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PubMedDate not supplied

Pharmacokinetic aspects of some behavioral effects of psychotropic drugs.

We have studied the distribution of antidepressant agents, morphine and apomorphine, in rat blood and tissues and correlated the pharmacokinetic data with pharmacological responses induced by these drugs. We have found a direct relationship between apomorphine concentration in its effective compartment and pharmacological response, while morphine and antidepressants showed such relations only to some limited extents. Investigations of interaction between neuroleptics and apomorphine and morphine have revealed that some pharmacokinetic alterations are involved in neuroleptic-induced changes of pharmacological responses to both drugs. We have also found that the route of administration, dosage schedule, and satiation of animals may affect the distribution and metabolism of drugs, and this in turn may change their pharmacological effects.

Animals↗

PubMed1982

Interaction of EEG sleep, antidepressants, and affective disease.

The major sleep characteristics of depression are summarized and new EEG sleep studies of antidepressants, including preliminary data on desipramine and zimelidine, are described. The relationship of steady-state plasma amitriptyline levels to REM sleep and the use of EEG sleep measures as predictors of clinical response to tricyclics will also be discussed. The effects of antidepressant agents on sleep are immediate and pronounced, and studies of these drug-induced effects may also represent a rational method for drug classification.

Amitriptyline↗

PubMed1997

Effects of dopaminergic agents on reversal of reserpine-induced impairment in conditioned avoidance response in rats.

Male Slc:Wistar, Std:Wistar, and Slc:F344/N rats had good acquisition of the conditioned avoidance response (CAR), while that of the male Slc:Wistar/ST, Jcl:Wistar, and Crj:Wistar rats was bad. Reserpine-induced impairment (RII) in CAR was observed 2-72 h after administration of dopaminergic (DAergic) agents in male Slc:Wistar rats. Amitriptyline (5-80 mg/kg, P.O.), imipramine, desipramine, cis-dosulepine, and trans-dosulepine at dose of 40 mg/kg, P.O. showed no antagonism against RII in CAR 20-23 h after reserpine injection (1 mg/kg, S.C.). However, the atypical antidepressive agents sibutramine (5-10 mg/kg, P.O.), bupropion (40 mg/kg, P.O.), and nomifensine (10-40 mg/kg, P.O.) exhibited antagonism against RII in CAR. The calcium channel antagonists flunarizine, nimodipine, and KP-840 at dose of 10 and 100 mg/kg, P.O., the cerebral improving agent indeloxazine (20-80 mg/kg, P.O.), the anticholinergic agent atropine (5-40 mg/kg, P.O.), 5-hydroxy-L-tryptophan (5-HTP) (40 mg/kg, I.P.), a precursor of 5-hydroxytryptamine (5-HT), and (+/-)-threo-dihydroxyphenylserine [(+/-)-threo-DOPS] (20-200 mg/kg P.O.), a norepinephrine (NE) precursor, showed no antagonism against RII in CAR. The DAergic agents methamphetamine (5 mg/kg, P.O.) and amantadine (50-250 mg/kg, P.O.), L-DOPA (200 mg/kg, P.O.), and the DAergic D1/D2 receptor agonist apomorphine (0.1-1 mg/kg, S.C.) showed marked antagonism against RII in CAR. Although the DAergic D1-receptor agonist KF-38393 (0.3-30 mg/kg, I.P.) and the DAergic D2-receptor agonist quinpirole (0.3-10 mg/kg, I.P.) induced only a weak recovery of RII in CAR when they were administered alone, in contrast to a potent synergistic recovery of RII in CAR, which was observed when SKF-38393 (1 mg/kg, I.P.) and quinpirole (1 mg/kg, I.P.) were administered together. These results suggest that the DAergic nervous system rather than the adrenergic or 5-HT nervous system is involved in RII in CAR, and that both the DAergic D1- and D2-mediated nervous systems play important roles in this process.

Animals↗

PubMed2001

How antidepressants work: new perspectives on the pathophysiology of depressive disorder.

BACKGROUND: New research in animals is beginning to change radically our understanding of the biology of stress and the effects of antidepressant agents. AIMS: To relate recent findings from the basic neurosciences to the pathophysiology of depressive disorder. METHOD: Drawing together findings from molecular and physiological studies in rats, social studies in primates and neuropsychological studies in humans, we review the neurotrophic and neuroplastic effects of antidepressants and stress. RESULTS: Stress and antidepressants have reciprocal actions on neuronal growth and vulnerability (mediated by the expression of neurotrophins) and synaptic plasticity (mediated by excitatory amino acid neurotransmission) in the hippocampus and other brain structures. Stressors have the capacity to progressively disrupt both the activities of individual cells and the operating characteristics of networks of neurons throughout the life cycle, while antidepressant treatments act to reverse such injurious effects. CONCLUSIONS: We propose a central role for the regulation of synaptic connectivity in the pathophysiology of depressive disorder.

Animals↗

PubMed1999

Antidepressant activity of Indian Hypericum perforatum Linn in rodents.

A standardised 50% aqueous ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its antidepressant activity on various experimental paradigms of depression, viz. behavioural despair (BD), learned helplessness (LH), tail suspension (TS) and reserpine-induced hypothermia (RIH) tests in rats and mice. Pilot studies indicated that single dose administration of IHp had very little or no acute behavioural effects, hence the IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.) once daily for three consecutive days, while imipramine (15 mg/kg, i.p.), a clinically used antidepressant agent, was administered acutely to rats (CF strain, 150 +/- 10 g) and mice (Wistar strain, 23 +/- 2 g) of either sex as the standard drug. Controls animals were treated similarly with equal volume of vehicle (0.3% carboxymethyl cellulose). Indian Hypericum perforatum extract showed significant antidepressant activity on all the paradigms of depression used. Thus IHp and imipramine treatments significantly reduced the immobility time in BD and TS tests. Significant reduction in escape failures was also observed in LH test. In RIH test IHp and imipramine inhibited reserpine induced hypothermia in a dose dependent manner. The observed antidepressant activity of IHp was qualitatively comparable to that induced by imipramine.

Animals↗

PubMedDate not supplied

Psychopharmacologic treatment of depression in the medically ill.

Appropriate selection of an antidepressant agent in medically ill patients requires a careful risk-benefit assessment matching the pharmacokinetic and pharmacodynamic properties of the drug being considered against the patient's physiological vulnerabilities, potential for drug interactions, and primary symptoms of the patient's depression. While in the past antidepressant drug selection was limited by the almost sole availability of the tricyclic antidepressants, newer drugs such as selective serotonin reuptake inhibitors, bupropion, and venlafaxine have vastly simplified treating depression in the medically ill. In refractory cases of depression in patients with medical illness, electroconvulsive therapy can be used with appropriate anesthetic management.

Antidepressive Agents↗

PubMed2000

The treatment of bipolar depression.

OBJECTIVES: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management. METHODS: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'. RESULTS: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate. CONCLUSIONS: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.

Anticonvulsants↗

PubMed1996

Spectroscopic analysis of charge transfer complex formation and peroxidase inhibition with tricyclic antidepressant drugs: potential anti-thyroid action.

Inspection of the chemical structures of tricyclic antidepressant drugs indicates that they might interfere with the synthesis of thyroid hormones. This iatrogenic potential was demonstrated in vitro by the spectrophotometric detection in both the visible and UV regions of the formation of a complex between antidepressants and iodine. The values of Kc, the formation constant of the drug-iodine complex, were calculated. The concentration of antidepressant which led to a 50% inhibition (IC50) of horseradish peroxidase was also determined. The anti-thyroid activity of drugs can be evaluated from these two parameters, Kc and IC50. The results were compared to those obtained with methimazole, a reference anti-thyroid agent. Antidepressants derived from imipramine appeared to have anti-thyroid activity. This result is now awaiting confirmation in animal experiments.

Antidepressive Agents, Tricyclic↗

PubMed2005

Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity.

A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic analyses by a Lineweaver-Burk plot clearly indicated that piperine competitively inhibited MAO-A and MAO-B with Ki values of 19.0+/-0.9 microM and 3.19+/-0.5 microM, respectively. The inhibition by piperine was found to be reversible by dialysis of the incubation mixture. In addition, the immobility times in the tail suspension test were significantly reduced by piperine, similar to that of the reference antidepressant fluoxetine, without accompanying changes in ambulation when assessed in an open-field. These results suggest that piperine possesses potent antidepressant-like properties that are mediated in part through the inhibition of MAO activity, and therefore represent a promising pharmacotherapeutic candidate as an antidepressant agent.

Alkaloids↗

PubMed1996

Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans.

This study investigates the possible interactions of antidepressant agents and hallucinogens in humans through structured interviews using a standardized questionnaire. Volunteer subjects recruited through announcements placed on the Internet or other sources were asked to describe the somatic, hallucinatory, and psychological effects of self-administered LSD prior to and during chronic administration of an antidepressant. Twenty-eight out of 32 subjects (88%) who had taken an antidepressant with inhibitory effects on serotonin (5-HT) reuptake (fluoxetine, paroxetine, sertraline, trazodone) for over 3 weeks had a subjective decrease or virtual elimination of their responses to LSD. An additional subject who had taken fluoxetine for only 1 week had an increased response to LSD. These data are in contrast to our previous study that reported increased responses to LSD during chronic administration of tricyclic antidepressants or lithium. Possible mechanisms of action for the effects from serotonergic antidepressants involve 5-HT2 and 5-HT1A receptors, changes in extracellular brain serotonin concentrations, and changes in brain catecholamine systems.

Adult↗

PubMed2001

The interaction of drug- and psychotherapy in the long-term treatment of depression.

Recent advances in our understanding of both short- and long-term therapeutic interventions for depressive disorders have necessitated greater precision in defining appropriate therapeutic interventions. While these remarkable changes in treatment have been based on the introduction of newer antidepressant agents, the advances have occurred because of more systematic clinical trials and a greater sophistication in defining diagnostic and treatment response criteria. This paper reviews key findings in recurrent depression with respect to long-term treatment. Particular attention is paid to the combination treatment of psychotherapy and antidepressant drugs.

Antidepressive Agents↗

PubMed2003

Modulation of the human glucocorticoid receptor function by antidepressive compounds.

Hyperactivity of the hypothalamic-pituitary-adrenal axis is associated with depression. We investigated the effect of various types of antidepressant agents in vitro on the function of glucocorticoid receptor (GR). Desipramine, clomiplamine, fluoxetine, milnacipran and clorgyline all induced rapid and sustained translocation of GR into the nucleus of human lymphocytes. In contrast, major and minor tranquilizers, lithium and verapamil, a blocker of membrane steroid transporter, were without effect. These antidepressants did not affect GR-mediated transcription by themselves, but significantly inhibited dexamethasone-induced transcription. These results indicate that structurally different antidepressants induce translocation of GR and inhibit GR-mediated transcription.

Animals↗

PubMed1999

Psychological aspects. A series of 104 posttraumatic cases of reflex sympathetic dystrophy.

Over a period of 12 years, 104 cases of posttraumatic reflex sympathetic dystrophy have been diagnosed followed up and treated according to a standard protocol, including, among other clinical items, a psychiatric examination. Apart from the traditional clinical recordings, the following has been noted: 1. All patients were over 30 years of age; 2. No relationship was found between the significance of the trauma and the severity of the dystrophy; 3. The dystrophy nearly always emerged at the time of the primary healing of the injury; 4. On psychiatric examination, 96% of the patients showed signs of chronic depression; 5. Forty-nine percent had elevated gamma GT suggestive of alcohol abuse; 6. The socioprofessional context always revealed: either a state of inactivity (jobless persons, disabled persons, childless housewives, pensioners); or an opportunity for inactivity (work injury suffered by workers, lower-rank employees, bankrupt self-employed people). There were no tradesmen, executives, lawyers, physicians, consultants, artists, sportsmen or musicians in the series, and no housewives with young children. 7. In the second phase of the survey, we decided to complement the drug therapy by systematically adding antidepressant agents. This led to a significant improvement in the course of the disease. These elements have led us to consider whether traumatic algodystrophy could be a psychosomatic disease.

Adult↗

PubMed1976

Tricyclic antidepressant drugs as antagonists of muscarinic receptors in sympathetic ganglia.

Close arterial injection of McN-A-343 into the superior cervical ganglion of the cat resulted in contractions of the nictitating membrane. The ganglionic effects of McN-A-343 but not those of DMPP were antagonized in a dose-related manner by 2-10 mug of desipramine, imipramine, chlorimpramine, iprindole and viloxazine. No correlation was found between the dose of each drug which blocked the effects of McN-A-343 and that required to potentiate the responses of the nictitating membrane to intra-arterial administration of noradrenaline. It is concluded that clinically effective antidepressant agents can block muscarinic receptors in neural tissue, even if they do not do so in smooth muscle and gland cells.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMedDate not supplied

Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial.

OBJECTIVE: Depression is a prevalent and chronic condition in diabetes and is associated with poor glucose regulation and poor compliance with diabetes treatment. This investigation evaluated the effects of nortriptyline on depression and glycemic control to see whether depression in diabetes is treatable and whether restoring mental health contributes to improved medical outcome. METHOD: Sixty-eight diabetic patients with poor glycemic control, 28 of whom had active major depression (DSM-IIIR), completed a randomized, placebo-controlled, double-blind trial involving 8 weeks of treatment with nortriptyline targeted to therapeutic plasma levels (50-150 ng/ml). Depression improvement was determined with the Beck Depression Inventory; glucose control was measured by glycated hemoglobin levels. Compliance behavior was assessed using medication dispensing devices and glucometers equipped with electronic memory. RESULTS: The reduction in depression symptoms was significantly greater in depressed patients treated with nortriptyline compared with those receiving placebo (-10.2 vs -5.8, p = .03). Nortriptyline was not statistically superior to placebo in reducing glycated hemoglobin of the depressed subjects (p = .5). However, path analysis indicated that the direct effect of nortriptyline was to worsen glycemic control whereas depression improvement had an independent beneficial effect on glycated hemoglobin. These findings were not explained by the relationships of nortriptyline treatment to weight change (r = -0.21, p = .31) or depression improvement to compliance with the protocol for self-monitoring of blood glucose (r = 0.01, p = .97). CONCLUSIONS: Major depression in diabetic patients can be effectively treated with nortriptyline at the expense of a direct hyperglycemic effect. Path analysis demonstrated a treatment-independent effect of depression improvement on glycemic control, suggesting that a more ideal antidepressant agent may both restore mental health and improve medical outcome.

Adult↗

PubMed1992

Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies.

For 39 controlled studies on the analgesic effect of antidepressants, a meta-analysis was conducted to get an estimation of the effect size, and to obtain a sight on the possible modes of action and the methodology used. The mean size of the analgesic effect was 0.64. It means that the average chronic pain patient who received an antidepressant treatment had less pain than 74% of the chronic pain patients who received a placebo. This quantification, however, is only as good as the studies on which it is based, and it could be differentiated for each of the pain syndromes and antidepressants examined. Real analgesic qualities of antidepressive agents seemed to offer the most plausible and economical explanation for the effect, but the predominant importance of serotonin reuptake blocking was not confirmed. Finally, the meta-analysis appeared to be fruitful for the generation of new hypotheses, for making some recommendations for future research, and for proposing some provisional guidelines for the clinical use of antidepressants in chronic non-malignant pain.

Analgesia↗

PubMed1997

The undertreatment of dysthymia.

BACKGROUND: Dysthymia is a chronic depressive condition that is quite prevalent. This condition can exact a significant toll on the general health and quality of life in the affected individual. Despite the frequency and consequences of dysthymia, however, the condition is often not diagnosed or treated. We present data on prior treatment from 410 patients with DSM-III-R dysthymia, primary type, early onset without concurrent major depression. METHOD: Axis I and II diagnoses were made by using the Structured Clinical Interviews for DSM-III-R, Patient Version (SCID-P) and SCID II for Personality Disorders. The Hamilton Rating Scale for Depression and the Clinical Global Impressions scale were also completed. Prior treatment was assessed, with special attention paid to previous antidepressant drug therapy and psychotherapy. RESULTS: Although the mean duration of dysthymia was about 30 years and almost half of the patients had previous episodes of major depression, only 41.3% had been treated with antidepressants and 56.1% with psychotherapy. A past history of major depression increased the frequency of prior antidepressant pharmacotherapy (45.7%) and psychotherapy (59.4%) compared with no history of major depression (36.8% and 40.9%, respectively). Comorbid personality disorder increased the likelihood of prior psychotherapy (70.7% vs. 49.6%) while having no effect on past pharmacotherapy. A history of substance abuse did not affect the history of antidepressant or psychotherapy treatment. In this study, dysthymia and psychosocial outcomes improved with sertraline and imipramine treatment. CONCLUSION: Dysthymic patients in this sample were significantly undertreated. Newer antidepressant agents may alter the potential for pharmacotherapy interventions in this vulnerable population.

1-Naphthylamine↗

PubMed1995

Maintenance therapies for late-life recurrent major depression: research and review circa 1995.

Major depression in the elderly is often a relapsing, chronic illness with high risk for chronic invalidism, poor treatment compliance, and suicide. In most cases, maintenance treatment to prevent recurrence and to enhance the quality of life is thought to be indicated. We review recent data from our ongoing studies that support both the efficacy and the safety of pharmacotherapeutic and psychotherapeutic maintenance treatments. However, the challenges of conducting maintenance therapy research (particularly with a placebo control) with the elderly are many, involving such areas as recruitment, retention, compliance, choice of outcome measures, and informed consent. We discuss each of these challenges and our responses to them. Finally, we suggest that maintenance therapy trials should be extended in several directions: (a) long-term treatment of bipolar and delusional subtypes in the elderly, as well as depression associated with progressive neurodegenerative disorders such as Alzheimer's dementia; (b) assessment of the benefits and risks of long-term therapy with other than tricyclic and monoamine oxidase inhibitor antidepressant agents, such as selective serotonin reuptake inhibitors; and (c) development of models of long-term course, including the interaction of treatments with medical and psychosocial variables that can have a profound impact on illness onset and offset. These issues are illustrated with a discussion of a new protocol designed to test the acute and maintenance efficacy of antidepressant therapy for depressed patients with Alzheimer's disease.

Alzheimer Disease↗