Antidepressant Compounds Research Articles

Inhibition of Synaptosomal Uptake of 3H-L-glutamate and 3H-GABA by Hyperforin, a Major Constituent of St. John's Wort The Role of Amiloride Sensitive Sodium Conductive Pathways

Extracts of St. John's Wort are widely used for the treatment of depressive disorders. The active principles have not yet been finally elucidated. We have recently shown that hyperforin, a major active constituent of St. John's Wort, not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine, but also that of L-glutamate and GABA. No other antidepressant compound exhibits a similar broad uptake inhibiting profile. To investigate this unique kind of property, kinetic analyses were performed regarding the uptake of 3H-L-glutamate and 3H-GABA into synaptosomal preparations of mouse brain. Michaelis-Menten kinetics revealed a reduction of Vmax (8.27 to 1.80 pmol/mg/min for 3H-L-glutamate, 2.76 to 0.77 pmol/mg/min for 3H-GABA) while Km was nearly unchanged in both cases, suggesting non-competitive inhibition. The unselective uptake inhibition by hyperforin could be mimicked by the Na+-ionophore monensin and by the Na+-K+-ATPase inhibitor ouabain. However, both mechanisms can be discarded for hyperforin. Several amiloride derivatives known to affect sodium conductance significantly enhance 3H-GABA and 3H-L-glutamate uptake and inhibit the uptake inhibition by hyperforin, while monensin or ouabain inhibition were not influenced. Selective concentrations of benzamil for amiloride sensitive Na+-channels and selective concentrations of 5'-ethylisopropylamiloride (EIPA) for the Na+-H+-exchangers both had an attenuating effect on the hyperforin inhibition of L-glutamate uptake, suggesting a possible role of amiloride sensitive Na+-channels and Na+-H+-exchangers in the mechanism of action of hyperforin.

Effect of Tricyclic Antidepressants on Taste Responses in Humans and Gerbils

One of the side effects of antidepressant pharmacotherapy reported clinically is impairment of the sense of taste. In this study, the taste effects of four tricyclic antidepressant compounds (clomipramine HCl, desipramine HCl, doxepin HCl, and imipramine HCl) were evaluated experimentally by topical application of the drugs to the tongue. Taste detection threshold concentrations for all four medications ranged from 0.1 mM to 0.2 mM in young persons but were elevated by as much as 7.71 times that in elderly individuals who were taking no concurrent medications. Each compound had a predominantly bitter taste with other qualities including metallic, sour, and sharp-pungent. In addition, each tricyclic antidepressant at concentrations from 1 mM to 5 mM blocked responses to a wide range of taste stimuli in both humans and gerbils. The differential suppression of other tastes by tricyclic antidepressants at the level of the taste receptors may contribute to the clinical reports of dysgeusia and hypogeusia.

Potential treatment for subthreshold and mild depression: A comparison of St. John's wort extracts and fluoxetine

Subthreshold depressive disturbances and depressive episodes of mild severity are frequently associated with disability and socioeconomic burden, and often show an increase in symptomatology over time if untreated. Thus, there is an urgent need for antidepressant active compounds that are more readily available than those that must be obtained by prescription. To get an impression of the efficacy of the widely used phytopharmaceutical St. John's wort, the antidepressant efficacy in mild depressive disorders was compared with that of the standard antidepressant fluoxetine. The present overview includes controlled trials of fluoxetine in depression with a mean initial score on the Hamilton Rating Scale for Depression (HAM-D) < or =24, which were compared to the respective studies on St. John's wort. The mean HAM-D reduction of all St. John's wort studies was 10.2 (52.9%), and the respective figures for fluoxetine were 12.5 points and 55.5%. Thus, no relevant efficacy difference between the groups of investigations was found based on the studies included. The most important restrictions of this overview are no meta-analysis was performed, the studies were performed with heterogeneous methodological standards, and the St. John's wort extracts used were very different. However, St. John's wort might be a treatment option to reduce symptoms in patients not suffering from full-blown depressive disorder.

Prolonged c-Jun expression in the basolateral amygdala following bulbectomy: possible implications for antidepressant activity and time of onset

Olfactory bulbectomy is a well established animal model of depression. Neurochemical and behavioral alterations observed following olfactory bulbectomy, are due, in part, to the neurodegeneration of specific brain structures. Amygdaloid dysfunction in particular, is known to play a substantial role in the syndrome of the olfactory bulbectomized rat. The present study examined both short- and long-term alterations in immediate early gene expression, tyrosine hydroxylase and serotonin immunoreactivity, and classical silver staining, following olfactory bulbectomy in the basolateral amygdala. The results indicated no consistent change in Fos expression observed over the experimental period. Following bulbectomy, long term (up to 64 days post-lesion) Jun expression, not coincident with silver staining, was observed in the basolateral nucleus. The basolateral nucleus was also intensely immunoreactive for serotonin at this timepoint post-bulbectomy. Thus, following bulbectomy long term alterations in Jun expression occurs in the serotonin rich basolateral amygdala. As a site of action for antidepressant compounds, alterations at the immediate early gene level in this region may have implications both for the model, and antidepressant drug action therein.

Strain Differences in the Behavioral Effects of Antidepressant Drugs in the Rat Forced Swimming Test

Wistar–Kyoto (WKY) rats provide a model of stress-induced depressive behavior, because they show enhanced vulnerability to the effects of stressors. The present study examined differences in the behavioral response to different types of antidepressant drugs between WKY and Sprague–Dawley (SD) rats in the forced swimming test (FST). WKY rats displayed significantly greater immobility than SD rats during their exposure to the FST. The noradrenergic antidepressant, desipramine, produced a dose-dependent reduction of immobility and increase of climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at a lower dose and produced increases of both swimming and climbing behavior. The serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent reductions of immobility and increases of swimming behavior in the FST in SD rats, but the response to the serotonergic drugs were blunted in WKY rats. These results indicate that genetic or constitutive differences may determine the distinct behavioral profiles for antidepressant compounds with selective pharmacological effects in different rat strains, and these effects may be related to genetic heterogeneity of antidepressant responses in depressed patients.

Behavioural consequences of repeated social defeat in the mouse: preliminary evaluation of a potential animal model of depression.

The behavioural consequences of repeated social defeat, coupled with the stress of continuously living opposite a dominant animal, were assessed in male NMRI mice. The method adopted here differed from the previously published techniques in that the physical element of the social defeat procedure was reduced to a minimum. The subordinate animals consistently weighed less than control animals, and displayed a reduced number of visits to the partition compared to the dominant animals, which has previously been used as a marker of social behaviour. The subordinate animals did not show any differences in the amount of ethanol solution consumed compared to controls, and did not display an increase in immobility time measured in the forced swimming test. The subordinate animals did, however, display anxiogenic-like behaviour as indicated by an increased aversion of the light section of the black/white test box, which was partially reversed by chronic treatment (3weeks; 20mg/kg/day) with the antidepressant, citalopram. Decreased exploration by the subordinate animals in the black/white test box was also observed, which was reversed by chronic citalopram treatment. It is suggested that, whilst the model requires further validation, it may be a useful approach for the study of antidepressant compounds.

Are antidepressants all the same? Surveying the opinions of Australian psychiatrists.

Controlled trials do not suggest differences in efficacy between antidepressant compounds. Psychiatrists, however, frequently express the view that real differences do exist and are relevant to clinical practice. Since multiple comparative trials are not feasible, an alternative method for expanding the evidence base is to survey regularly the opinions of practising psychiatrists. Two surveys of psychiatrists' opinions were conducted. Participants in the first survey were drawn from contact with 'SPHERE: A National Depression Project', while those in the second survey responded to a brief questionnaire distributed with Australasian Psychiatry. Reported volumes of scripts written, ratings of efficacy and tolerability, and preferences in specific clinical situations indicate that clinical psychiatrists now strongly prefer the newer antidepressant agents. They rate serotonin and noradrenalin re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs) highest for antidepressant efficacy, serotonin receptor subtype 2 (5HT2) antagonists and some SSRIs highest for anti-anxiety efficacy, and some SSRIs and reversible inhibitors of monoamine oxidase inhibitor-A (RIMAs) lowest for side-effect burden. Further, SSRIs were their first preferences for most clinical situations. Serotonin and noradrenalin re-uptake inhibitors were the preferred choice for treatment-resistant depression and patients who had failed to respond to one SSRI. Serotonin receptor subtype 2 antagonists were the second choice to SSRIs for mixed anxiety and depression, and major depression with sleep disturbance. Reversible inhibitors of monoamine oxidase inhibitor-A were the second choice to SSRIs for adolescents with major depression, patients aged over 65 years, patients with serious medical illnesses and patients with chronic fatigue. Tricyclic antidepressants (TCAs) were the preferred choice for patients with chronic pain, and second choice to SSRIs for patients with major depression with panic disorder, postnatal disorders and patients with psychotic depression. Psychiatrists believe that important differences do exist between available antidepressant compounds. Such opinions are divergent from limited controlled data but may be influenced by a wide range of factors other than direct clinical experience. The role of such surveys in ongoing evaluation of clinical practice is emphasised.

Do α 2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. α-Adrenoceptors play an important role in pain processing and α 2-adrenoceptor agonists have been used in clinical pain management so we have investigated whether α-adrenoceptor sub-types mediate the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following α 1- or α 2-adrenoceptor antagonism. The antidepressants or monoamine reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin–noradrenaline reuptake inhibitor sibutramine, the resolved (+)- and (−)-enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline and dothiepin. All these compounds have been previously shown to be antinociceptive in this paradigm. The respective α 1- and α 2-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not produce antinociception though at 1.0 mg kg −1; s.c., RX821002 but not prazosin blocked clonidine antinociception. The antinociceptive activity produced by sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, (+)- and (−)-oxaprotiline were all blocked by RX821002 but not by prazosin. Additionally, both morphine and aspirin antinociception was resistant to α 1- and α 2-adrenoceptor antagonism. Thus, α 2- rather than α 1-adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia.

Development and validation of a new high-performance liquid chromatographic assay of centpropazine, a new antidepressant compound, in serum

Centpropazine is a new anti-depressant compound developed by Central Drug Research Institute, Lucknow (India). We report here the development and validation of a new HPLC assay of a parent drug in the serum of humans, monkeys and rats for pharmacokinetic studies. Centpropazine was eluted on a C 18 column with a mobile phase consisting acetonitrile–phosphate buffer (60:40) pumped at 1.5 ml min −1 flow rate and quantitated by UV detector at 270 nm. Considering the sample volume available from different species and to enhance the sensitivity of assay, three sample clean up methods requiring 0.05, 0.5 and 4 ml serum for a linear quantitation range of 312.5 ng ml −1–5 μg ml −1, 0.04–2.5 μg ml −1 and 2.5–80 ng ml −1 respectively were developed. The lowest limit of quantitation of the method was 2.5 ng ml −1 requiring 4 ml serum, 40 ng ml −1 requiring 0.5 ml serum and 312 ng ml −1 requiring 50 μl serum sample. All these methods were fully validated in human serum and extended to monkey and rat serum. The recovery of centpropazine at 5, 80, 625, 1280 and 2500 ng ml −1 ranged between 92 and 105%. The within and between run variability in precision and accuracy were less than 10% and the drug in serum was stable up to three freeze-thaw cycles. Overall the method is simple, quick and robust for biopharmaceutical applications. The method was applied to analyse concentrations of centpropazine in rat serum after administering single 20 mg kg −1 peroral and 5 mg kg −1 iv dose. The chromatograms of treated rat serum exhibited three well resolved peaks of metabolites and one of them was identified as hydroxy-metabolite of centpropazine.

Neuroleptic and antidepressant tricyclic compounds: Theoretical study for predicting their biological activity by semiempirical, density functional, and Hartree–Fock methods

The biological activity as antidepressants and/or neuroleptic of tricyclic compounds is investigated by molecular structure calculations. These calculations were carried out with semiempirical, local spin density, and Hartree–Fock methods. Using the computed highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy values, together with their atomic orbital conformation, we have been able to establish a trend to predict the possible biological activity (BA) of tricyclic compounds. We have found that qualitatively it is possible to use any of the applied theoretical methods to obtain a trend for biological activity prediction. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 71: 415–432, 1999

Neuroleptic and antidepressant tricyclic compounds: Theoretical study for predicting their biological activity by semiempirical, density functional, and Hartree-Fock methods

The biological activity as antidepressants and/or neuroleptic of tricyclic compounds is investigated by molecular structure calculations. These calculations were carried out with semiempirical, local spin density, and Hartree–Fock methods. Using the computed highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy values, together with their atomic orbital conformation, we have been able to establish a trend to predict the possible biological activity (BA) of tricyclic compounds. We have found that qualitatively it is possible to use any of the applied theoretical methods to obtain a trend for biological activity prediction. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 71: 415–432, 1999

Effects of Antidepressant Drugs on Sleep EEG in Patients with Major Depression

The ability of many antidepressant drugs to decrease rapid eye movement (REM) sleep can be attributed to facilitation of noradrenergic and/or serotonergic function or to muscarinic cholinergic blockade. A common characteristic of antidepressant compounds devoid of a clear REM suppressant effect, such as amineptine, buspirone, iprindole, nefazodone, tianeptine, trazodone and trimipramine, is their weak (or absent) ability to inhibit serotonergic uptake. In this regard, some preliminary results suggest that serotonin (5-hydroxytryptamine; 5-HT) may inhibit REM sleep via post-synaptic serotonin 5-HT1A receptors.

Noradrenaline (Norepinephrine) and Depression

In the pharmacological treatment of depression the focus has recently shifted from serotonin (5-hydroxytryptamine; 5-HT) to noradrenaline (norepinephrine), with the advent of new antidepressants such as noradrenaline reuptake inhibitors, noradrenergic and selective serotonergic antidepressants, and serotonin/noradrenaline reuptake inhibitors. It has been suggested that noradrenergic compounds may prove to have beneficial activity in those depressions that are characterised by a ‘noradrenergic deficiency syndrome’, which is clinically manifested through emotional withdrawal, psychomotor retardation, as well as concentration and memory deficits. The role of noradrenergic mechanisms in the aetiology of depression has been assumed since the catecholamine hypothesis, based on the inhibitory action of tricyclic antidepressants and monoamine oxidase inhibitors on noradrenaline uptake, was formulated. In this article, the aetiological significance of noradrenaline in depression is discussed with regard to the anatomical basis of the noradrenergic system (the locus caeruleus), noradrenaline metabolites, noradrenergic receptors, some aspects of thyroid function and the hypothalamic-pituitary-adrenal axis. The efficacy and tolerability profiles of new antidepressant compounds reboxetine, milnacipran, mirtazapine and venlafaxine are discussed in view of their noradrenergic activity.

Facile Synthesis of 5,6-Dimethoxy-1-tetralone

A facile synthesis of 5,6-dimethoxy-1-tetralone, a key intermediate in the synthesis of an antidepressant compound, ABT-200, was developed from the inexpensive starting material guaiacol.

Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.

Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.

Quantitative Determination of Tricyclic Antidepressants and Their Metabolites in Plasma by Solid-Phase Extraction (Bond-Elut TCA) and Separation by Capillary Gas Chromatography With Nitrogen-Phosphorous Detection

An analytical method for the simultaneous determination of amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, and desmethylclomipramine in human plasma using promazine as internal standard is described. The method is based on a solid-phase extraction procedure using the Bond-Elut TCA columns followed by separation and detection using capillary gas chromatography with a specific nitrogen phosphorous detector (GC/NPD). Using the new extraction procedure, the problem of adsorption losses was overcome, and good recoveries were achieved for all compounds tested (>87%). Furthermore, clean extracts free of chromatographic interferences were obtained. Complete separation of underivatized, tricyclic antidepressant compounds was achieved in <11 minutes with reliable chromatographic performance. The limits of detection ranged from 1.2 to 5.8 microg/l. Calibration curves, showing good linearity, were prepared covering the therapeutic concentrations range expected (20 to 500 microg/l). The interassay precision values (RSD) ranged from 4.5% to 9.8%. It is concluded that extraction of amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, and desmethylclomipramine, with Bond Elut TCA solid-phase columns followed by their detection using GC/NPD provides a sensitive and reproducible method that can be easily automated for immediate and routine analysis of clinical samples.

Safety of mirtazapine in overdose.

We report 6 confirmed cases of substantial overdose with mirtazapine, a new antidepressant compound, that occurred up to January 1997 in the United States during postmarketing surveillance or in the clinical trials. In 6 patients, the mirtazapine doses ranged from 10 to 30 times the maximum recommended dose, and there were no serious adverse effects of overdose. Two patients at special risk, a 90-year-old man and a 3-year-old child, took higher-than-usual doses without serious sequelae. The 4 patients who combined other central nervous system (CNS) depressants with mirtazapine appeared to experience more CNS depression. One patient who ingested 60 mg of alprazolam had clinically significant respiratory depression in the emergency room but recovered fully within 24 hours. After an overdose of substantial multiples of mirtazapine that exceed the maximum recommended daily dosage, the new antidepressant mirtazapine appears to be safe in a limited number of cases.

ANXIOLYTIC AND ANTIDEPRESSANT PROPERTIES OF METHYLENE BLUE IN ANIMAL MODELS

Methylene blue (MB) has been intermittently used in manic depressive illness over the past century. However, to our knowledge, it has not been studied in the behavioural animal models. The present study was designed to evaluate whether the intravenous (i.v.) administration of MB in a dose range of 1.87–60 mg kg−1would affect the performance of rats in the elevated plus-maze and the forced swimming (FST) tests. In the plus-maze, MB in doses ranging from 3.25 to 30 mg kg−1significantly increased the percentage of open arm entries and exhibited an inverted U-shaped dose-response curve. Over a dose range, 7.5–30 mg kg−1, MB also increased time spent in open arms. These data suggest that MB has anxiolytic properties. On the other hand, MB, at doses of 15 and 30 mg kg−1significantly decreased the immobility time in the FST and behaved as an antidepressant compound in these doses. As known, MB has prominent effects on the nitrergic system; Nitric oxide (NO) produced froml-arginine by the enzyme NO-synthase (NOS) activates soluble guanylyl cyclase (sGC) and exerts its effects on tissues through cGMP. MB acts as a direct inhibitor of NOS as well as of sGC. It also inactivates NO extracellularly through generation of superoxide anions. Thus, it can be speculated that NOS-NO-cGMP pathway may be involved in the antidepressant and anxiolytic actions of MB, and this may lead to search for new antidepressant and anxiolytic compounds

PHARMACOLOGICAL ASPECTS OF HUMAN AND CANINE NARCOLEPSY

Narcolepsy-cataplexy is a disabling neurological disorder that affects 1 2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafinil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming. © 1997 Elsevier Science Ltd. All rights reserved

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.