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There is currently available evidence that suggests that drugs combining 2 synergistic mechanisms of action (e.g., enhancement of both noradrenergic and serotonergic neurotransmission) may yield superior therapeutic efficacy compared with a single therapeutic mechanism of highly selective agents such as selective serotonin reuptake inhibitors (SSRIs). The differences in antidepressant efficacy favoring dual-acting drugs may exist in particular for 3 difficult-to-treat groups of patients: those with endogenous depression, those with severe depression, or hospitalized depressed patients. Mirtazapine differs from other new dual-acting antidepressants by not being a reuptake inhibitor. Its antidepressant activity may be related to a direct enhancement of noradrenergic neurotransmission by blockade of alpha2-autoreceptors. The rapid increase in serotonin (5-HT) synaptic levels by blockade of alpha2-heteroreceptors indirectly enhances 5-HT1A-mediated neurotransmission since 5-HT2 and 5-HT3 are blocked by mirtazapine. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. Currently available evidence suggests that mirtazapine is effective in all levels of severity of depressive illness, as well as is in a broad range of symptoms associated with depression.
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Glial fibrillary acidic protein (GFAP) is the major intermediate filament protein of astrocytes in the vertebrate central nervous system. Increased levels of GFAP are the hallmark feature of gliosis, a non-specific response of astrocytes to a wide variety of injuries and disorders of the CNS, and also occur in Alexander disease where the initial insult is a mutation within the coding region of GFAP itself. In both settings, excess GFAP may cause or exacerbate astrocyte dysfunction. With the goal of finding drugs that reduce the expression of GFAP, we have devised screens to detect changes in GFAP promoter activity or protein levels in primary cultures of mouse astrocytes in a 96-well format. We have applied these screens to libraries enriched in compounds that are already approved for human use by the FDA. We report that several compounds are active at micromolar levels in suppressing the expression of GFAP. Treatment of mice for 3 weeks with one of these drugs, clomipramine, causes nearly 50% reduction in the levels of GFAP protein in brain.
A clear improvement was observed in the active treatment period. No placebo or carry-over effects were observed.
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To investigate the antidepressant-like effect of an alkaloid extract from the aerial parts of Annona cherimola (TA) in mice.
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A study has been made in rodents of the interactions between a range of psychotropic drugs, narcotic agonist and partial agonist analgesics, and pain. In rodents, tricyclic antidepressants do not alone reduce pain responses but, in combination with morphine or pentazocine, clomipramine enhances analgesic activity after single doses yet increases the onset and degree of tolerance to morphine on repeated injection. The tricyclic antidepressant maprotiline, in contrast, reduced both the rate of development and extent of morphine tolerance. In morphine-dependent rats, repeated injections of clomipramine or maprotiline exerted a mixed effect upon the abstinence syndrome, some behavioural signs being potentiated whilst others were suppressed. These studies suggest that combining maprotiline with morphine will improve the control of chronic pain states.
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The excitability of hypoglossal (XII) motoneurons innervating genioglossal muscles is markedly suppressed during the rapid-eye-movement (REM) stage of sleep. This may contribute to airway obstructions in sleep apnea patients. Based on our earlier studies in decerebrate cats using injections of carbachol into the pons to induce a REM sleep-like atonia and microinjections of serotonin (5HT) into the XII motor nucleus, we hypothesized that a sleep-related withdrawal of the serotonergic excitatory input to XII motoneurons may play a major role in these processes. To test one aspect of this hypothesis, we inserted microdialysis probes into the XII nucleus region of decerebrate, paralyzed, vagotomized and artificially ventilated cats. The probes were perfused without or with the addition of a 5HT reuptake blocker, clomipramine. The levels of 5HT and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined using HPLC and electrochemical detection in dialysate samples collected over successive 20 min periods under four successive experimental conditions: control (at least 2 h after probe insertion); during the postural atonia and respiratory depression produced by pontine microinjection of carbachol; recovery from the effects of carbachol produced by pontine microinjection of atropine; and, to verify that the presence of 5HT in the dialysate was related to the activity of serotonergic cells of the brainstem, following administration of 8-OH-DPAT, a 5HT 1A receptor agonist known to suppress activity in the serotonergic cells of the raphe system. After correcting for recovery rates of individual probes, the mean control 5HT level in the extracellular space of the XII nucleus region was 7.9 +/- 4.4 nM (S.D.) in eight experiments without reuptake blockers. During the carbachol-induced depression, it was reduced to 70 +/- 20% of the pre-carbachol level. It increased to the original control level 98 +/- 27% after pontine injection of atropine. 8-OH-DPAT reduced the 5HT level to 43 +/- 14% of the post-atropine level. Changes in the 5HIAA level were not as consistent as for 5HT and did not reach statistical significance under any of the experimental conditions. Thus, a functionally significant amount of 5HT is present in the extracellular space within the XII nucleus region, and its decrement during carbachol-induced, REM sleep-like atonia is likely to reflect that occurring during natural REM sleep; this may contribute to the decreased tone of upper airway muscles and airway patency.
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Antinociceptive responses were determined before and 30, 60, 90, 120 min after drug injection by tail-flick (TFT) and hot-plate (HPT) tests. Results for each treatment group are given as mean %MPE +/- SEM (Student's t-test, ANOVA).
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The effects of intravenous 1 and 2 mg./Kg. duloxetine or clomipramine on lower urinary tract function were studied in a total of 32 male and 32 female rabbits, under nonirritative conditions (intravesical infusion of saline) and in a model of bladder irritation (i.e., transvesical infusion of 0.5% acetic acid). A transurethral double-lumen catheter in male rabbits, and a subcutaneous cystostomy in female rabbits, were used for liquid infusion and recording of intravesical pressure during a cystometrogram. Simultaneously, SAS-EMG was recorded through electromyography electrodes placed in the perianal striated muscle.
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Tricyclic antidepressive agents are widely used in suicide attempts and present a variety of deleterious effects. Rhabdomyolysis is a rare complication of such poisoning.
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The plasma protein binding of amitriptyline, imipramine, clomipramine, and their primary demethylated metabolites were studied by means of a method combining dialysis and gas chromatography. Equilibrium in dialysis of serum containing amitriptyline and its metabolite nortriptyline was attained in about 0.5 h with the drug dissolved in the serum compartment, and in about 2 h with the drug passing from the buffer to the serum compartment. The calculation of free fractions was influenced by variations with dialysis time in the volumes of serum and buffer. Increase of pH in serum increased the protein binding of the weakly basic drugs studied, and made the Donnan distribution effects more pronounced. At pH 7.4, the Donnan effect was negligible. Binding parameters for the 6 tricyclic antidepressant substances studied were estimated for the binding to alpha 1-acid glycoprotein and for total binding in serum. For alpha 1-acid glycoprotein, the k-values ranged from 1 X 10(5) to 8 X 10(5) M-1, and for pooled serum from 0.4 X 10(5) to 8 X 10(5) M-1. The determined number of binding sites on the alpha 1-acid glycoprotein was, on average 0.87 for the 6 substances. In serum, the binding capacity was 2-14 times the concentration of alpha 1-acid glycoprotein.
To measure opiate receptor sensitivity, the effects of naloxone on beta-endorphin and cortisol serum levels were determined before and after 3 weeks of clomipramine treatment (75 mg/day i.v.) in 12 patients with major depressive disorder. The opiate antagonist significantly increased both hormonal levels. The only significant endocrine differences between pre- and post-treatment were basal and maximal cortisol levels, which were elevated before antidepressant therapy. The rise in the cortisol or beta-endorphin serum level after naloxone injection was not affected by clomipramine treatment. There was no significant relationship between depression score and basal or stimulated endocrine variables. These data do not indicate a distinct effect of antidepressants on opiate receptor sensitivity.
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The relative cytotoxic effects of ten psychotropic drugs were assessed in rat hepatocyte monolayer cultures. Clear concentration-related toxicity was seen in the narrow range of 10(-5) M to 5 X 10(-5) M. The four cytotoxicity endpoints chosen were: release of the cytosolic enzyme, lactate dehydrogenase, and impairment of biosynthesis and secretion of proteins, bile acids and glycerolipids. LDH leakage and inhibition of protein secretion into the culture medium proved to be the parameters which allowed the best differentiation between the test compounds. The inhibition of glycerolipid secretion was the most sensitive test in relation to concentration and time of exposure. Based on the effects of these endpoints, the following ranking of relative in vitro toxicity, using equimolar drug concentrations, could be established: clomipramine greater than imipramine = thioridazine greater than chlorpromazine greater than amitriptyline = fluperlapine greater than haloperidol greater than promazine greater than clozapine much greater than sulpiride. This ranking order of in vitro cytotoxicity correlated well with the potential of the drugs to impair liver function in man. Only clozapine had to be classified as a false negative. There was, however, no correlation between the cytotoxicity and the intracellular accumulation of the test drugs. Furthermore, the comparison of the data obtained with psychotropics with the data from five other amphiphilic cationic drugs was consistent with the widely accepted concept of a direct toxic interaction of the drugs with cytomembranes. This nonspecific toxicity of the membrane-active drugs was further corroborated by a positive correlation between their potential to induce LDH leakage in hepatocytes and their ability to induce hemolysis in red cells. In conclusion, the results obtained in our study strongly suggest that it is possible to assess the relative cytotoxicity of psychotropic drugs in rat hepatocyte cultures. It is proposed that this in vitro system provides a useful tool to evaluate new drugs at an early stage of their development, and to identify the most promising candidates within a class of structurally related compounds. In addition, it allows information to be obtained on possible mechanisms of cytotoxicity.
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In an open, uncontrolled trial flupenthixol was administered to 45 patients with endogenous depression. The drug was markedly effective in eight patients, effective in nine patients, fairly effective in 12 patients, and ineffective or aggravating in 16 patients. Four patients showed transient manic symptoms. Dosage was 1-3 mg daily. In 36 patients flupenthixol was used in combination with previously administered tricyclic antidepressants, and in nine patients it was used alone. Clinical effect was quickly apparent. It appeared within 1 week in 63% and within 2 weeks in 93% of subjects. Side-effects were observed in 13 patients: insomnia, five patients; slight extrapyramidal symptoms, nine patients. Sedative-hypnogenic effects were rarely seen. In 71% of 17 patients in whom the drug was found to be markedly effective or effective, flupenthixol's influence on psychomotor retardation was particularly striking. Other clear benefits were relief of depressive mood, psychic anxiety, and agitation. It is recommended that flupenthixol is given, as supplementary medication, to patients (1) whose depressive symptoms other than psychomotor retardation have already improved with current tricyclic antidepressants, and (2) in whom, before antidepressant medication, psychomotor retardation is a principal feature.
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Fluvoxamine is the selective serotonin re-uptake inhibitor with the largest database in the treatment of obsessive-compulsive disorder, a severe, and often chronic, anxiety disorder associated with substantial impairment in functioning. The selective serotonin re-uptake inhibitors represent a first-line treatment in patients with obsessive-compulsive disorder. These agents work primarily by blocking the re-uptake of serotonin into the presynaptic nerve terminal, which is believed to be mediated by their effects on the serotonin transport system. In the last two decades, the anti-obsessional effect of fluvoxamine has been tested in several double-blind, placebo-controlled and active-comparison studies, demonstrating its superior efficacy over obsessions and compulsions compared with non-serotonergic antidepressants (i.e., desipramine) and equal efficacy to clomipramine (a tricyclic antidepressant with potent serotonin re-uptake inhibition) and other selective serotonin re-uptake inhibitors (paroxetine and citalopram). However, compared with clomipramine, the selective serotonin re-uptake inhibitor fluvoxamine showed fewer side effects and better tolerability. This reflects the poor affinity of this compound for adrenergic, muscarinic, cholinergic or histaminergic receptors.
A case of akinesia and mutism is described in a menopausal, depressed woman with onset following a mood challenge with 40 mg of methylphenidate taken orally over a 3-hour period. Various diagnoses are considered with preference given on clinical grounds to conversion disorder precipitated by drug-induced dysphoria. It is suggested that increased susceptibility to dysphoria may have been related to prior clomipramine administration and hypoestrogenism.
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The aim of this study was to test the hypothesis of noradrenergic and serotoninergic depressive subtypes. For this purpose, the correlation between three variables was investigated: urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), dexamethasone suppression test (DST), and clinical response profiles to clomipramine and maprotiline, the effects of which are relatively selective on the uptake of noradrenaline (NA) and 5-hydroxytryptamine (5HT). Our results showed no correlation between these measures. Therefore, the hypothesis of two subtypes of depression was not supported. The only significant finding in this study was the obvious decrease in MHPG excretion during the antidepressant treatment in the group with high pretreatment MHPG.
Several concerns have been raised regarding the reproductive safety of the antidepressants most frequently used in clinical practice, such as selective serotonin reuptake inhibitors (SSRIs).
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Several compounds of pharmaceutical importance from a variety of chemical families, for example chlorpromazine and clomipramine, have been found to form charge-transfer complexes with iodine. We have investigated the influence of dietary iodine on thyroid-gland dysfunction induced by clomipramine, chlorpromazine or 2-thiazoline-2-thiol. We suggest that iodine is partly diverted from its metabolic pathway by complexation with drugs, and so the urinary concentration of iodide is increased. Both chlorpromazine and clomipramine, at doses which do not inhibit thyroperoxidase, enhanced urinary iodine excretion when dietary iodine was restricted (3.944+/-0.96 microg/day for chlorpromazine-tested rats, 3.43+/-1.33 microg/day for clomipramine-tested rats, compared with 2.34+/-0.11 microg/day in control rats). Concurrently, these pharmaceutical compounds increased the level of free thyroid-stimulating hormone (TSH) in comparison with controls and induced histological modifications in, and enlargement of, the thyroid gland. We have demonstrated that drug-induced loss of iodine in the urine was associated with antithyroid action when iodine intake was limited.
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The neuroendocrine responsivity to an acute serotonergic challenge with low-dose i.v. clomipramine was studied in seven drug-free depressed patients and seven age-matched healthy control subjects. The depressed patients had higher baseline prolactin concentrations than the healthy subjects, and their prolactin response to clomipramine, assessed as either the percent of baseline or the log-transformed concentration, was significantly different (delayed and blunted peak response) compared to healthy controls. The growth hormone response was exaggerated in the depressed patients, and there were also trends toward blunting in their cortisol and adrenocorticotropic hormone responses. These results are consistent with previous findings of altered neuroendocrine responses to a variety of putative serotonin agonists in depressed patients.
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We describe a case of severe serotonin syndrome. The patient was simultaneously taking the atypical antidepressant olanzapine and a tricyclical antidepressant, clomipramine. Symptoms included altered mental state resulting in coma, myoclonus, hyperreflexia, diaphoresis, diarrhoea, disorientation and fever. After suspension of antidepressant drugs, intensive symptomatic treatment and administration of biperiden and cyproheptadine, the patient's condition improved.
The various clinical types of depression may correspond to biochemically distinct forms of the condition. If these could be characterized, antidepressant treatment might be tailored to correction of the underlying biochemical change(s) in individual patients. In particular, the selective actions of clomipramine and maprotiline on the serotonergic and noradrenergic systems respectively might be exploited therapeutically. Studies of the clinical response to these two antidepressants included tests of urinary 5-hydroxy-indoleacetic acid (5-HIAA) excretion and of serum thyroxine levels. While thyroid stimulation tests may prove of value for investigating depressed patients, urinary 5-HIAA levels are inconvenient, subject to extraneous influences and hard to interpret in terms of brain chemistry. (An alternative is proposed in the next paper.)
Randomized controlled multicenter clinical trial.
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The present study was undertaken to investigate the spontaneous epileptiformic activity induced by antidepressants using amygdala-kindled rats. The intraperitoneal injection of imipramine and amitriptyline resulted in potent behavioral and electroencephalogram (EEG)-detected seizures in amygdala-kindled rats compared with those seen in sham rats (non-kindled rats). Almost the same findings were observed with clomipramine and maprotiline. On the other hand, paroxetine caused no or little behavioral or EEG seizures in either amygdala-kindled or sham rats, even at a dose of 50 mg/kg. In conclusion, our results indicate that epileptiformic activity induced by kindling increases the susceptibility to cyclic antidepressant-induced seizures.
The fortuitous detection of SIADH is described in a patient receiving clomipramine therapy.
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Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the criteria for our search. In addition, we performed a retrospective case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.
NCB-20 cells (neuroblastoma X fetal Chinese hamster brain hybrids) are equipped with a [3H]5-hydroxytryptamine [( 3H]5-HT) uptake system and [3H]imipramine recognition sites. Approximately 80% of the radioactivity taken up by cells incubated with [3H]5-HT was identified with 5-HT. [3H]5-HT uptake was temperature-dependent, partially sodium-dependent, saturable (Km = 7.3 +/- 0.6 microM; Vmax = 2.0 +/- 0.6 pmol/min/mg), and inhibited by clomipramine, imipramine, fluoxetine, and desipramine, but not by iprindole, mianserin, or opipramol. Lineweaver-Burk plots showed a competitive type of inhibition by imipramine and fluoxetine. [3H]5-HT uptake was not inhibited by nisoxetine or benztropine. [3H]Imipramine binding sites had a KD of 12 +/- 2 nM and a Bmax of 22 +/- 7 pmol/mg protein. The binding was sodium-sensitive although to a lesser extent than that found with brain membranes. Imipramine binding was displaced by tricyclic antidepressants with the following order of potency: clomipramine greater than imipramine greater than fluoxetine greater than desipramine much greater than iprindole = mianserin greater than opipramol. These results suggest that imipramine binding sites are present together with the 5-HT uptake sites in NCB-20 cells and that these sites interact functionally but are different biochemically.
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Neonatal treatment with CLI reliably produces enhanced levels of REM (p < 0.01) and reduced sexual activity (p < 0.05). Theta power was enhanced during NREM sleep in the CLI group (p = 0.02). CLI-treated animals experienced increased frequency at the NRT (p < 0.01), as well as additional epileptiform activity of continuous (CTS; p < 0.05) and petite-continuous (P-CTS; p < 0.01) types, across the sleep-wake cycle. There is a strong temporal correlation with increased REM sleep duration, increased frequency of NRT bursts, and increased theta power during NREM sleep in CLI-treated animals.