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PubMed1999

Effects of anxiogenic drugs in rat forced swimming test.

The effect of antidepressants and anxiogenics in the forced swimming (Porsolt') test was investigated in rats. On the second day of an experiment, desipramine (10 mg/kg), pentylenetetrazole (20 mg/kg), picrotoxin (2.5 mg/kg), and clonidine (1.0 mg/kg) shortened while buspirone (1.0 mg/kg), yohimbine (2.5 mg/kg), DMCM (1.0 mg/kg), and Ro-15-4513 (1.0 mg/kg) prolonged the time of immobility or behavioral despair; fluoxetine (10 and 20 mg/kg), citalopram (10 mg/kg), and flumazenil (10 mg/kg) were ineffective. While clonidine, given in a subeffective dose (0.1 mg/kg), augmented the effect of desipramine (10 mg/kg), buspirone (1.0 mg/kg) had an opposite effect. The picrotoxin (2.5 mg/kg) challenge prominently shortened the time of immobility after desipramine (10 mg/kg) or citalopram (10 mg/kg) treatment. In conclusion, our results indicate that pharmacologically enhanced anxiety interacts with the effects of acute drug treatment in the forced swimming test.

Animals↗
PubMed1997

Regulation of Peripheral Catecholamine Responses to Acute Stress in Young Adult and Aged F-344 Rats.

Young adult (3-month-old) and aged (24-month-old) Fischer-344 male rats received i.v. infusions of 3H-labeled norepinephrine (NE) and epinephrine (EPI) to examine the effects of aging on the neuronal uptake of NE and sympathoadrenal release of NE and EPI. Spillovers of NE and EPI into plasma and their clearance from the circulation were estimated from plasma concentrations of endogenous and 3H-labeled NE and EPI. The efficiency of neuronal uptake was assessed from changes in plasma clearance of NE and concentrations of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG), during immobilization stress or neuronal uptake blockade with desipramine. Stress-induced increases in plasma NE and higher plasma NE concentrations in aged compared to young adult rats were due to both decreases in NE clearance and increases in NE spillover. EPI spillover and clearance were reduced in aged compared to young adult rats, so that plasma EPI levels did not differ between groups. Young adult and aged rats had similar desipramine-induced decreases in NE clearance, whereas desipramine-sensitive decreases and stress-induced increases in plasma DHPG were larger in aged rats. This indicates that neuronal uptake is intact and that increased NE spillover at rest and during stress in aged rats reflects increased NE release from sympathetic nerves. The results show that aging is associated with divergent decreases in EPI release from the adrenal medulla and increases in NE release from sympathetic nerves. Increased plasma concentrations of NE in aged compared to young adult rats also result from decreased circulatory clearance of NE, but this does not reflect any age-related impairment of NE reuptake.

Journal Article↗
PubMed1982

Hemoperfusion for imipramine overdose: elimination of active metabolites.

The serum concentrations of imipramine and its pharmacologically active metabolites were followed during resin hemoperfusion for imipramine overdose. The initial serum concentration of 2-hydroxy-imipramine plus 2-hydroxy-desipramine was 13.3% of the total tricyclic antidepressant level (imipramine + desipramine + hydroxymetabolites). Despite high extraction ratio (greater than or equal to 0.75) and clearances (130--180 mL/min) for both imipramine and its metabolites, the calculated amount of drug removed was small. Only 0.91% of the estimated dose ingested was removed as imipramine, 0.52% as desipramine, and 0.33% as hydroxylated metabolites. While the hydroxylated metabolites of imipramine may contribute to its toxicity, it is unlikely that the small amount removed can explain reports of apparent clinical benefit from hemoperfusion.

Adult↗
PubMed1997

Evaluation of a colloidal metal immunoassay device for the detection of tricyclic antidepressants in urine.

BACKGROUND: The sensitivity and selectivity of a colloidal metal immunoassay device (Triage Plus TCA) which is designed for the rapid detection of tricyclic antidepressant drugs in urine at a total tricyclic antidepressant concentration of 1000 ng/mL or greater were evaluated. METHODS: The sensitivity of the Triage Plus assay was determined by adding known amounts of amitriptyline, nortriptyline, imipramine, desipramine, doxepin and desmethyl-doxepin to drug free urine. The selectivity of the assay was determined by adding known concentrations of 32 drugs or drug metabolites commonly encountered in emergency department admissions to drug free urine. Triage Plus results from clinical urine specimens containing either amitriptyline, nortriptyline, imipramine, desipramine, doxepin and desmethyl-doxepin were compared to those obtained with thin layer chromatography and high performance liquid chromatography. RESULTS: Triage Plus yielded a positive response to gravimetrically prepared urines of tricyclic antidepressant at the stated cut-off value (1,000 ng/mL), and at 80% (800 ng/mL) and 50% (500 ng/mL) of the cut-off with amitriptyline, nortriptyline, imipramine, desipramine and doxepin. Other tricyclic antidepressant drugs, clomipramine and protriptyline were positive at 1000 ng/mL. Significant cross-reactivity was observed only with cyclobenzaprine at 1000 ng/mL. No significant cross reactivity was found at 1.0 g/L for 32 drugs commonly encountered in emergency department admissions. A 95% (70/74) agreement of positive tricyclic antidepressant results was observed between Triage Plus and thin layer chromatography. Discordant urines were found by high performance liquid chromatography to contain tricyclic antidepressant concentrations below the cut-off value of the colloidal metal assay. CONCLUSION: Triage Plus was found to be an accurate device for the detection of tricyclic antidepressants in urine at the stated cut-off value of 1000 ng/mL tricyclic antidepressant. With the exception of cyclobenzaprine, significant cross-reactivity was not observed with other drugs commonly encountered in emergency department admissions.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Effects of some centrally active drugs on the allopregnanolone synthesis in rat brain.

Effects of antidepressants (desipramine, amitriptyline), anticonvulsants (phenytoin, diazepam, carbamazepine) and addictive drugs (amphetamine, morphine), used at a concentration of 100 microM on the conversion of [14C]-progesterone to 5alpha-pregnane-3,20-dione and allopregnanolone in slices of the frontal cortex and olfactory bulb from rat brain were studied. The synthesis of 5alpha-pregnane-3,20-dione and allopregnanolone was stronger in the olfactory bulb than in the frontal cortex. The biosynthesis of allopregnanolone in the frontal cortex was higher by 74, 109 and 187% when stimulated by amitriptyline, desipramine and carbamazepine, respectively, and, to a lesser degree, by phenytoin and morphine. Desipramine and morphine decreased the concentration of 5alpha-pregnane-3,20-dione. In the olfactory bulb, only carbamazepine enhanced allopregnanolone production, but none of the tested drugs had any effect on 5alpha-pregnane-3,20-dione synthesis. It is concluded that some psychotropic drugs may increase allopregnanolone synthesis by stimulating the activity of the enzyme, 3alpha-hydroxysteroid dehydrogenase, in the frontal cortex, and that this neurosteroid may be partly involved in the mechanism of action of the drugs under study.

5-alpha-Dihydroprogesterone↗
PubMed2005

Effect of pharmacologically selective antidepressants on serotonin uptake in rat platelets.

We tested a hypothesis that a long-term administration of antidepressants acting through different primary biochemical mechanisms is associated with changes in the platelet serotonin (5-hydroxytryptamine, 5-HT) transport. Laboratory rats were administered norepinephrine reuptake inhibitors (desipramine, maprotiline), selective 5-HT reuptake inhibitor (citalopram), reversible monoamine oxidase inhibitor (moclobemide), and lithium (inositol monophosphatase inhibitor among others) during a 4-week period. Apparent kinetic parameters of platelet 5-HT transport were analyzed. Significant decrease in apparent Michaelis constant (K(M)) was found after the administration of all tested antidepressants except for desipramine. There was certain increase in maximal velocity (V(max)) values following the administration of desipramine, maprotiline, and citalopram; however, the all V(max) changes were not significant. V(max)/K(M) ratio representing limiting permeability at low extracellular concentrations of 5-HT was systematically increased in all the tested drugs, but significant changes were occurred only in maprotiline- and citalopram-treated rats. Adaptive changes in platelet 5-HT transport induced by citalopram were opposite to the acute inhibitory effect of this drug on 5-HT transporter activity. An increase in limiting membrane permeability for 5-HT could be included in the common adaptive effect of the long-term administration of antidepressants that differ in pharmacologic selectivity.

Adaptation, Physiological↗
PubMedDate not supplied

Effect of short- and long-term treatment with antidepressant drugs on the activity of rat CYP2A in the liver.

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2A measured as a rate of testosterone 7alpha-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg/kg i.p.; desipramine, fluoxetine, sertraline 5 mg/kg i.p.; mirtazapine 3 mg/kg i.p.), in the absence of the antidepressants in vitro. Most of the investigated drugs directly inhibited the CYP2A activity when added in vitro to control liver microsomes. Their inhibitory effects were strong (clomipramine, fluoxetine and desipramine: Ki = 15, 20 and 25 microM, respectively), moderate (sertraline and imipramine: Ki = 50 and 75 microM, respectively) or weak (amitriptyline, nefazodone and mirtazapine: Ki = 107, 127 and 250 microM, respectively). A one-day (i.e. 24-h) exposure to the investigated antidepressant drugs did not produce any significant changes in the rate of 7alpha-hydroxylation of testosterone in the rat liver microsomes, while chronic treatment with clomipramine or sertraline significantly increased the activity of CYP2A, which suggests enzyme induction. In summary, two different mechanisms of the antidepressant-CYP2A interaction have been found in rat liver: 1) the direct inhibition of CYP2A by most of the investigated TADs and SSRIs; 2) the in vivo weak induction of CYP2A by clomipramine and sertraline. This observation may be important to the interpretation of the results of pharmacological tests carried out on rats. It seems of primary importance to determine whether the influence of antidepressants on CYP2A6 in humans is analogous as on CYP2A1/2 in rats.

Animals↗
PubMed1986

Single-site model of the neuronal 5-hydroxytryptamine uptake and imipramine-binding site.

Recently, a high affinity [3H]imipramine-binding site of protein nature that appeared to be related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated. This binding site was only part of desipramine-displaceable [3H]imipramine binding, which contained a significant amount of additional binding not related to 5-HT uptake. The present study further investigates the [3H]imipramine-binding site of protein nature in the rat brain. Displacement by 5-HT and 6-methoxytetrahydro-beta-carboline (6-MeO-TH beta C) revealed monophasic displacement patterns with 60% displaceable binding. This binding fraction was abolished by protease treatment of the brain tissue prior to binding assay. Saturation studies of [3H]imipramine binding (1-30 nM) in rat cortex showed that the binding displaced by 30 microM 5-HT [Bmax 322 +/- 16 fmol/mg of protein, Kd 4.17 +/- 1.07 nM (means +/- SE)] was not different from the binding displaced by 1.0 microM norzimeldine (Bmax 349 +/- 15 fmol/mg of protein, Kd 4.47 +/- 1.07 nM) or 30 microM 6-MeO-TH beta C (Bmax 439 +/- 28 fmol/mg of protein, Kd 5.49 +/- 1.09 nM). When 100 microM desipramine was used in saturation studies, the binding was different from that displaced by 5-HT with Bmax 608 +/- 42 fmol/mg of protein and Kd 6.68 +/- 1.09 nM. Both displacement and saturation studies in which two displacing agents were combined indicated that most of the binding competed by 5-HT (30 microM) and norzimeldine (1.0 microM) is identical. Similarly, the binding displaced by 5-HT or norzimeldine is subsumed within 6-MeO-TH beta C (30 microM)-displaceable binding. Lesion studies with parachloroamphetamine, a selective toxin for 5-HT terminals, which resulted in a 83% reduction of [3H] 5-HT uptake ( [3H]noradrenaline uptake unaffected), abolished cortical [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine. (greater than 80% reduction). However, with 100 microM desipramine as displacer, 40% of the binding remained in lesioned animals. The [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine was sodium dependent, and an increase in NaCl concentration from 0 to 120 mM resulted in a 10-fold increase in affinity without effect on Bmax, whereas no change in binding was observed with increasing concentrations of LiCl.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Influence on the electrocardiogram of rats by antidepressants.

The influence of lofepramine on the heart has been studied in anaesthetized rats. Lofepramine and other antidepressants were infused i.v. during 4 h at a rate of 0.5 mg/kg/min for lofepramine (equimolar concentrations for the other antidepressants). ECG and survival time were recorded. It was shown that lofepramine in contrast to the other antidepressants tested did not influence the PQ- and QRS-times at all. The other antidepressants tested increased the PQ-time 20-170% and the QRS-time 40-130%. Only the rats in the lofepramine group survived the whole experiment. The occurrence of multiple arrhythmias was low in this study and the difference between the groups was not striking. In further 13 rats the plasma level of desipramine, the main metabolite of lofepramine, after 200 min of lofepramine and 100-135 min of desipramine infusion was measured. The levels of desipramine at that time were found approximately comparable after infusion of the two different substances.

Animals↗
PubMed1983

Antagonism by tricyclic antidepressants of reserpine-induced hypothermia in mice. Involvement of postsynaptic alpha 2-adrenoceptors.

The effects of adrenoceptor blocking agents and cyproheptadine on the antagonism by the antidepressants imipramine, desipramine and maprotiline, of reserpine-induced hypothermia in mice were studied. The anti-reserpine effect of the antidepressants was reduced by phenoxybenzamine, prazosin, yohimbine and d,1-propranolol, the two latter drugs exhibiting the strongest effect. Practolol was ineffective, while cyproheptadine potentiated the effect of maprotiline and was inactive towards imipramine and desipramine. Furthermore, the anti-reserpine effect of desipramine (the other antidepressants not being studied) was also reduced by piperoxan and l-propranolol, but not by d-propranolol. The reserpine-induced hypothermia was antagonized by clonidine and this effect was completely blocked by yohimbine and partly reduced by prazosin. These results confirm that the antagonism by tricyclic antidepressants of reserpine-induced hypothermia depends on the activation of noradrenergic mechanisms and indicate that this effect is mediated not only by alpha 1- and beta-, but also by postsynaptic alpha 2-adrenoceptors.

Animals↗
PubMed1994

Metabolic disposition of imipramine in oriental subjects: relation to metoprolol alpha-hydroxylation and S-mephenytoin 4'-hydroxylation phenotypes.

We studied the metabolic disposition of imipramine by measuring imipramine and its metabolites in plasma and urine simultaneously after a single oral dose of 25 mg of imipramine hydrochloride administered to 16 healthy (three Japanese and 13 Korean) volunteers. Four of the subjects were poor metabolizers (PMs) of metoprolol but extensive metabolizers (EMs) of S-mephenytoin (PMML/EMMP), five subjects were EMs of metoprolol but PMs of S-mephenytoin (EMML/PMMP) and seven subjects were EMs of both metoprolol and S-mephenytoin (EMML/EMMP). The mean (+/- S.D.) oral clearances of imipramine were smaller in the PMML/EMMP group and the EMML/PMMP group than in the EMML/EMMP group, although a statistical difference (P < .05) was found only in the EMML/PMMP vs. the EMML/EMMP group. The mean area under the plasma concentration-time curve (AUC) of desipramine was 9 times greater (P < .01) in PMML/EMMP group, whereas the mean value was 0.6 times smaller (P < .05) in the EMML/PMMP group than in the EMML/EMMP group. The log10 metoprolol/alpha-hydroxymetoprolol ratio correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of desipramine/imipramine (P < .05) but negatively with the AUC ratio of 2-hydroxyimipramine/imipramine (P < .05). Log10 percent 4'-hydroxymephenytoin excreted in 8-hr urine correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of desipramine/imipramine (P < .01). The urinary excretions of imipramine and its metabolites also reflected the data derived from plasma samples in the three different phenotype-paired panels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants.

Brain catecholamines can be rapidly reduced by inhibiting their synthesis with alpha-methyl-para-tyrosine (AMPT). In order to assess the role of catecholamines in antidepressant action AMPT challenges were administered in a double-blind, placebo-controlled, crossover fashion to 14 depressed patients having maintained a therapeutic antidepressant response for > or = 2 weeks (3 desipramine, 2 mazindol, 5 fluoxetine, 4 sertraline). Each patient participated in two challenges one week apart. Each challenge included a baseline, two days of either AMPT or diphenhydramine (active placebo), and a followup. Antidepressant drugs were continued throughout testing. The 3 desipramine- and 2 mazindol-responders had a rapid increase in depression score during AMPT but not placebo (diphenhydramine) challenge whereas only 1 of 9 selective serotonin reuptake inhibitor (SSRI)-treated patients did. The implication of this is that the antidepressant response to desipramine may be more acutely dependent on brain catecholamine content than the response to SSRIs. In the context of our previous work with tryptophan depletion, these results suggest that the neurobiological mechanisms underlying the antidepressant responses to different drugs involve alterations in the functioning of different neurotransmitter systems and reinforce the importance of changes in both the serotonin and catecholamine systems for successful antidepressant responses.

Adult↗
PubMed1993

Citalopram: interaction studies with levomepromazine, imipramine, and lithium.

The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.

Adult↗
PubMed1995

Structural domains of catecholamine transporter chimeras involved in selective inhibition by antidepressants and psychomotor stimulants.

Reuptake systems for monoamines are the initial sites of action for a wide range of therapeutic antidepressants and drugs of abuse, such as cocaine. To delineate structural domains of the dopamine and norepinephrine transporters that contribute to differential interaction with reuptake inhibitors with antidepressant or reinforcing properties, a series of recombinant transporter chimeras were generated and transiently expressed in HeLa cells. The inhibition constants (Ki values) for cocaine and a variety of selective transport inhibitors were determined for each chimera. Analyses of functional chimeras delineate a segment spanning transmembrane domains 5-7 of the norepinephrine transporter of primary importance for high affinity binding of tricyclic and nontricyclic antidepressants (e.g., Ki < 20nM desipramine or nisoxetine). In contrast, all chimeras containing dopamine transporter sequences from this region resemble the dopamine transporter, which demonstrates higher affinity for psychomotor stimulants compared with antidepressants (e.g., Ki = 391 +/- 39 nM cocaine compared with 9365 +/- 1260 nM desipramine). A region including transmembrane domains 1-3 of the norepinephrine transporter also contributes to the interaction of desipramine and nisoxetine, whereas the analogous region of the dopamine transporter influences the affinity for piperazine derivatives (e.g., GBR12909 and LR1111) that are selective for the dopamine transporter. These analyses provide a framework for identifying the precise structural determinants of monoamine transporters involved in selective interactions with antidepressant and psychomotor stimulant reuptake inhibitors.

Animals↗
PubMedDate not supplied

Long-term outcomes of initial antidepressant drug choice in a "real world" randomized trial.

OBJECTIVE: To compare the long-term clinical, quality-of-life, and economic outcomes after an initial prescription for fluoxetine, imipramine hydrochloride, or desipramine hydrochloride. DESIGN: Randomized, controlled trial. SETTING: Primary care clinics of a staff-model health maintenance organization in the Seattle, Wash, area. PATIENTS: Four hundred seventy-one adults beginning antidepressant drug treatment for depression. INTERVENTION: Random assignment of initial medication (desipramine, fluoxetine, or imipramine), with treatment (dosing, medication changes or discontinuation, and follow-up visits) managed by a primary care physician. MEASUREMENTS: Interviews at baseline and at 6, 9, 12, 18, and 24 months examined medication use, clinical outcomes (Hamilton Depression Rating Scale and depression subscale of the Hopkins Symptom Checklist), and quality of life (Medical Outcomes Study SF-36 Health Survey). Medical costs were assessed using the health maintenance organization's accounting data. RESULTS: Patients assigned to fluoxetine therapy were significantly more likely to continue taking the initial antidepressant but no more likely to continue any antidepressant therapy. The fluoxetine group did not differ significantly from either tricyclic drug group on any measure of depression severity or quality of life. For 24 months, antidepressant drug costs were approximately $250 higher for patients assigned to fluoxetine therapy, but total medical costs were essentially identical. CONCLUSIONS: Initial selection of fluoxetine or a tricyclic antidepressant drug should lead to similar clinical outcomes, functional outcomes, and overall costs. Differences in antidepressant prescription costs are blunted by the large minority of tricyclic-treated patients who switch to use of more expensive medications. Restrictions on first-line use of fluoxetine in primary care will probably not reduce overall treatment costs.

Adrenergic Uptake Inhibitors↗
PubMed1980

Childhood enuresis. II. Psychopathology, tricyclic concentration in plasma, and antienuretic effect.

The efficacy of treatment with imipramine hydrochloride, desipramine hydrochloride, methscopolamine bromide, and placebo was compared in a study with 40 severely enuretic boys. Both tricyclic antidepressants were superior to placebo and methscopolamine, but they did not differ from each other. Psychiatric disturbance, sleep measures, and other clinical parameters did not predict antienuretic response to tricyclics nor was there a psychotropic response. Plasma concentrations of imipramine and desipramine showed a significant correlation with clinical effect. However, true nonresponders were found, and tolerance to the antienuretic drugs developed in some boys.

Child↗
PubMed1995

Pharmacotherapy of impaired affect in recovering schizophrenic patients.

BACKGROUND: Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken. METHODS: In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks. RESULTS: For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression. CONCLUSION: Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.

Adolescent↗
PubMed1996

Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression.

BACKGROUND: Most hypotheses of the therapeutic mechanism of action of antidepressant drugs have focused on the role of the monoamines. We examined the effect of catecholamine depletion on antidepressant-induced remission. METHOD: The tyrosine hydroxylase inhibitor alpha-methylparatyrosine and the antihistamine diphenhydramine hydrochloride were administered, during separate test sessions, to depressed patients in remission maintained with either norepinephrine reuptake inhibitors (desipramine [n = 7] or mazindol [n = 2]) or serotonin reuptake inhibitors (fluoxetine hydrochloride [n = 9] or sertraline hydrochloride [n = 1]). Because of considerable sedation associated with alpha-methylparatyrosine testing, diphenhydramine was used as an active control rather than an inactive placebo. The effects of alpha-methylparatyrosine and diphenhydramine on depression, anxiety, and plasma catecholamine metabolites were assessed. RESULTS: alpha-Methylparatyrosine produced similar significant decreases in plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels in the treatment groups. alpha-Methylparatyrosine produced a robust increase in depressive symptoms on the Hamilton Depression Rating Scale, including depressed mood, decreased concentration, anhedonia, loss of interest, and feelings of worthlessness, helplessness, and hopelessness, in the desipramine-mazindol but not in the fluoxetine-sertraline group. Diphenhydramine had no effects on mood in either treatment group. CONCLUSIONS: The therapeutic effects of norepinephrine reuptake inhibitors, but not serotonin reuptake inhibitors, are reversed by catecholamine depletion. Considered with previous reports that serotonin depletion produces depressive relapses in patients in remission maintained with serotonin reuptake inhibitors, but not norepinephrine reuptake inhibitors, these findings suggest that antidepressants may not work via a single monoamine-related mechanism.

1-Naphthylamine↗