New goals in the treatment of depression: moving toward recovery

Depression is associated with marked suffering, morbidity, and high risk of recurrence and/or chronicity. As a result, the disorder represents a considerable public health problem and economic burden on society. Treatment of patients with depression to a state of remission is associated with a significantly improved long-term outcome, including a reduced risk of relapse and improved functioning. Thus, remission (which can be defined as attainment of a total score < or = 7 on the Hamilton Rating Scale for Depression) should be the goal of the acute phase of pharmacotherapy. Although it is widely assumed that available antidepressants are comparably effective, comparisons of the efficacy of antidepressants in clinical trials are flawed by a number of factors. Most notable problems are higher-than-expected placebo effects and low statistical power. Double-blind, comparative studies are also compromised by relatively high attrition rates and the often underestimated effects of patient nonadherence. Large study groups (in the order of 300 patients per treatment group) are needed to differentiate between a good and a potentially better antidepressant. The statistical technique of meta-analysis has been used to examine the results of studies of various antidepressants; these meta-analyses have shown that the selective serotonin reuptake inhibitors (SSRIs) have overall "within group" comparability and, overall, an efficacy profile comparable to the previous standard, tricyclic antidepressants (TCAs). However, in studies of hospitalized patients, TCAs affecting both serotonergic and noradrenergic systems (eg, amitriptyline or clomipramine) have been found to have greater efficacy when compared with SSRIs. Results of some individual studies, as well as a pooled analysis of the outcomes of more than 2,000 depressed patients, indicate that venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, may have a similar advantage relative to SSRIs across a broader range of patients. These findings suggest antidepressants that affect both serotonergic and noradrenergic neurotransmission may be more likely to accomplish the goal of remission. Compared with TCAs, the better safety profile of venlafaxine has established the drug as a more appropriate first-line treatment option.     

Panic Disorder—a Condition for Life? Treatment Issues

Panic disorder is a readily diagnosed, chronic condition which has received substantial attention since its recognition as a distinct condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III (American Psychiatric Association, 1980). Effective anti-panic therapy should show efficacy in reducing the frequency of panic attacks and associated symptomology, and be well tolerated. Benzodiazepines have a rapid onset of action, but have disadvantages of dependence and withdrawal problems and are thus less suitable for long-term use. Since depression occurs as a comorbid condition in 60 per cent of patients with panic disorder, the use of antidepressants is a logical choice. The first-generation monoamine oxidase inhibitors are little used in panic disorder, since they present a major problem of a potential hypertensive crisis, particularly when ingested with tyramine. Tricyclic antidepressants (TCAs), such as imipramine and clomipramine, are widely used and are effective but they are not well tolerated. The TCAs appear to exert their anti-panic effect via the serotonin reuptake pathway. Selective serotonin reuptake inhibitors (SSRIs) do not have anti-cholinergic effects or act on the noradrenergic system, thus there is a clear pharmacological rationale for believing that SSRIs should be as effective as TCAs in panic disorder and be better tolerated. Indeed, the SSRI paroxetine is as effective as clomipramine in panic disorder but has an improved tolerability profile; paroxetine is the only agent of its class licensed as a treatment for panic disorder. © 1997 John Wiley & Sons, Ltd.     

Cost effectiveness of representatives of three classes of antidepressants used in major depression in the UK

OBJECTIVE: To estimate the cost effectiveness of representatives of three different classes of antidepressants used in major depression in the UK NHS. DESIGN, PATIENTS AND INTERVENTIONS: A decision-tree model for the treatment of major depression was constructed by interviewing UK GPs and psychiatrists (as part of a Delphi panel). An important part of the tree was that patients in primary care were treated until remission (pre-morbid state). Three classes of antidepressants (serotonin and noradrenaline reuptake inhibitors [SNRIs; venlafaxine], selective serotonin reuptake inhibitors [SSRIs; fluoxetine, paroxetine and fluvoxamine] and tricyclic antidepressants [TCAs; amitriptyline]) were compared by populating the tree with clinical success rates determined by a meta-analysis and a clinical trial. Where there were insufficient data from clinical trials a Delphi panel was used. Costs within the tree were taken from UK data sources. Six-monthly costs and cost effectiveness were then calculated. MAIN OUTCOME MEASURES AND RESULTS: Treatment costs for 6 months were pound 1285 for venlafaxine, pound 1348 for SSRIs and pound 1385 for amitriptyline. Cost effectiveness as measured by cost per symptom-free day was pound 21 for venlafaxine, pound 26 for SSRIs and pound 32 for TCAs (2001 values). Incremental cost-effectiveness analyses showed a treatment strategy of using venlafaxine and switching if necessary to an SSRI was dominant over all other strategies considered. Sensitivity testing demonstrated that the cost of an SSRI could be reduced to 4 pence daily and amitriptyline to zero before the expected 6-monthly cost of venlafaxine ceased to be the lowest. CONCLUSION: The SNRI, venlafaxine, may be a cost-effective option compared with the SSRIs and TCAs when used as a first-line drug for depression in primary care in the UK. As this is a model, cost effectiveness can be suggested but not proven.     

Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are used to treat depression. Whereas cardiovascular effects have occasionally been reported during controlled studies with SSRIs, TCA treatment poses a well-known problem in this respect. To investigate the putative correlation between antidepressant dose or serum levels and adverse effects, the authors devised a naturalistic study to evaluate the tricyclic antidepressants' and SSRIs' effect on the cardiovascular system. The authors also compared antidepressant serum levels to adverse effects. Inpatients treated with TCAs or SSRIs were included; an electrocardiogram (ECG) and a Schellong test were carried out on the day patients entered the hospital and during steady-state treatment with antidepressant drugs when blood was drawn for therapeutic drug monitoring. The patient population consisted of 114 acutely depressed patients; 81 patients were treated with TCAs and 33 with SSRIs. The TCAs comprised amitriptyline (n = 43), clomipramine (n = 11), doxepin (n = 19) and imipramine (n = 8); the SSRIs comprised fluvoxamine (n = 14) and paroxetine (n = 19). In TCA-treated patients, the authors observed the same type of abnormalities in conduction and orthostatic hypotension as had been observed earlier. The authors also observed cases of first-degree atrioventricular block, prolonged QTc interval, and orthostatic hypotension in SSRI-treated patients. Thus SSRIs also appear to affect the cardiovascular system, which might pose a problem for patients with preexisting conduction disease. The authors observed a strong correlation between the decrease in systolic pressure and antidepressant serum concentration (except for clomipramine and paroxetine), suggesting that antidepressant serum level is a better correlate than dose.     

Severe depression: is there a best approach?

A major depressive episode can be categorised as severe based on depressive symptoms, scores on depression rating scales, the need for hospitalisation, depressive subtypes, functional capacity, level of suicidality and the impact that the depression has on the patient. Several biological, psychological and social factors, and the presence of comorbid psychiatric or medical illnesses, impact on depression severity. A number of factors are reported to influence outcome in severe depression, including duration of illness before treatment, severity of the index episode, treatment modality used, and dosage and duration of and compliance with treatment. Potential complications of untreated severe depression include suicide, self-mutilation and refusal to eat, and treatment resistance. Several antidepressants have been studied in the treatment of severe depression. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin 5-HT(2) receptor antagonists, monoamine oxidase inhibitors, and amfebutamone (bupropion). More recently, atypical antipsychotics have shown some utility in the management of severe and resistant depression. Data on the differential efficacy of TCAs versus SSRIs and the newer antidepressants in severe depression are mixed. Some studies have reported that TCAs are more efficacious than SSRIs; however, more recent studies have shown that TCAs and SSRIs have equivalent efficacy. There are reports that some of the newer antidepressants may be more effective than SSRIs in the treatment of severe depression, although the sample sizes in some of these studies were small. Combination therapy has been reported to be effective. The use of an SSRI-TCA combination, while somewhat controversial, may rapidly reduce depressive symptoms in some patients with severe depression. The combination of an antidepressant and an antipsychotic drug is promising and may be considered for severe depression with psychotic features. Although the role of cognitive behaviour therapy (CBT) in severe depression has not been adequately studied, a trial of CBT may be considered in severely depressed patients whose symptoms respond poorly to an adequate antidepressant trial, who are intolerant of antidepressants, have contraindications to pharmacotherapy, and who refuse medication or other somatic therapy. A combination of CBT and antidepressants may also be beneficial in some patients. Electroconvulsive therapy (ECT) may be indicated in severe psychotic depression, severe melancholic depression, resistant depression, and in patients intolerant of antidepressant medications and those with medical illnesses which contraindicate the use of antidepressants (e.g. renal, cardiac or hepatic disease).     

Safety and antidepressant efficacy of selective serotonin re-uptake inhibitors

This review deals with the safety and antidepressant efficacy of selective serotonin re-uptake inhibitors (SSRIs). At present, five SSRIs are used therapeutically in European countries (fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram). The antidepressant efficacy of these drugs has been tested both versus placebo and versus reference antidepressants (amitriptyline, imipramine) revealing comparable antidepressant efficacy to the active compounds and a significant superiority compared with placebo. Furthermore, the available studies provide initial evidence that SSRIs have good antidepressant efficacy in severe depression and suggest that they might lead to a faster decline of suicidal tendencies within major depression. Since they have a favourable side-effects profile in sum, compared with tri- and tetracyclic antidepressants, they can be recommended from the aspect of a ‘side-effects-derived indication’.     

Treatment of depression in comorbid medical illness

The rate of comorbid depression and medical illness varies from 10 to 40%. Over the years, there has been a paucity of studies completed despite the importance of knowing which antidepressants are the most effective and safest to use in comorbid states. In this review, focus is placed on disorders in these important areas: cardiovascular disease, neurological disorders, diabetes mellitus and cancer. Cardiovascular disease complications can be related in many cases to platelet clumping produced by medications; reductions in morbidity can be achieved by reducing platelet adhesiveness. Specific results have shown sertraline administration to be safe in the post myocardial infarction (MI) state. This is a time of depression-induced increases of 200 - 300% in mortality. Evidence for safe administration of bupropion, as well as the selective serotonin re-uptake inhibitors (SSRIs) fluoxetine and paroxetine, is also available. The appearance of major depression and diabetes mellitus has been successfully treated with fluoxetine, sertraline and nortriptyline (NTI) , however, NTI may lead to a worsening of glucose indices due to its noradrenergic specificity. Regarding neurologic disorders, there is controlled data showing the safety and efficacy of citalopram, sertraline and fluoxetine in post stroke depression. Parkinson’s disease has been associated frequently with depression, as might be expected from its characteristic dopamine deficient state. For perhaps the same reason, the agents that can block re-uptake of dopamine i.e., tricyclic antidepressants (TCAs), have been effective in comorbid depression with Parkinson’s disease. In dementia, there is a paucity of information on new agents. However, double-blind data seems to show efficacy for sertraline, paroxetine and citalopram. There are few studies of cancer-related depression treated in a controlled fashion with antidepressants; imipramine, amitriptyline, fluoxetine, paroxetine, mirtazapine and mianserin (not available in the USA) all have support from some published studies.     

Treatment of depression in comorbid medical illness

The rate of comorbid depression and medical illness varies from 10 to 40%. Over the years, there has been a paucity of studies completed despite the importance of knowing which antidepressants are the most effective and safest to use in comorbid states. In this review, focus is placed on disorders in these important areas: cardiovascular disease, neurological disorders, diabetes mellitus and cancer. Cardiovascular disease complications can be related in many cases to platelet clumping produced by medications; reductions in morbidity can be achieved by reducing platelet adhesiveness. Specific results have shown sertraline administration to be safe in the post myocardial infarction (MI) state. This is a time of depression-induced increases of 200-300% in mortality. Evidence for safe administration of bupropion, as well as the selective serotonin re-uptake inhibitors (SSRIs) fluoxetine and paroxetine, is also available. The appearance of major depression and diabetes mellitus has been successfully treated with fluoxetine, sertraline and nortriptyline (NTI), however, NTI may lead to a worsening of glucose indices due to its noradrenergic specificity. Regarding neurologic disorders, there is controlled data showing the safety and efficacy of citalopram, sertraline and fluoxetine in post stroke depression. Parkinson's disease has been associated frequently with depression, as might be expected from its characteristic dopamine deficient state. For perhaps the same reason, the agents that can block re-uptake of dopamine i.e., tricyclic antidepressants (TCAs), have been effective in comorborbid depression with Parkinson's disease. In dementia, there is a paucity of information on new agents. However, double-blind data seems to show efficacy for sertraline, paroxetine and citalopram. There are few studies of cancer-related depression treated in a controlled fashion with antidepressants; imipramine, amitriptyline, fluoxetine, paroxetine, mirtazapine and mianserin (not available in the USA) all have support from some published studies.     

Antidepressants and their effect on sleep

Given the relationship between sleep and depression, there is inevitably going to be an effect of antidepressants on sleep. Current evidence suggests that this effect depends on the class of antidepressant used and the dosage. The extent of variation between the effects of antidepressants and sleep may relate to their mechanism of action. This systematic review examines randomised-controlled trials (RCTs) that have reported the effect that antidepressants appear to have on sleep. RCTs are not restricted to depressed populations, since several studies provide useful information about the effects on sleep in other groups. Nevertheless, the distinction is made between those studies because the participant's health may influence the baseline sleep profiles and the effect of the antidepressant. Insomnia is often seen with monoamine oxidase inhibitors (MAOIs), with all tricyclic antidepressants (TCAs) except amitriptyline, and all selective serotonin reuptake inhibitors (SSRIs) with venlafaxine and moclobemide as well. Sedation has been reported with all TCAs except desipramine, with mirtazapine and nefazodone, the TCA-related maprotiline, trazodone and mianserin, and with all MAOIs. REM sleep suppression has been observed with all TCAs except trimipramine, but especially clomipramine, with all MAOIs and SSRIs and with venlafaxine, trazodone and bupropion. However, the effect on sleep varies between compounds within antidepressant classes, differences relating to the amount of sedative or alerting (insomnia) effects, changes to baseline sleep parameters, differences relating to REM sleep, and the degree of sleep-related side effects.     

Pharmacoeconomic analysis of antidepressants for major depressive disorder in the United Kingdom

OBJECTIVE: To estimate the cost effectiveness of different classes of antidepressants in the UK National Health Service. DESIGN, PATIENTS AND INTERVENTIONS: The use of the serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake inhibitor (SNRI) venlafaxine was compared with that of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in patients with major depressive disorder (MDD). A meta-analysis determined the clinical success rate, and a decision tree was constructed by interviewing general practitioners and psychiatrists. Adding pharmacological and nonpharmacological treatment costs, meta-analytic rates were applied to the decision tree to calculate the expected cost and outcome for each drug. Cost effectiveness was determined using a composite measure of outcome [symptom-free days (SFD)]. MAIN OUTCOME MEASURES AND RESULTS: The meta-analysis included data from 44 studies on 4033 patients. The highest overall efficacy rate for outpatients with MDD was with venlafaxine use (73.7%), compared with 61.4% for SSRIs and 59.3% for TCAs. Treatment with venlafaxine yielded the lowest outpatient cost for a SFD (10.53 Pounds), compared with 13.23 Pounds for SSRIs and 15.52 Pounds for TCAs (1998 values). CONCLUSIONS: Using this economic model, venlafaxine appears to be a cost-effective treatment for outpatients with MDD in the UK.     

Fluvoxamine: a selective serotonin re-uptake inhibitor for the treatment of obsessive-compulsive disorder

Fluvoxamine is the selective serotonin re-uptake inhibitor with the largest database in the treatment of obsessive-compulsive disorder, a severe, and often chronic, anxiety disorder associated with substantial impairment in functioning. The selective serotonin re-uptake inhibitors represent a first-line treatment in patients with obsessive-compulsive disorder. These agents work primarily by blocking the re-uptake of serotonin into the presynaptic nerve terminal, which is believed to be mediated by their effects on the serotonin transport system. In the last two decades, the anti-obsessional effect of fluvoxamine has been tested in several double-blind, placebo-controlled and active-comparison studies, demonstrating its superior efficacy over obsessions and compulsions compared with non-serotonergic antidepressants (i.e., desipramine) and equal efficacy to clomipramine (a tricyclic antidepressant with potent serotonin re-uptake inhibition) and other selective serotonin re-uptake inhibitors (paroxetine and citalopram). However, compared with clomipramine, the selective serotonin re-uptake inhibitor fluvoxamine showed fewer side effects and better tolerability. This reflects the poor affinity of this compound for adrenergic, muscarinic, cholinergic or histaminergic receptors.     

Fluvoxamine: a selective serotonin re-uptake inhibitor for the treatment of obsessive-compulsive disorder

Fluvoxamine is the selective serotonin re-uptake inhibitor with the largest database in the treatment of obsessive-compulsive disorder, a severe, and often chronic, anxiety disorder associated with substantial impairment in functioning. The selective serotonin re-uptake inhibitors represent a first-line treatment in patients with obsessive-compulsive disorder. These agents work primarily by blocking the re-uptake of serotonin into the presynaptic nerve terminal, which is believed to be mediated by their effects on the serotonin transport system. In the last two decades, the anti-obsessional effect of fluvoxamine has been tested in several double-blind, placebo-controlled and active-comparison studies, demonstrating its superior efficacy over obsessions and compulsions compared with non-serotonergic antidepressants (i.e., desipramine) and equal efficacy to clomipramine (a tricyclic antidepressant with potent serotonin re-uptake inhibition) and other selective serotonin re-uptake inhibitors (paroxetine and citalopram). However, compared with clomipramine, the selective serotonin re-uptake inhibitor fluvoxamine showed fewer side effects and better tolerability. This reflects the poor affinity of this compound for adrenergic, muscarinic, cholinergic or histaminergic receptors.     

Utility of selective serotonin reuptake inhibitors in premature ejaculation

The introduction of selective serotonin reuptake inhibitors (SSRIs) has revolutionized our understanding of the treatment of premature ejaculation. Lifelong premature ejaculation may be a neurobiological phenomenon, namely part of a biological variability of the intravaginal ejaculation latency time in men. Animal studies support this view, and an animal model for premature and delayed ejaculation has recently been developed. It is proposed that drug treatment of premature ejaculation should consist of 5-hydroxytryptamine (5-HT)2c receptor stimulation and/or 5-HT1A receptor inhibition. A meta-analysis of 35 daily treatment studies with selective serotonin reuptake inhibitors (SSRIs) and clomipramine demonstrated comparable efficacy of clomipramine with the SSRIs sertraline and fluoxetine in delaying ejaculation, whereas the efficacy of the SSRI paroxetine was greater than all other SSRIs and clomipramine. It is postulated that acute treatment with SSRIs, including those with short half-lives, will not produce an ejaculation delay equivalent to that induced by daily treatment of SSRIs.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Selective serotonin reuptake inhibitors (SSRIs) are now generally regarded as effective and better tolerated alternatives to tricyclic antidepressants (TCAs) for the treatment of depression. SSRIs also seem to be as well tolerated as moclobemide, mirtazapine, venlafaxine, reboxetine and nefazodone and show comparable efficacy. Minor differences have been observed between some SSRIs and some of the newer antidepressants but these findings are far from conclusive. Widespread use of the SSRIs has highlighted some unforseen adverse effects associated with SSRIs, namely hyponatraemia, EPSE and sexual dysfunction. Overall, differences in efficacy and tolerability between individual SSRIs are small and clinically insignificant.     

Critical flicker fusion threshold and anticholinergic effects of chronic antidepressant treatment in remitted depressives

The persistence of deficits in cognitive performance in major depressive patients taking maintenance antidepressant medication was assessed by examining groups of patients in clinical remission, stable on one of a range of tricyclics or selective serotonin re-uptake inhibitors (SSRIs) for at least 3 months, compared with controls. Measures of critical flicker fusion (CFF), choice reaction time (CRT), subjective sedation, and anticholinergic side-effect score were made. Tricyclic antidepressants (TCAs) produce a significant deficit in critical flicker fusion threshold compared both to controls and SSRIs. Similar effects were seen with choice reaction times which were significantly affected by age. Sedation scores were significantly higher with TCAs than SSRIs. Anticholinergic side effects were strongly related to CFF, less so to visual analogue sedating scales and not significantly to CRT. The effect measured by CFF is different from sedation, and may be related to the anticholinergic potency of the drug; it may be considered a drug-induced pseudodementia. This effect represents a risk factor for accidents during maintenance therapy and may impair work and leisure performance. The relative risk of weight gain with TCAs compared to SSRIs in women was 5.92 (95% CI 1.79-19.50).     

Milnacipran, a new specific serotonin and noradrenaline reuptake inhibitor

Milnacipran is a new antidepressant which inhibits equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo with no effect on dopamine reuptake. Microdialysis studies have shown increased extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor. In particular, and unlike tricyclic antidepressants (TCAs), it has no activity at noradrenergic, muscarinic or histaminergic receptors. Contrary to TCAs, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. Milnacipran has a high bioavailability, low plasma protein binding, and is largely eliminated in the urine as the parent drug or as a glucuronide. These features suggest that interactions with other drugs given concurrently are unlikely. Studies in patients with liver dysfunction and in the elderly suggest that dose adjustment is not necessary. In patients with renal impairment, decreased elimination of milnacipran is correlated to the degree of renal impairment allowing an easy dosage adjustment. An intermediate half-life of approximately 8 h is compatible with twice-daily administration. Clinical studies comparing milnacipran, placebo and other antidepressants provide evidence of its efficacy in moderate to severe depression in both hospitalized and outpatient settings. Meta-analyses of the original data of controlled trials comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs) show that milnacipran provides antidepressant efficacy similar to that of TCAs and significantly superior to that of SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of TCAs with notably less cholinergic side effects. The tolerance of milnacipran was comparable to that of SSRIs with a higher incidence of dysuria with milnacipran but a higher frequency of nausea and anxiety with the SSRIs. Milnacipran represents an interesting new therapeutic option in depression, being as well tolerated as the SSRIs but offering clinical efficacy similar to the TCAs.     

Clomipramine enhances the cortisol response to 5-HTP: implications for the therapeutic role of 5-HT2 receptors

We measured the cortisol response to the 5-HT precursor, 5–hydroxytryptophan, (5-HTP) in seven patients with major depression before and after 8 weeks treatment with the tricyclic antidepressant, clomipramine. The cortisol response to 5-HTP was significantly increased following clomipramine treatment, suggesting that clomipramine, like selective serotonin re-uptake inhibitors (SSRIs), enhances this 5-HT₂ receptor mediated response. Because other tricyclic antidepressants do not increase 5-HTP-mediated cortisol release, it seems unlikely that enhancement of 5-HT₂ receptor function is a critical mechanism for antidepressant action. However, facilitation of neurotransmission at 5-HT₂ receptors could account for the efficacy of clomipramine and SSRIs in the treatment of obsessive compulsive disorder and also for their liability to cause orgasmic dysfunction. Received: 20 May 1998/Final version: 5 July 1998     

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.     

The impact of tricyclic antidepressants and selective serotonin re-uptake inhibitors on handwriting movements of patients with depression

RATIONALE: Psychomotor retardation is a common symptom of patients with major depressive disorder. While a variety of clinical examinations using different techniques have been undertaken to assess the motor component of psychomotor retardation in depression, the effects of antidepressants on psychomotor functions have been examined less extensively. OBJECTIVE: The aim of the present study was to examine the effect of various pharmacological treatments on handwriting movements of patients with depression. METHODS: Kinematic data of automated handwriting movements of 18 depressed patients receiving tricyclic antidepressants (TCAs), 18 patients on selective serotonin re-uptake inhibitors (SSRIs) and 18 healthy subjects was recorded and analysed. Groups were matched according to age, sex, handedness and education level. For the assessment of fine motor movements, a digitising tablet was used. Subjects were asked to perform a simple writing task. Movement time, velocity and acceleration of the handwriting movements were measured. RESULTS: Statistical analysis of writing movements revealed motor slowing in patients receiving TCAs. In comparison with both healthy subjects and patients receiving SSRIs, the TCA group displayed an increased movement time, reduced automation of handwriting, lower maximum velocities and reduced acceleration of descending strokes. CONCLUSIONS: The results suggest either that TCAs have adverse effects on motor functioning or that they are less effective in the treatment of motor retardation than SSRIs.