Dose Of Venlafaxine Research Articles

Venlafaxine Treatment of Cocaine Abusers with Depressive Disorders

Objective: There appears to be a link between depression and cocaine that is both complex and elusive. The purpose of this study was to examine the effect of venlafaxine, a broad spectrum antidepressant, in the treatment of 13 patients who were diagnosed with cocaine dependence and comorbid major depressive disorder (MDD). Method: The majority of the patients in the study were part of a larger double-blind trial using desipramine. This subgroup consisted of people who had failed to respond to desipramine or could not tolerate its side effects. Thirteen patients were enrolled, 10 men and 3 women. Of the patients, 11 completed the 12-week study. All of the patients had a Hamilton Depression (HAM-D) score greater than 14 at baseline, and each had used at least $20 worth of cocaine per week in the 4 weeks prior to entering the study. In addition, all of the patients received weekly relapse prevention therapy throughout the study. The median dose of venlafaxine was 150 mg/day. Results: The 11 patients who completed the study had significant reductions in mood symptoms by the end of the study. The average total HAM-D score at baseline was 18.0 ± 3.2; at Week 2, it was 1.9 ± 0.94; and at the end of the study, it was 1.4 ± 1.8. The majority of patients reported reductions of cocaine use short of abstinence. All subjects reported a greater than 75% reduction in cocaine use compared to baseline. There were no serious side effects. Conclusions: The results of this small study indicate that venlafaxine may be a safe, well-tolerated, rapidly acting, and effective treatment for patients with a dual diagnosis of depression and cocaine dependence.

Efficacy and tolerability of venlafaxine in patients hospitalized with moderate to severe depression: an open-label pilot study

Among the latest generation of antidepressants, venlafaxine has been well characterized in terms of dosage, dose-response relationship, metabolic pattern, tolerability, and safety profile. The aim of this naturalistic open-label study was to contribute further information on the efficacy and tolerability of venlafaxine in patients hospitalized with moderate to severe depression. Twenty-three patients were included in the study; all patients underwent a complete assessment at baseline, on days 4, 7, and 14, and at discharge. At baseline, 2 semistructured clinical interviews for the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, were used for the diagnosis of axis I (mental) and II (personality) disorders. The primary efficacy variables were the mean changes from baseline in the total scores for the Hamilton Rating Scale for Depression, the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression Scale. Thirteen patients (56.5%) had recurrent major depression; for 5 patients (21.7%) this was their first episode. The remaining 5 patients (21.7%) had various bipolar disorders, mood disorder caused by a medical condition, or dysthymia. Twelve (52.2%) of the 23 patients had a personality disorder. The mean dose of venlafaxine was 68.5 ± 14.5 mg/d initially and 207.1 ± 52.9 at discharge. Patients also received a benzodiazepine (n = 11); a benzodiazepine and a neuroleptic (n = 7); a benzodiazepine and a mood stabilizer (n = 3); or a benzodiazepine, a neuroleptic, and a mood stabilizer (n = 2). Venlafaxine led to a significant reduction from baseline in all primary efficacy variables, beginning on day 4 and continuing to discharge. Venlafaxine appeared to have a rapid onset of action, although this finding could have been influenced by titration of the dose of venlafaxine more quickly than was recommended. Although this was an open-label study subject to various limitations, results indicated good efficacy and tolerability of venlafaxine in patients hospitalized with moderate to severe depression.

The antinociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms

The antinociceptive effects of the novel phentylethylamine antidepressant drug venlafaxine and its interaction with various opioid, noradrenaline and serotonin receptor subtypes were evaluated. When mice were tested with a hotplate analgesia meter, venlafaxine induced a dose-dependent antinociceptive effect following i.p. administration with an ED 50 of 46.7 mg/kg (20.5; 146.5; 95% CL). Opioid, adrenergic and serotoninergic receptor antagonists were tested for their ability to block venlafaxine antinociception. Venlafaxine-induced antinociception was significantly inhibited by naloxone, nor-BNI and naltrindole but not by β-FNA or naloxonazine, implying involvement of κ1- and δ-opioid mechanisms. When adrenergic and serotoninergic antagonists were used, yohimbine ( P<0.005) but not phentolamine or metergoline, decreased antinociception elicited by venlafaxine, implying a clear α 2- and a minor α 1-adrenergic mechanism of antinociception. When venlafaxine was administered together with various agonists of the opioid and α 2- receptor subtypes, it significantly potentiated antinociception mediated by κ1- κ3- and δ-opioid receptor subtypes. The α 2-adrenergic agonist clonidine significantly potentiated venlafaxine-mediated antinociception. Summing up these results, we conclude that the antinociceptive effect of venlafaxine is mainly influenced by the κ- and δ-opioid receptor subtypes combined with the α 2-adrenergic receptor. These results suggest a potential use of venlafaxine in the management of some pain syndromes. However, further research is needed in order to establish both the exact clinical indications and the effective doses of venlafaxine when prescribed for pain.

Safety and efficacy of high dose venlafaxine added to electroconvulsive therapy (ECT) in therapy-resistant depression

Cette étude est une évaluation clinique et cognitive des effets d’une Thérapie Comportementale et Cognitive de groupe chez des patients bipolaires I. Douze patients (4 hommes, 8 femmes) cliniquement en rémission au moment de l’évaluation ont participé à l’étude. La TCC de groupe a consisté en 20 séances hebdomadaires de 2 heures. Les patients ont été évalués avant et après traitement à l’aide d’échelles hétéro-évaluatives (Echelle de Dépression de Hamilton, Echelle de Manie de Bech et Rafaelsen, Echelle d’Anxiété de Hamilton), d’autoquestionnaires (Inventaire de Depression de Beck, Echelle d’Estime de Soi de Rosenberg, Echelle d’Attitudes Dysfonctionnelles de Weissman), et d’une tâche de rappel libre de mots à valence émotionnelle (positive, neutre et négative). Les résultats montrent que les patients ayant suivi une TCC de groupe selon le modèle de Lam marquent une préférence de rappel pour les mots positifs comparés aux mots négatifs. Les données métrologiques indiquent une tendance à une amélioration clinique, avec un niveau de dépression plus faible, une meilleure estime de soi et moins d’attitudes dysfonctionnelles. L’apprentissage de stratégies de coping comportementales et cognitives semblerait ainsi permettre une meilleure gestion émotionnelle et une meilleure inhibition du rappel des stimuli négatifs.The aim of this pilot study was the clinical and cognitive assessment of bipolar patients after cognitive and behavioural group therapy. Twelve outpatients were included and attended the 20 sessions of therapy according to Lam's model. The assessments were performed before and after therapy using scales and questionnaires: Hamilton's Depression Rating Scale, Hamilton's Anxiety Rating Scale, Beck's Depression Inventory, the Dysfunctional Attitude Scale, and a free recall task of emotional words (positive, neutral and negative).The results showed that after behavioural and cognitive therapy the patients recalled the positive words more easily rather than the negative words.The clinical assessment showed an improvement in: depression, self-esteem and dysfunctional attitudes. The patient who learned cognitive and behavioural strategies could cope with emotions and recall more positive information than recall the negative stimuli.

The Acute Effects of Monoamine Reuptake Inhibitors on the Stimulus Effects of Hallucinogens

In a previous study it was observed that fluoxetine potentiates the stimulus effects of lysergic acid diethylamide (LSD). In the present investigation, stimulus control was established in groups of rats using as training drugs the hallucinogens lysergic acid diethylamide (LSD); 0.1 mg/kg), (−)-2,5-dimethoxy-4-methylamphetamine [(−)-DOM; 0.56 mg/kg], ibogaine (10 mg/kg), and 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT; 3 mg/kg). A two-lever, fixed-ratio 10, positively reinforced task with saline controls was employed. The hypotheses tested were that (a) monoamine uptake inhibitors other than fluoxetine potentiate the discriminative effects of LSD, and (b) hallucinogens other than LSD are potentiated by acute pretreatment with monoamine uptake inhibitors. The effects of a range of doses of each of the training drugs were determined both alone and following pretreatment with the monoamine reuptake inhibitors fluoxetine, fluvoxamine, and venlafaxine. In LSD-trained subjects, all three reuptake inhibitors caused a significant increase in LSD-appropriate responding. Similar results were observed in rats trained with (−)-DOM and with ibogaine. In 5-MeO-DMT–trained subjects, only fluoxetine resulted in an enhancement of drug-appropriate responding. The reuptake inhibitors given alone elicited varying degrees of responses appropriate for the respective training drugs. For fluoxetine in rats trained with LSD and ibogaine, for venlafaxine in LSD trained, and for fluvoxamine in (−)-DOM trained, the degree of responding met our criterion for intermediate responding, i.e., significantly different from both training conditions. Subsequent experiments in (−)-DOM–trained subjects examined a range of doses of each of the reuptake inhibitors in combination with a fixed dose of ( −)-DOM (0.1 mg/kg), which alone yielded about 50% (−)-DOM–appropriate responding. With the exception of the point obtained with the highest dose of venlafaxine, all data were compatible with additivity of effects rather than true potentiation. In summary, the present data extend our previous observation of the augmentation of the stimulus effects of LSD by fluoxetine to include other hallucinogens. The mechanisms by which these interactions arise and possible differential effects of acute and chronic treatment remain to be established.

Effect of Venlafaxine on CYP1A2‐Dependent Pharmacokinetics and Metabolism of Caffeine

Venlafaxine is a clinically effective antidepressant. Caffeine is a metabolic probe for the quantitative measurement of CYP1A2 activity in vivo. This open-label study evaluated the effect of steady-state venlafaxine on CYP1A2-dependent metabolism, as measured by the pharmacokinetic disposition of caffeine, and urinary caffeine metabolite ratios (CMRs). Sixteen healthy subjects received 200 mg of caffeine orally before (Day 1) and after (Day 8) venlafaxine was titrated to steady-state (37.5 mg every 12 hours on Days 2-4, then 75 mg every 12 hours on Days 5-8). Samples were collected before and for 24 hours after caffeine dosing for the determination of caffeine in plasma and 1,7-dimethylxanthine, 3,7-dimethylxanthine, 1,7-dimethyluric acid (17U), 1-methylxanthine (1X) and 1-methyluric acid (1U), and 5-acetylamino-6-amino-3-methyluracil (AAMU) in urine. Blood samples were obtained before venlafaxine doses on Days 7 and 8 (morning dose only) for the determination of trough venlafaxine and O-desmethylvenlafaxine levels. Venlafaxine did not significantly alter the pharmacokinetics of caffeine and its metabolites. Plasma caffeine AUC was unchanged and remained within the bioequivalence criteria (90% confidence interval: 87.9%-102%) in the presence of venlafaxine. Urine metabolite data showed variable increases and decreases in the CMR [(AAMU + 1U + 1X)/17U] for individual subjects. However, the mean CMR was altered by < 10% in the presence of venlafaxine. This in vivo study demonstrated that venlafaxine did not alter the pharmacokinetic profile of caffeine and confirms in vitro data that venlafaxine does not inhibit CYP1A2 metabolism. Therefore, venlafaxine appears to have a relatively low potential for drug interactions based on CYP1A2 inhibition.

Experience with Venlafaxine (Efexor®) in adolescents with depressive disorders

Venlafaxine is a serotonin-noradrenaline reuptake inhibitor (SNRI) that has no affinity for muscarinic, adrenergic or histaminergic receptors. In short-term trials, the adverse effects that occurred more often with venlafaxine than with placebo included nausea, somnolence, dizziness, dry mouth, and sweating. Rapid titration of the dose of venlafaxine to higher levels appeared, not unexpectedly, to be associated with an increased incidence of side effects. Side effects that appeared to be dose related included insomnia, nausea and sexual dysfunction. The incidence of nausea and dizziness was highest during the first 2 or 3 weeks of therapy and decreased rapidly thereafter. Somnolence also decreased over time. At high doses blood pressure increases were reported in a small percent of patients on venlafaxine and antidepressant drugs but were uncommon at the venlafaxine dose of 75–150 mg daily. Studies with venlafaxine in healthy volunteers indicate a low potential for drug-drug interactions. Overdoses have been reported in 14 of 3,082 patients administered venlafaxine in clinical trials, and no deaths were reported among these patients. Overdoses of venlafaxine induced mainly drowsiness and lethargy.

Effect of venlafaxine on pineal melatonin and noradrenaline in the male rat.

Studies in vitro indicate that the antidepressant drug, venlafaxine (VEN), inhibits the reuptake of both serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) but has little activity on other neurotransmitter receptors. There are, however, few studies on the effects of VEN on monoamine neurotransmission in vivo. In the present study we examined the effect of VEN treatment on the melatonin content of the rat pineal gland because the synthesis of melatonin is regulated by the release of NA onto pinealocyte beta-adrenoceptors. Acute treatment with higher doses (15 mg/kg) of VEN significantly increased pineal melatonin and NA but this effect was attenuated by subchronic treatment. These data are consistent with in vitro data suggesting that VEN increases NA neurotransmission at higher doses and that repeated treatment can desensitize pinealocyte beta-adrenoceptors.

Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients

Pattern analysis has been used to distinguish between the true effect of an antidepressant and a placebo effect. The placebo effect constitutes clinical improvement that is attributable to the caregiver, treatment setting, or placebo substance. Pattern analysis allows identification of patients who have early persistent responses, delayed persistent responses, or no responses to a drug. In our study, we used this method to assess the onset and persistence of antidepressant activity of high daily doses of venlafaxine. Our analysis considered scores on the Global Improvement item of the Clinical Global Impressions scale for intent-to-treat patients in two double-masked, placebo-controlled studies of at least 6 weeks' duration. Dosages in both studies were rapidly titrated upward so patients received at least 200 mg/d within the first week of treatment. Improvement within the first 2 weeks was considered early, and improvement not followed by a relapse through the scheduled end of treatment was considered persistent. Significantly greater percentages of patients in the venlafaxine group (27% and 20% in study 1 and study 2, respectively) than in the placebo group (9% and 2%, respectively) had a clinically meaningful drug response within the first 2 weeks of treatment. This early response persisted for the duration of each trial. We concluded that venlafaxine in dosages of at least 200 mg/d demonstrates an early and persistent onset of efficacy compared with placebo.

Antidepressant efficacy and cardiovascular safety of venlafaxine in young vs old patients with comorbid medical disorders.

To determine whether venlafaxine exerts a differential effect on blood pressure in young versus old depressed patients. We compared thirty-four consecutive patients treated with 50-250 mg/day venlafaxine for major depressive disorder or another major mood disorder at our medical college's ambulatory neuropsychiatry program. We obtained baseline and follow-up blood pressure measurements. Each patient also received a baseline and final Clinical Global Impressions (CGI) score; global improvement was determined by consensus of two clinicians. Sixteen nongeriatric patients (age, 13 to 56 years) were compared with eighteen elderly patients (age, 65 to 86 years). Most patients (88%) had serious medical comorbidities or histories. Despite a higher mean daily venlafaxine dosage for patients in the young group, no significant changes in systolic blood pressure were noted in either group. For the older group, we found a non-statistically significant 4.7 mm Hg mean increase in diastolic blood pressure. No patient became hypertensive. We also found a negative correlation between baseline diastolic blood pressure and change in diastolic blood pressure during treatment with venlafaxine. This inverse relationship was statistically significant in the older patients. Venlafaxine was not associated with significant, sustained changes in blood pressure in any patient receiving dosages of 50-250 mg/day. Minimal changes in diastolic blood pressure were no more likely to occur in older venlafaxine-treated patients than in younger ones. Higher baseline diastolic blood pressure in older patients, but not in younger ones, seemed to protect against diastolic adrenergic blood pressure effects of venlafaxine.

Effects of venlafaxine in the sleep architecture of rats.

Different venlafaxine doses (1, 5, and 10 mg/kg) and saline solution were administered to ten male Wistar rats (Latin-Square design). Compared with saline, venlafaxine produced a dose-related suppression of REM sleep and an increase in wake time while slow wave sleep was reduced. This effect is similar to the one that has been reported with some tricyclic antidepressants.

Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers.

The purpose was to examine the effect of the antidepressant drug venlafaxine on sleep architecture and periodic leg movements of sleep (PLMS) in normal volunteers. Eight normal volunteers were studied under laboratory sleep conditions as follows: 1 acclimatization night, 1 baseline night, and 4 consecutive nights of venlafaxine p.o. administration (75 mg during the first 2 nights and 150 mg the last 2 nights). Venlafaxine increased both wake time and sleep stage I. Sleep stages II and III were reduced. REM sleep time was reduced after the first venlafaxine dose, and, by the fourth night, REM sleep was completely suppressed in all volunteers. Six of the eight volunteers showed PLMS at a frequency above 25 per hour. Venlafaxine produces several sleep disturbances, which include abnormal leg movements.

Antidepressant use in the elderly. Current status of nefazodone, venlafaxine and moclobemide.

Depression is a significant problem in the elderly. Because of aging-related pharmacokinetic and pharmacodynamic changes, it is not possible to automatically extrapolate findings on the efficacy or tolerability of antidepressants from younger to older populations. Venlafaxine inhibits both noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake. Analysis of data from phase II and III trials showed that venlafaxine was comparably effective in the young and in a subset of over 350 elderly patients. Venlafaxine dosage needs to be lowered in the elderly with renal impairment. As a weak cytochrome P450 (CYP) inhibitor, it is unlikely to have clinically significant drug interactions. Venlafaxine may be associated with some increase in supine diastolic blood pressure, especially at dosages above 150 mg/day. Nefazodone is a serotonin uptake inhibitor and serotonin 5-HT2A receptor antagonist. Pooled analysis of about 250 patients found nefazodone to be effective in elderly individuals with moderate or severe depressive symptoms, with or without melancholia, in both primary and recurrent episodes. Nefazodone clearance is reduced in patients with hepatic impairment, and plasma concentrations have been reported to be higher in the elderly. Nefazodone is an inhibitor of the CYP3A4 family. There does not appear to be any increase in the frequency or severity of adverse effects in the elderly. Moclobemide is a selective inhibitor of monoamine oxidase type A. Studies in the elderly have found it to be well tolerated and meta-analysis has shown it to be comparably effective in young and elderly populations, and comparable to other antidepressants in terms of efficacy. Neither age nor renal impairment necessitate dosage adjustment, but hepatic impairment does necessitate dosage reduction. Dietary restrictions are not required. Overall, there is a relative paucity of data on the tolerability and efficacy of newer antidepressants in the elderly, especially those with concomitant medical disorders. Data that are available indicate that venlafaxine, nefazodone and moclobemide have comparable efficacy in older and younger patients.

A RANDOMISED, DOUBLE‐BLIND, PARALLEL‐GROUP COMPARISON OF VENLAFAXINE AND DOTHIEPIN IN GERIATRIC PATIENTS WITH MAJOR DEPRESSION

SUMMARYThis randomised, double‐blind study conducted at nine sites in the UK and the Netherlands compared the safety and antidepressant efficacy of venlafaxine and dothiepin. Ninety‐two geriatric patients (aged 64‐87 years) with major depression were randomly assigned to receive either venlafaxine or dothiepin for up to 43 days. The dose of venlafaxine or dothiepin was titrated up to a maximum of 150 mg per day for the first 15 days, and thereafter could range from 50 to 150 mg per day. Adjusted mean scores on the MADRS and the HAM‐D decreased significantly (p 0.05) from baseline to the end of the study in both groups. A response to therapy was observed in 60% of patients in the venlafaxine group and 53% of patients in the dothiepin group on the MADRS, and in 60% of patients in both groups on the HAM‐D. Suicidal ideation scores on the MADRS were significantly (p=0.042) lower in the venlafaxine group at week 6. Treatment‐emergent study events were the primary reason for withdrawal in only 7% of venlafaxine‐treated patients and 8% of dothiepin‐treated patients. The results confirm the efficacy and tolerability of venlafaxine for treating major depression in the elderly.

A review of the efficacy and tolerability of venlafaxine

Venlafaxine is a selective serotonin norepinephrine reuptake inhibitor with no activity at muscarinic, histaminergic or adrenergic receptors. The antidepressant activity of venlafaxine has been demonstrated in placebo-controlled and active comparator-controlled clinical trials. Venlafaxine was effective in outpatients and hospitalized patients with major depression and in those with melancholia, agitated or retarded symptoms, and refractory or treatment-resistant depression. Venlafaxine was at least as effective as comparative antidepressants and was more effective than fluoxetine or imipramine in some trials. A positive dose-response relationship has been shown with venlafaxine. When doses of venlafaxine are titrated rapidly upward, an onset of antidepressant action has been detected within one week in some studies. Venlafaxine is well tolerated during short- and long-term treatment. The most common adverse effects are nausea, somnolence and dry mouth. The overall tolerability of venlafaxine appears to exceed that of tricyclic antidepressants and compares favorably with that of selective serotonin reuptake inhibitors. Venlafaxine is a novel antidepressant that is appropriate for first-line therapy in patients with major depression.

Neurobiologic basis of antidepressant safety profiles

Venlafaxine is a serotonin-noradrenaline reuptake inhibitor (SNRI) that has no affinity for muscarinic, adrenergic or histaminergic receptors. In short-term trials, the adverse effects that occurred more often with venlafaxine than with placebo included nausea, somnolence, dizziness, dry mouth, and sweating. Rapid titration of the dose of venlafaxine to higher levels appeared, not unexpectedly, to be associated with an increased incidence of side effects. Side effects that appeared to be dose related included insomnia, nausea and sexual dysfunction. The incidence of nausea and dizziness was highest during the first 2 or 3 weeks of therapy and decreased rapidly thereafter. Somnolence also decreased over time. At high doses blood pressure increases were reported in a small percent of patients on venlafaxine and antidepressant drugs but were uncommon at the venlafaxine dose of 75-150 mg daily. Studies with venlafaxine in healthy volunteers indicate a low potential for drug-drug interactions. Overdoses have been reported in 14 of 3,082 patients administered venlafaxine in clinical trials, and no deaths were reported among these patients. Overdoses of venlafaxine induced mainly drowsiness and lethargy.

Venlafaxine:a novel antidepressant compound

Venlafaxine is a new antidepressant that inhibits the reuptake of both 5-hydroxytryptamine (serotonin; 5-HT) and noradrenaline (NA). It is somewhat more potent as an inhibitor of the reuptake of 5-HT than NA. Its potency to inhibit the reuptake of 5-HT is comparable to that of tricyclic antidepressants (TCAs) such as amitriptyline or imipramine, but it is less potent than these drugs at inhibiting the reuptake of NA. Consequently, at low doses, venlafaxine may be a more effective inhibitor of the reuptake of 5-HT than that of NA. The major metabolite of venlafaxine in humans, O-desmethylvenlafaxine, has comparable potency to the parent drug for inhibiting the reuptake of either NA or 5-HT in vitro, but it is less potent in vivo. Both venlafaxine and O-desmethylvenlafaxine are essentially devoid of activity at muscarinic cholinergic, H1 histaminergic, and 1-adrenoceptors. This probably accounts for venlafaxine having a side-effect profile similar to that of selective serotonin reuptake inhibitors (SSRIs) rather than that of TCAs. Venlafaxine is subject to extensive first-pass metabolism and is metabolised by the cytochrome P450 isoenzyme IID6 in the liver. The half-life of venlafaxine is 3 - 4 h and that of its principal metabolite is about 10 h. The daily dose of venlafaxine can be administered as either two or three divided doses without altering significantly the pharmacokinetics of venlafaxine. The most common side-effects of venlafaxine are nausea, sedation, dizziness, dry mouth and sweating, as well as sexual dysfunctions, primarily problems with erection and delayed ejaculation. In some patients, venlafaxine also causes sustained elevations in both systolic and diastolic blood pressure; this effect is dose-dependent. Venlafaxine is much safer in overdosage than the TCAs. Antidepressant efficacy of venlafaxine has been found both in out-patients and in-patients. In general, its efficacy is comparable to that of comparator drugs (primarily TCAs or SSRIs), and in some cases even greater, and its efficacy is greater than that measured with placebo.

Clinical measures of rapid onset of action

The benefits of an antidepressant with an early or rapid onset of action include a more rapid resolution of the debilitating symptoms of depression, a potential reduction in the risk of suicide and cost savings associated with a reduction in hospitalization. While these benefits are valuable, this promise has yet to be fulfilled by any antidepressant. Venlafaxine is a unique serotoninnoradrenaline reuptake inhibitor (SNRI) which produces rapid and prolonged desensitization of beta-adrenergic receptors in preclinical studies after both acute and chronic administration of venlafaxine. Results from placebo-controlled and active comparator clinical studies provide evidence that venlafaxine may have an early onset of activity which is most apparent at higher dosages. The early onset is most apparent with rapid escalation of the venlafaxine dosage, and the incidence, therefore, of side effects tends to be higher early after initiating therapy with venlafaxine. Thus, venlafaxine may fill the long awaited need for an antidepressant with an early onset of action.

A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia

A double-blind, randomized, parallel study in 167 hospitalized patients with major depression and melancholia was conducted to determine if rapidly escalated doses of venlafaxine produced an earlier response, compared with rapidly escalated doses of imipramine. The daily dose of venlafaxine was rapidly increased to 375 mg/day over a five-day period, was maintained at this level for 10 days, and then was reduced to 150 mg/day for the remainder of the study. The imipramine dose was rapidly increased to 200 mg/day over five days and was maintained at this level to the end of the study. The primary efficacy variables were time to response and time to sustained response on the HAM-D and MADRS. No differences in the response rates on the HAM-D or MADRS were observed between treatments. However, among patients who demonstrated a response on the HAM-D, there was a significantly faster onset of response (p = 0.036) and sustained response (p = 0.018) in the venlafaxine group. The median time to response on the HAM-D among responders was 14 days with venlafaxine and 21 days with imipramine. However, no differences between treatments were observed among responders on the MADRS (median time to response: 15 days for venlafaxine, 18 days for imipramine). Study events were reported in 69% of venlafaxine-treated patients and 76% of imipramine-treated patients. In severely depressed patients with melancholia, a faster onset of response was observed with venlafaxine on the HAM-D, but not the MADRS, and maximal tolerated doses of venlafaxine and imipramine were comparable for overall efficacy. These results confirm and extend previous observations and suggest that venlafaxine may have an early onset of action and may produce a rapid response in hospitalized patients with severe depression complicated by melancholia.

Venlafaxine in Obsessive-compulsive Disorder-Reply

In Reply Yaryura-Tobias and Neziroglu have thoughtfully presented their experience with a small, double-blind, placebo-controlled trial of venlafaxine as a treatment for OCD. They note trends toward efficacy and suggest that the failure to find statistically significant differences is related to the short duration of their trial (8 weeks) and low doses of venlafaxine hydrochloride (225 mg/d, maximum dose). They are correct that a longer duration of treatment would be needed to conclude that venlafaxine was ineffective as a treatment for OCD, as most potent serotonin-reuptake inhibitors studied to date have showed continued improvement beyond 8 weeks. Whether higher doses of venlafaxine are needed is less clear, and their assertion that mean daily doses of fluoxetine and sertraline were or near the manufacturers' recommended maximum for treating patients who have depression is inaccurate. Both fluoxetine and sertraline were effective at low doses (20 and 50 mg/d, respectively) and exhibited a flat