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PubMed2006

Repeated treatment with antidepressants enhances dopamine D1 receptor gene expression in the rat brain.

Many pharmacological investigations have demonstrated that antidepressant agents profoundly affect serotonergic and noradrenergic neurotransmission. The molecular mechanisms by which these drugs exert their therapeutic action have not been clearly established. In our study, the possibility that antidepressant drug action is associated with dopamine neurotransmission was examined. To this end, the effect of 21-day treatment with 10 mg/kg of amitryptyline, mirtazapine and sertraline on the striatal and nucleus accumbens dopamine receptors was verified. The striatum and nucleus accumbens tissues were dissected 24 h after the last dose of the drug and total RNA was isolated. The expression of dopamine D1 to dopamine D5 receptors using reverse-transcriptase polymerase chain reaction (RT-PCR) procedure was compared to the glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) as constitutive gene activation internal control. Lab Works UV program has analyzed the mean optical density values of RT-PCR products. Statistical comparison of relative optical densities by a one-way analysis of variance (ANOVA) followed by Dunnett's test was performed. Despite their different pharmacological profiles, all three above-presented antidepressants significantly increased dopamine D(1) mRNA content. Our findings indicate that repeated antidepressant administration triggers induction of the brain dopaminergic receptors which is correlated with neuroadaptation of the brain dopaminergic pathway.

Amitriptyline↗

PubMed1999

Outcome of different types of long-term antidepressant treatments: a 3-year follow-up study of 14182 patients.

BACKGROUND: Antidepressant efficacy studies are rare in large populations for prolonged periods. METHODS: The efficacy of antidepressants was investigated by using disability pensions due to major affective disorders as the efficacy variable from a large Finnish population (n = 14182) during a 3-year follow-up. RESULTS: Of all males, 345 (6.0%) were receiving disability pension due to major affective disorder, and of all females, 498 (5.9%). A logistic regression analysis showed a significantly higher risk (age-adjusted ORs, 1.42-4.09) for disability pension in every antidepressant group except the amitriptyline group when compared with fluoxetine group. Those who used a combination of antidepressive agents (age-adjusted OR 4.09) or moclobemide (age-adjusted OR 2.18) had the highest risks. CONCLUSIONS: In the study population fluoxetine and amitriptyline were the most efficient antidepressants in the long-term treatment of depression.

Adult↗

PubMed1997

Bupropion and sexual function: a placebo-controlled prospective study on diabetic men with erectile dysfunction.

Many antidepressant agents interfere with sexual function. The purpose of this single-blind, prospective study was to determine sexual side effects, both positive and negative, of the amino-ketone antidepressant bupropion in a group of nondepressed diabetic men with somatic erectile dysfunction. Fourteen men participated in a 10-week protocol consisting sequentially of 2 weeks of baseline testing, 2 weeks of placebo, and 6 weeks of bupropion. Participants also completed daily and weekly questionnaires concerning sexual functioning, and a team of investigators rated various dimensions of sexual function every 2 weeks. In addition, a variety of physiologic measures, relevant either to erectile function or to neural/vascular systems that underlie sexual response, were assessed during baseline and bupropion treatment. Results indicated that neither subjective nor objective measures of erectile and overall sexual functioning worsened during bupropion. In fact, several measures suggested a trend toward improved sexual functioning. Furthermore, diabetic control was unaffected by bupropion administration. Given the lack of adverse effects on sexual function, along with the potential for improved erectile response, bupropion may provide an attractive choice for the treatment of depression in diabetic men or others for whom sexual dysfunction is a concern.

Adult↗

PubMed1996

Management of psychotic, treatment-resistant depression.

As there are no controlled studies on approaches to patients with treatment-resistant psychotic depression many questions remain to be answered. Those that seem worthy of high priority include (1) the efficacy of novel antipsychotic agents (e.g., clozapine, risperidone) for acute and maintenance treatment; (2) the efficacy of newer antidepressant agents such as the SSRIs and nefazodone plus neuroleptic medications; (3) decision trees to delineate the second and third lines of treatment when the first treatment is ineffective; (4) the comparative efficacy of bilateral versus unilateral ECT; (5) the length of time patients should be maintained on medications (which is of particular importance in the case of neuroleptic agents with their potential to cause tardive dyskinesia); (6) the optimal dose of neuroleptic agent for acute treatment; (7) the optimal length of time for medication trials; (8) the use of antidepressant medications during ECT treatments; (9) the importance of the sequence in which TCAs and neuroleptic agents are administered; (10) the delineation of the clinical characteristics of responders to medication versus ECT treatments; and (11) the role of antiglucocorticoid strategies. The answers to these questions would provide clinicians with important tools to treat patients with psychotic depression, an illness that all too frequently can become treatment-resistant.

Affect↗

PubMed2000

The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder. A critical review.

The roles of the N-methyl-D-aspartate (NMDA) receptor and NMDA receptor-mediated synaptic plasticity are reviewed in the context of depressive disorder and its treatment. The mode of action of antidepressant treatment is poorly understood. Animal studies have suggested that many antidepressant drugs show activity at the NMDA receptor and that NMDA antagonists have antidepressant profiles in preclinical models of depression. A post-mortem study in humans has suggested that certain binding characteristics of the NMDA receptor may be down-regulated in the brains of suicide victims. "Depressogenic" stressors in animals and chronic administration of antidepressant agents perturb NMDA-dependent synaptic plasticity in the hippocampus.

Animals↗

PubMed1993

Management of recurrent depression.

Research completed over the past decade has established the chronic and recurrent nature of major depression. To date, treatment for the prevention of recurrence has promoted the use of "maintenance" doses of antidepressant medications that are lower than the effective for the acute phase of treatment. Long-term randomized, double-blind studies of tricyclic antidepressant (TCA) maintenance therapy have shown, however, that full-dose treatment strategy has a highly significant prophylactic effect in preventing a new episode of depression for up to 5 years. Monthly interpersonal psychotherapy has also been shown to have a modest but significant effect on survival. Although prophylaxis with full-dose TCAs can be well tolerated by patients when proper education and support are provided, newer antidepressant agents with milder side effect profiles are being studied for their efficacy in long-term management of depression. The results of 1-year studies of maintenance therapy with serotonin selective reuptake inhibiting agents suggest that these medications will play a major role in prophylaxis for recurrent depression.

1-Naphthylamine↗

PubMedDate not supplied

[Pharmacologic treatment of bulimia].

The rationale for pharmacological treatment of bulimia nervosa is summarized and a review of controlled therapeutic trials shows contradictory results. A number of antidepressant agents (tricyclics: imipramine, desipramine, amitriptyline; IMAO: phenelzine, isocarboxazide; trazodone; fluoxetine) appear more effective than placebo in double-blind controlled trials of 6 to 16 weeks. In similar studies, other antidepressants (mianserine, fluvoxamine) are ineffective. Improvement reported is often incomplete and the low percentage of patients totally abstinent at the end of treatment appears of poor pronostic value for long-term outcome. Methodological limitations of existing studies are discussed, and some psychopathological factors to consider in the assessment of therapeutic response are proposed.

Antidepressive Agents↗

PubMed1997

Pharmacotherapy of bulimia nervosa and binge eating disorder: longer-term outcomes.

The longer-term effects of antidepressant medication, with and without the addition of psychotherapy, for the treatment of bulimia nervosa and binge eating disorder are reviewed. The use of a single antidepressant agent results in recovery of about 25 percent of patients entering treatment; continued treatment is accompanied by relapse in about one-third of these patients. Substituting one or more antidepressants for the initial agent in patients who fail to improve or cannot tolerate side effects improves long-term maintenance. Adding cognitive-behavioral therapy (CBT) may prevent relapse once medication is discontinued, and the combination of CBT and antidepressant treatment is more effective than a single medication. There is also evidence that antidepressant treatment combined with CBT is more effective than placebo plus CBT. The problem of how to sequence medication and CBT has not been resolved, although a recent study demonstrating that pharmacotherapy is more cost-effective than CBT suggests that treatment might begin with medication.

Antidepressive Agents↗

PubMed2006

Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study.

CONTEXT: The Food and Drug Administration has issued a boxed warning concerning increased suicidal ideation and behavior associated with antidepressant drug treatment in children and adolescents. It is unknown whether antidepressant agents increase the risk of suicide death in children or adults. OBJECTIVE: To estimate the relative risk of suicide attempt and suicide death in severely depressed children and adults treated with antidepressant drugs vs those not treated with antidepressant drugs. DESIGN: Matched case-control study. SETTING: Outpatient treatment settings in the United States. PARTICIPANTS: Medicaid beneficiaries from all 50 states who received inpatient treatment for depression, excluding patients treated for pregnancy, bipolar disorder, schizophrenia or other psychoses, mental retardation, dementia, or delirium. Controls were matched to cases for age, sex, race or ethnicity, state of residence, substance use disorder, recent suicide attempt, number of days since hospital discharge, and recent treatment with antipsychotic, anxiolytic/hypnotic, mood stabilizer, and stimulant medications. MAIN OUTCOME MEASURES: Suicide attempts and suicide deaths. RESULTS: In adults (aged 19-64 years), antidepressant drug treatment was not significantly associated with suicide attempts (odds ratio [OR], 1.10; 95% confidence interval [CI], 0.86-1.39 [521 cases and 2394 controls]) or suicide deaths (OR, 0.90; 95% CI, 0.52-1.55 [86 cases and 396 controls]). However, in children and adolescents (aged 6-18 years), antidepressant drug treatment was significantly associated with suicide attempts (OR, 1.52; 95% CI, 1.12-2.07 [263 cases and 1241 controls]) and suicide deaths (OR, 15.62; 95% CI, 1.65-infinity [8 cases and 39 controls]). CONCLUSIONS: In these high-risk patients, antidepressant drug treatment does not seem to be related to suicide attempts and death in adults but might be related in children and adolescents. These findings support careful clinical monitoring during antidepressant drug treatment of severely depressed young people.

Adolescent↗

PubMed1996

Signal-averaged ECG in patients with antidepressant therapy.

The signal-averaged electrocardiography (SAECG) identifies patients at risk of ventricular arrhythmias and sudden cardiac death. Since the similarity has been known of the pharmacology of class I antiarrhythmics and tricyclic antidepressants, the potential proarrhythmic effects of antidepressants has become a particular problem. The influence of sodium channel blocking antidepressant drugs on the SAECG time-domain parameters was evaluated, using high-pass filters of 25 Hz and 40 Hz. SAECG was performed in 11 depressed patients with normal cardiac status before and for 4 weeks after antidepressant initiation. At the filter setting of 25 Hz, a significant worsening of all studied SAECG parameters (filtered QRS duration, low-amplitude signal duration, root mean square voltage in the first and in the last 40 ms of the filtered QRS) was found in our patient group. Using a 40 Hz high-pass filter, the results were similar. Antidepressant therapy significantly prolonged filtered QRS duration, significantly reduced root mean square voltages in the first and in the last 40 ms of the filtered QRS and non-significantly prolonged low amplitude signal duration. Amitriptyline and maprotiline induced late potentials (LP) in 2 patients at 40 Hz high pass filter setting. No patient had LP at 25-250 Hz. Our pilot study indicates that sodium channel blocking antidepressant drugs may affect SAECG variables similarly to class I antiarrhythmics. SAECG might be useful in categorizing of antidepressant agents and risk stratification of psychiatric patients.

Adult↗

PubMed1996

Feeling hopeless and helpless. When anxiety symptoms coexist with depressive disorder.

Among patients with psychiatric disorders, a significant number have a depressive disorder and coexisting symptoms of anxiety. The overlapping conditions present physicians with a confusing array of symptoms that, in the past, has made diagnosis and therapy difficult. Although the anxiety symptoms may not be sufficient to meet diagnostic criteria for an anxiety disorder, they can have a profound influence on the severity of and prognosis for the depressive illness. To clarify diagnosis when symptoms of both depression and anxiety are present, it is important to consider elements such as predominant mood, sleep patterns, psychomotor signs, and suicidal ideation, which serve to differentiate between the two disorders. Once a diagnosis is established, appropriate use of pharmacotherapy (especially antidepressant agents that have anxiolytic side effects) and psychotherapy can help relieve symptoms and lead to a favorable outcome.

Antidepressive Agents↗

PubMed2003

A 15-year follow-up study of patients with panic disorder.

BACKGROUND: Panic disorder (PD) is generally regarded as a chronic condition with considerable variation in severity of symptoms. AIMS: To describe the long-term outcome of naturalistically treated PD. METHODS: Fifty-five outpatients with PD, who participated in a placebo-controlled drug trial of the efficacy of alprazolam and imipramine 15 years ago were reassessed with the same instruments used in the original study. RESULTS: Complete recovery (no panic attacks and no longer on medication during the last 10 years) was seen in 18% of patients, and an additional 13% recovered but were still on medication. Fifty-one percent experienced recurrent anxiety attacks whereas 18% still met diagnostic criteria for PD. The incidence of agoraphobia decreased from 69% to 20%. Patients with agoraphobia at admission tended to have a poorer long-term outcome according to daily functioning compared with patients without agoraphobia at admission, although both groups reported improved daily functioning at follow-up. Maintenance medication was common. No benzodiazepine abuse was reported. CONCLUSION: PD has a favourable outcome in a substantial proportion of patients. However, the illness is chronic and needs treatment. The short-term treatment given in the drug trial had no influence on the long-term outcome.

Activities of Daily Living↗

PubMed1997

The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization.

Drugs that are clinically effective (mexiletine and desipramine) or ineffective (fluoxetine) in the treatment of human neuropathic pain were evaluated for efficacy in rat models involving central sensitization (i.e., formalin model and the L5/L6 spinal nerve ligation model of neuropathic pain) using tests that differ in stimulus modality: noxious chemical stimulus (formalin model) as well as noxious (pin prick) and innocuous mechanical stimuli (application of von Frey filaments). Mexiletine (10-100 mg/kg, s.c.) significantly (P < 0.05) attenuated hyperalgesia in formalin-treated (60 mg/kg and 100 mg/kg) and neuropathic rats (100 mg/kg) as well as tactile allodynia in neuropathic rats (100 mg/kg). Desipramine (1-100 mg/kg, s.c.), on the other hand, reduced hyperalgesia significantly (P < 0.05) in formalin-treated (3, 10, 30 and 100 mg/kg) and neuropathic rats (10 mg/kg and 100 mg/kg), but did not reduce tactile allodynia in the neuropathic rats. Fluoxetine (3-30 mg/kg, s.c.) did not inhibit either hyperalgesia or allodynia in any of the tests employed. Fluoxetine, which is relatively ineffective in reducing neuropathic pain in humans, was also ineffective in reducing hyperalgesia and allodynia associated with central sensitization in rats. Thus, drugs which are effective in reducing human neuropathic pain consistently attenuated hyperalgesia in formalin-treated or neuropathic rats. Desipramine also distinguished mechanical hyperalgesia from tactile allodynia in rats rendered neuropathic by spinal nerve ligation. These data are consistent with the hypothesis that the neuronal mechanisms underlying these two manifestations of neuropathic pain are different.

Animals↗

PubMed2002

Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department.

Bupropion is a relatively new and popular medication with seizures as its major side effect. This drug can produce seizures with an overdose. The purpose of this investigation was to determine the relative importance of this medication as the etiology of new-onset seizures relative to other drugs and new-onset seizures in general. The study design was a retrospective case series. All new onset generalized seizures were evaluated over a 4-year period in subjects 16 years of age and older. Etiologic diagnosis was determined from the neurology consultation and all patients with new-onset seizures were admitted to the hospital as per hospital policy and received a routine chemistry screening and a neuroimaging study as a minimum. The results indicate that 17 of 279 or 6.1% of the new-onset seizures were drug related. After cocaine intoxication (6/279 or 2.2%) and benzodiazepine withdrawal (5/279 or 1.8%) seizures, bupropion (4/279 or 1.4%) was the third leading cause of drug related seizures. In addition, all the bupropion related seizures occurred in patients taking what was considered to be a therapeutic dose or 450 mg/day or less. Sleep deprivation, previous history of attention deficit disorder and bulimia, and previous heavy alcohol use were associated in three of the patients taking bupropion who had seizures. We conclude that although drug related new-onset seizures are not a common cause of seizures overall, bupropion might be a more common cause of drug related new-onset generalized seizures presenting to the Emergency Department than previously thought, occurring in more than one-fifth of this subgroup of cases. Possibly, greater exclusion criteria are needed than currently recommended for the use of bupropion at therapeutic doses.

Adult↗

PubMed1999

Metabolism and pharmacokinetics of selective serotonin reuptake inhibitors.

1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. 2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug-drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring. 3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.

Age Factors↗

PubMed1998

Response to high doses of citalopram in treatment-resistant obsessive-compulsive disorder.

We report a severe case of obsessive-compulsive disorder (OCD) that responded to very high doses of citalopram (160 mg/day) after a poor response to clomipramine 250 mg/day for several years, alone or in combination with buspirone 30 mg/day or flupenthixol 4 mg/day. The patient had previously been submitted for capsulotomy which was declined, probably due to the magical content of her obsessions, which resembled delusions.

Adult↗

PubMed1994

TRH gene products are implicated in the antidepressant mechanisms of seizures.

1. After a series of electroconvulsive seizures, levels of TRH-Gly (the immediate precursor of TRH) in four limbic regions correlate significantly and highly with increased swimming in the forced-swim test model of antidepressant efficacy. Only in hippocampus did TRH itself correlate with swimming. 2. After ECS, limbic forebrain regions differ in the relationship of TRH to its precursor peptides. This probably results from differences in the coordination of induction of TRH-processing enzymes, as well as differences in the level of prepro-TRH following seizures. 3. Sprague-Dawley rats that are partially kindled with corneal stimulation swim less in the forced-swim test, opposite to the effect seen with antidepressant agents. 4. Pyriform cortex is unique among the four limbic regions examined in showing decreased amounts of the TRH precursor following swim/stress. 5. Combining ECS with the forced-swim test of antidepressant effects creates a useful model for studying the involvement of TRH and its precursor peptides in both the antidepressant and anticonvulsant effects of controlled therapeutic seizures in the treatment of major depressive disorders. Regional differences between the effects of pinnate and corneal ECS on peptides and behavior support the idea that corneal ECS is a better model than pinnate ECS for human bitemporal ECT. 6. Together with recent results in other laboratories, our results suggest that a series of generalized seizures results in prolonged and increased release and action of TRH in limbic forebrain.

Animals↗

PubMed2002

Seed finding in golden hamsters: a potential animal model for screening anxiolytic drugs.

Fasting hamsters overnight, followed by temporary isolation in a novel environment are stressful conditions that hamper their ability or motivation to find hidden sunflower seeds when returned to their home environment. Studies were done to test whether treatment with antianxiety drugs would reduce stress and shorten the latency to find the hidden seeds. Prior to testing, the animals were fasted for 18-20 h. Ninety minutes after intraperitoneal injection of test drugs (fluoxetine, buspirone, chlordiazepoxide, clozapine, desipramine, yohimbine), the animals were taken from their home cage and placed into a novel holding cage for 2 min. During their absence, 6 sunflower seeds were buried under the bedding in one corner of their home cage. The animals were placed back into their home cage and timed for their latency to find the seeds in a 5-min observation period. Treatment with anxiolytics caused a dose-dependent reduction in the latency to find the sunflower seed, while treatment with other psychotherapeutics were ineffective. Seed finding is an extremely sensitive bioassay, responding to anxiolytics given in doses as low as 1 microg/kg. These data provide evidence that seed finding in hamsters may serve as an animal model for screening potential anxiolytic drugs.

Adrenergic alpha-Agonists↗