents show activity against melanoma in vitro. This could be related to the lysosomal effects based on their cationic amphiphilic properties, or effects at the mitochondrial membrane.
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A male patient aged 43 years, suffering from symptoms of obsessive-compulsive disorder (OCD), such as washing hands and feet frequently and checking documents compulsively, had received intensive pharmacotherapeutic and behavior therapy. Although the administration of anxiolytic drugs and/or clomipramine did not show curative effects, a combination of clomipramine and risperidone showed much greater effect in improving these symptoms.
Obsessional states show an average point prevalence of 1%-3% and a lifetime prevalence of 2%-2.5%. Most treatment-seeking patients with obsessions continue to experience significant symptoms after 2 years of prospective follow-up. A significant burden of impairment, distress, and comorbidity characterize the course of the illness, leading to an increased need for a better understanding of the nature and management of this condition. This review aims to give a representation of the current pharmacological and psychotherapeutic strategies used in the treatment of obsessive-compulsive disorder. Antidepressants (clomipramine and selective serotonin reuptake inhibitors) are generally the first-line choice used to handle obsessional states, showing good response rates and long-term positive outcomes. About 40% of patients fail to respond to selective serotonin reuptake inhibitors. So far, additional pharmacological treatment strategies have been shown to be effective, ie, administration of high doses of selective serotonin reuptake inhibitors, as well as combinations of different drugs, such as dopamine antagonists, are considered efficacious and well tolerated strategies in terms of symptom remission and side effects. Psychotherapy also plays an important role in the management of obsessive-compulsive disorder, being effective for a wide range of symptoms, and many studies have assessed its long-term efficacy, especially when added to appropriate pharmacotherapy. In this paper, we also give a description of the clinical and psychological features likely to characterize patients refractory to treatment for this illness, with the aim of highlighting the need for greater attention to more patient-oriented management of the disease.
Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.
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Notwithstanding the emerging literature on comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorder, relatively few systematic data exist on the clinical characteristics of this interface and its treatment. The aim of the present study is to address this challenge as it appears in a setting of routine clinical practice.
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Tricyclic antidepressants (TCA) are well-known xerogenic drugs, while antidepressants such as selective serotonin reuptake inhibitors (SSRI) are considered less xerogenic. The antimuscarinic effect of the TCAs has been considered to be the principal mechanism causing a dry mouth. Although the muscarinic receptor is commonly targeted by xerogenic pharmaceuticals, the salivation reflex arc may be affected at other levels as well. We currently wondered whether or not antidepressants exert an inhibition of the salivary reflex not only at the glandular level but at a central level as well. In this study, the effects of a TCA (clomipramine), a SSRI (citalopram) and a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine) were examined on reflex- (0.5M citric acid applied on the tongue) and methacholine-evoked salivary secretion. While all three compounds inhibited citric acid-evoked secretion (-40 to -60% at 5mg/kg i.v. of the antidepressants), only clomipramine inhibited methacholine-evoked secretion (-30% at 5mg/kg i.v.). On the contrary, both citalopram and venlafaxine increased the methacholine-evoked secretion (+44 to 49%). This was particularly obvious for the salivary protein output (>200%). In the presence of α- and β-adrenoceptor antagonists, the citalopram- and venlafaxine-induced increases were reduced. Thus, antidepressants irrespective of type may exert xerogenic effects by inhibiting the salivary reflex in the central nervous system. However, while TCAs may also hamper the secretory response by antimuscarinic effects, the SSRI and the SNRI groups of pharmaceuticals seem to lack this additional xerogenic mechanism indicating a better therapeutic profile and better opportunities for pharmacological treatment of drug-induced xerostomia.
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Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day.
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We investigated the role of neuronal and mast cell histamine in the analgesic effect of clomipramine.
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To assess the efficacy of clomipramine for treatment of canine compulsive disorder (CCD).
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The purpose of this study was to assess the sexual and psychosocial efficacy of clomipramine for rapid ejaculation.
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The proposition is an important one as a diagnosis of morbid jealousy often invites therapeutic pessimism, and as managements effective for OCD (both drug and behavioural) may well be helpful.
Outpatients (n = 150) with MDD were randomized to receive clomipramine or a control treatment. Patients completed the Hamilton Rating Scale for Depression (Ham-D) and the Tridimensional Personality Questionnaire (TPQ) prior to treatment initiation, and then again after at least 8 weeks of treatment. Using structural equation modeling, we evaluated a 'mediation model' in which change in HA is a mechanism of depression change in response to clomipramine, and a 'complication model' in which reduction in HA is a by-product of depression change.
Moclobemide, a novel benzamide, is a reversible inhibitor of monoamine oxidase-A (RIMA). It has been extensively evaluated in the treatment of a wide spectrum of depressive disorders. Comparative studies have shown that the drug is more effective than placebo and as effective as other antidepressants. In terms of efficacy, moclobemide offers no more benefits than do existing agents. On the other hand, moclobemide is better tolerated than tricyclic antidepressants and, unlike irreversible monoamine oxidase inhibitors, has a much lower propensity to cause a 'cheese reaction' (a potentially fatal syndrome caused by an interaction with tyramine-rich foods). These are significant clinical benefits, particularly in elderly patients. Furthermore, moclobemide lacks significant effects on psychomotor performance and cognitive function, has few clinically important drug interactions and is safe on overdose. The drug has a relatively short plasma elimination half-life, a property that allows a change to an alternative agent within 24 hours in cases of nonresponse. Since it is well tolerated, therapeutic dosages can often be achieved from the onset of treatment. These benefits need to be considered against the potential risks of moclobemide therapy. To date, the most significant hazards of therapy appear to arise from drug interactions with clomipramine or selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors, where the occurrence of the serotonin syndrome is potentially fatal. Similarly, in preclinical tests moclobemide has been shown to potentiate the effects of pethidine (meperidine) and dextropropoxyphene, so that combined use of moclobemide is a useful addition to the therapeutic agents used for depressive disorders.(ABSTRACT TRUNCATED AT 250 WORDS)
The principal components analysis identified five factors that explained 65.5% of variance in outcome: symmetry/ordering, hoarding, contamination/cleaning, aggressive/checking, and sexual/religious obsessions. Serotonin reuptake inhibitors were significantly superior to placebo on all outcome measures. Initial severity of OCD was related to greater posttreatment severity of OCD. Higher scores on the hoarding dimension predicted poorer outcome following treatment with serotonin reuptake inhibitors, after control for baseline severity. No predictors of placebo response were identified. Exclusion of clomipramine did not modify the overall results, suggesting a cross-serotonin reuptake inhibitor effect.
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Selective literature review.
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A 27-y-old male was admitted deeply comatosed 5-6 h after taking approximately 15 g clomipramine. The prominent feature of the case was a biphasic course of clomipramine and desmethylclomipramine serum concentrations, possibly caused by delayed drug absorption. Clinically, 2 serious episodes requiring mechanical ventilation and aggressive pressor agent infusions occurred as the serum concentrations declined. However, the severe adult respiratory distress syndrome--related inflammatory process that required 4 w of intensive care may also be an explanation, although blood cultures were negative and neither liver nor renal functions were severely compromised.
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Of 842 patients 89.9% received at least one psychotropic drug and 67.6% a combination of at least two psychotropic drugs. The drug groups prescribed most often were antidepressants (78.0%), antipsychotics (46.7%), and tranquilizers (19.7%). In 58.0% of all cases selective serotonin reuptake inhibitors (SSRIs) were used as antidepressants, followed by tricyclic antidepressants (TCAs, 17.8%), mainly clomipramine (10.9%). Second-generation antipsychotics (SGAs) were administered in 37.8% of all cases, first-generation antipsychotics (FGAs) in 13.7%. While the use over time significantly increased for psychotropic drugs, antidepressants, antipsychotics, tranquilizers, SSRIs and SGAs, it remained stable for FGAs and decreased for TCAs.