Chair person: Dr. V.K.

Sinha,

Seminar: Newer Antidepressants Presentee: Dr. Binita Sharma, Discussant: Dr. Sujit Sarkhel Date: 26-10-2004

Depressive disorders afflict at least 20% of women and 12% of men at some time during their lives. By the year 2020 the global burden of depression is projected to rank second only to that of ischaemic heart disease (Murray et al. 1997). However, When correctly diagnosed and aggressively managed, depression is a highly treatable disease (Angst, 1992; Burvill, 1995; Cohen & Guthrie, 1997). Pharmacotherapy represents a first line option in the management of major depressive illness (Evais et al. 1997; Brugha & Bebbington, 1992. Hence, antidepressant drugs have become an indispensable tool in modem medicine. Evolution of antidepressants The area of pharmacotherapy of depression started in the 1950s, with landmark publications and discoveries that still govern the manner in which we treat depression. In 1951, the tuberculostatic drug isoniazid was synthesized, together with a series of variants, including iproniazid, the first monoamine oxidase inhibitor, which induced more psychostimulation than did isoniazid. Thorough clinical observation led to the recognition of iproniazid's antidepressant effects by Kline & Colleagues, Crane & Colleagues and Schrebel & colleagues (Favis, 1958). In 1957, Kuhn described the antidepressant effect of imipramine, a tricyclic compound initially intended as an antipsychotic. From these auspicious beginnings, further antidepressant drugs have been developed using the same biological mechanisms. The first generation of monoamine oxidase inhibitors (MAOI) (such as tranylcypromine and phenelzine) were non-selective and irreversible. The discovery of subtypes of monoamine oxidase (MAO) led to the hypothesis that subtype selective inhibitors of MAO devoid of the 'cheese effect' could be developed. More recently, reversible MAO-A inhibitors have been developed, an example being moclobemide. Following the finding that tricyclic antidepressants inhibited noradrenaline and serotonin reuptake, efforts were directed at developing agents that inhibited only one of these neurotransmitters. The first such compound was the principal metabolite of imipramine itself, desipramine, which selectively blocked noradrenaline uptake. A variety of noradrenaline-selective tricyclic drugs was subsequently developed, including nortriptyline and maprotiline. The most recent such drug has been reboxetine. The first drug to be identified with some selectivity for serotonon was clomipramine. This tricyclic drug was believed to be a more potent antidepressant than imipramine. This stimulated the development of a novel series of SSRIs. The first to be developed were zimelidine and indalpine, introduced in the late 1970s.They were subsequently withdrawn as a result of unexpected adverse events (Guillaine-Barre syndrome for zimelidine and leukocytopenia for indalpine). However, the subsequent development of safe SSRIs (fluvoxamine, paroxetine, fluoxetine, sertraline and citalopram) has provided drugs that are now the mainstay of the treatment of depression. Nonetheless, there has been an impression that SSRIs are less effective than tricyclic antidepressants in the treatment of severe depression (Anderson and Tomenson, 1994). For this reason, dual action drugs have been developed that combine inhibitory effects on both serotonin and noradrenaline reuptake sites with absence of affinity for monoamine receptors. Venlafaxine and Milnacipran are two such serotonin and noradrenaline reuptake inhibitors (SNRIs). An exception to this rational history of the discovery of antidepressants is the empirical discovery of Mianserin and Trazodone in the 1970s. Better-tolerated derivatives of Mianserin and Trazodone have been introduced more recently, namely Mirtazapine and Nefazodone. Specific 2-adrenoceptor (e.g. Idazoxan) and 5-HT2 receptor (e.g. Ritanserin) antagonists have been developed for depression, but their clinical efficacy has never been unambigously demonstrated. Need for Newer Antidepressant Given the relatively recent introduction, established effectiveness, and wide spread clinical use of selective serotonin reuptake inhibitors, one might ask,why do we need new antidepressant agents? There are several reasons for such search. First, currently all available antidepressants have two major limitations: an unfortunate time delay to full clinical response and an overall efficacy (% response) that is far less than desirable (only 65% in moderately to severely depressed patients) (Paul et al. 1997). Second, it has been increasingly recognized that for many depressed patient maintenance treatment is required to prevent frequent relapses and / or to maintain a euthymic state. Moreover, in relative long prospective studies of treatment outcomes gathered from large cohort of depressed patients, a surprisingly low percentage of patient remain symptom free from even while taking maintenance antidepressant therapy (Thase & Kupfer, 1987). This again underscores the need for better (faster acting and more efficacious) antidepressant drugs. Classification of Antidepressants Historically, the older drugs were divided into Tricyclic Antidepressants and Monoamine Oxidase Inhibitors which are also called the first generation antidepressants. The second generation antidepressants became available after the late 1970s.These included many structurally unrelated drugs, including bicyclics (Viloxazine), tricyclics (Lofepramine, Amoxapine), and tetracyclics (Maprotiline, Mianserin). SSRIs and RIMAs are also included in the second generation. More recently another group of antidepressants have come which are called the third generation antidepressants which include recent molecules as Mirtazapine, Nefazodone, Milnacipran and Reboxetine. The distinction between first, second and third generation antidepressants is not absolute for eg., Mirtazapine and Nefazodone were recently launched in the market; however they resemble Mianserin and Trazodone respectively, the two compounds that were developed decades ago. Based on the mechanism of action, Antidepressants can be divided into Cyclic Antidepressants 1. Selective Serotonin Reuptake Inhibitors (SSRI) which include Citalopram - Phthalene derivative, Its S Isomer-Escitalopram Fluoxetine - Bicyclic Fluvoxamine - Monocyclic Paroxetine - Phenylpiperidine Sertraline - Tetradrynaphythlyl methylamine 2. Selective Dopamine Reuptake Inhibitor (SDRI) Bupropion (Also called Amfebutamone) A Monocyclic

Oter prodopaminergic agents available as antidepressants in some countries Amineptine Brasofensine Modafinil-Approved for Narcolepsy but not depression. 3. Selective Serotonin Norepinephrine Reuptake Inhibitor(SNRI) which includes Venlafaxine-A Bicyclic Duloxetine Milnacipram 4. Selective Nor Adrenergic Reuptake Inhibitors Reboxetine 1555U 88, Tomoxetine are in clinical testing.Org4428 has been dropped from further testing. 5. Serotonin -2 Antagonists\Reuptake Inhibitors(SARI) includes Nefazodone-Phenylpiperidine Trazodone Triazolopyridine YM992 is another serotonin antagonist with serotonin reuptake inhibition properties that is in testing as an antidepressant. Other more selective 5HT2 antagonists have been tested and discarded as antidepressants, including Ritanserin and amesergide. Agents with 5HT2A antagonist property but also 5HT1A agonist properties are in testing as potential novel antidepressants; these include Flibanserin, and possibly Adatanserin and BMS181,101. 6. Non Selective Cyclic Agents(Mixed Reuptake Inhibitor\Receptor Blockers) include Tricyclic (eg. Amitryptaline) Dibenzoxazepine (eg. Amoxapine) Tetracyclic (eg. Maprotiline) Mixed 5HT\NE reuptake inhibitors (e.g. Amityptaline) Serotonin reuptake inhibitors, e.g. Clomipramine 7. Nor adrenergic \specific serotonergic agent (NASSA) Mirtazapine Mianserin Septiline (Japan) Several selective alpha 2 antagonists, including Idazoxan and Fluparoxan have been tested but not demonstrated robust antidepressant efficacy. MAO Inhibitors 1. Irreversible MAO Inhibitors - Phenelzine,Tranylcypromine,Isocarboxazid 2. Reversible MAO Inhibitors Moclobemide Toloxatone-A weak inhibitor of MAO-A. Brofaromine-A RIMA with demonstrated antidepressant efficacy, currently under active investigation. Befloxatone-Undergoing clinical trial investigation. Other potential candidates-RS-8359, Cimoxatone and Toloxatone. Mechanism of action For over 30 years, the leading theory to explain the biological basis of depression has been the monoamine hypothesis of depression. This hypothesis proposes that depression is due to a deficiency in one or another of three biogenic monoamines, namely serotonin, norepinephrine, and or dopamine. The newer antidepressant too exploit the same neurochemical mechanisms. Hence it is important to discuss the effect of antidepressants on noradrenergic and serotonergic neurotransmission before proceeding further. Effect of antidepressants on central noradrenergic neurotransmission The neuronal substrate of the pro-noradrenergic effects of antidepressants is the ascending bundle of noradrenergic neurons that have their cell bodies in the locus coeruleus in the midbrain and innervate an extensive range of targets in the limbic system and the neocortex. Noradrenaline released from these neurones in the forebrain acts on receptors on postsynaptic neurons. A variety of subtypes of adrenergic receptors are present, including 1, 2. 1 and 2. Although no direct evidence for this exists, it is thought that it is activation of the 1 receptors by noradrenaline that is responsible for the mood elevating effects of antidepressants acting on the noradrenergic system. This belief stems from the observation that -blockers that penetrate the brain have little effect on mood, whereas 2 receptor antagonists have mood elevating properties. In addition to acting on postsynaptic receptors, noradrenaline also acts on inhibitory presynaptic 2 autoreceptors on the terminals of the noradrenergic neurons (Lacroix et al. 1991). Activation of these receptors leads to an inhibition on noradrenaline release. This system thus acts as a negative feedback brake to limit extracellular noradrenaline concentrations. In the locus coeruleus, noradrenaline can also be released from local collaterals and dendrites of the projection neurons. Released neurotransmitter can interact here with 2 receptors on the cell bodies of the noradrenergic neurons. The consequence of this is to inhibit firing of the neurons, and this represents a second negative feedback control over the activity of the noradrenergic system (Svensson and Usdin, 1978; Lacroix et al. 1991; Szabo and Blier, 2001). Synaptic levels of noradrenaline in the forebrain and in the locus coeruleus are regulated by two processes. The first of these is reuptake by specific transporter proteins in the membranes of the noradrenergic neurons. These transporter proteins are the target of antidepressants such as desipramine, reboxetine and milnacipran. The second process is control of transmitter release by the presynaptic 2 autoreceptors; these are targets for antidepressants such as mianserin and mirtazepine. The action of antidepressants is thus to override the control mechanisms that regulate extracellular noradrenaline levels. Blockade of reuptake produces a rise in extracellular noradrenaline, although the extent of this is limited by increased activation of the inhibitory 2 autoreceptors (Svensson and Usdin, 1978; Dennis, 1987). Similarly, blockade of these 2 autoreceptors by mianserin or mirtazepine increases extracellular noradrenaline levels to some degree, although reuptake limits this rise. Combination of a reuptake inhibitor antidepressant and an 2 receptor blocking antidepressant will block both control mechanisms, and thus provoke a greater increase in extracellular noradrenaline level than either substance alone ( Dennis, 1987; Thomas et al., 1994; Nutt et al., 1997).

Chronic treatment with antidepressants may lead to desensitization of these 2 autoreceptors that control the firing rate of noradrenergic neurons in the locus coeruleus. Data from behavioural experiments in rodents suggest that such a phenomenon does indeed occur (Spyraki and Fibiger, 1980; Heal, 1987). However, more recent electrophysiological experiments do not support the idea that 2 receptor sensitivity on cell bodies is modified by long term reuptake inhibition (Szabo and Blier, 2001), and it is possible that these compensatory changes may involve sensitivity changes on nerve terminals (Mongeau et al. 1994). Effect of Antidepressants on central serotonergic neurotransmission Serotonergic neurons have their cell bodies in the raphe nucleus of the midbrain, and project to those same forebrain areas that are innervated by noradrenergic neurons. There are a large variety of different subtypes of serotonin receptor on postsynaptic neurons, including the 5-HT1 receptor family, the 5-HT2 receptor family and 5-HT3 receptors. It is probable that the beneficial effects of antidepressants on mood are mediated by an enhancement of serotonergic neurotransmission mediated by 5-HT1A receptors. This hypothesis is based on the observation that 5-HT3-receptor antagonists have no effect on mood and 5-HT2-receptor antagonists are either without effect or improve mood. In addition 5-HT1A-receptor agonists, such as buspirone, may have some beneficial effect in certain forms of depression (Rickels et al. 1990; Stahl et al. 1998). Again, synaptic levels of serotonin are regulated by two mechanisms, reuptake and an autoreceptor-mediated feedback inhibition of cell firing (Blier and De Montigny, 1987) and transmitter release (Hjorth et al. 1995). Blockade of reuptake with SSRIs or SNRIs will increase the synaptic concentration of serotonin, but the consequence of this is to activate somatodendritic 5-HT1A receptors and thus turn off cell firing (Biler and de Montigny, 1994; Gardier et al. 1996). However, over a period of around 4 weeks, firing rates slowly recover, presumably as a result of desensitization of the 5-HT1A receptors, and thus extracellular serotonin levels rise once again and remain permanently elevated (Bel and Artigas, 1993; Rutter et al. 1994). This phenomenon may well provide an explanation of the lag-time in the onset of clinical antidepressant action. It may be possible to use 5-HT1A receptor antagonists to prevent pharmacologically the feedback brake on raphe neuron firing, and thus to obtain a more incisive antidepressant action with rapid onset. In animal experiment, this has been clearly demonstrated with for example, pindolol (Hjorth, 1993; Arborelius et al. 1995, 1996; Gartside et al. 1995). Finally, it is important to realize that the effects of antidepressants on serotonergic neurons and on noradrenergic neurons are not independent, because there is a close anatomical and functional relationship between the two pathways. Noradrenergic neurons contact serotonergic neurons in the raphe nucleus, and excite these through activation of 1 receptors on their cell bodies (Aghajanjan, 1985). Antidepressants acting on monoamine receptors Interactions between noradrenergic and serotonergic neurons may provide the biological substrate for those antidepressant effects of drugs that are devoid of activity on monoamine reuptake. This is the case, for example, for 2 receptor antagonists. Selective antagonists such as idazoxan and fluparoxan have weak antidepressant action, presumably by switching off the autoreceptor control of noradrenaline release. The antidepressant efficacy of the non-selective 2 antagonists mainserin and mirtazapine is more pronounced. These drugs also have 5HT2-receptor blocking activity, and will thus turn off the serotonergic inhibition of noradrenergic neurons, as well as the noradrenergic inhibition of serotonergic neurons mediated by 2 receptors (De Boer, 1995). Antidepressants with antagonist activity at 5-HT2 receptors include not only mainserin and mirtazapine, but also trazodone and nefazodone. These drugs presumably act by relieving serotonergic inhibition of noradrenergic neurons. Moreover, evidence from animal studies suggests that blockade of 5-HT2-receptor pathways may lead to a compensatory increase in 5-HT1A-receptor mediated serotonergic tone (Charig et al. 1986), which as described above, has a beneficial effect on mood. Thus although these drugs have no direct effect on monoamine uptake, they do all lead to an increase in serotonin and noradrenaline release, and thus of synaptic levels, and thereby enhance postsynaptic transmission. However, this has only been demonstrated clearly in experimental animals for mirtazapine (Westenberg, 1999). Glutaminergic system The chronic administration of N-methyl-D-aspartate (NMDA) in animal experiments leads to downregulation of cortical 1-receptors, similar to what occurs with antidepressants. In other animal experiments, it was found that treatment with 17 different antidepressants (including SSRIs) led to changes in the binding of radioligands to NMDA receptors. (Maes et al.1995;Nowak et al.1996;Skolnick et al.1996) The changes first occurred after approximately 14 days and were maintained for a further 1-2 weeks after the antidepressants had been discontinued. It has recently been shown that there are changes to binding to NMDA receptors in the cortex of suicide victims.(Nowak et al.1995). A further interesting mechanism of certain antidepressants is binding to sigma receptors. It is assumed that sigma receptors modulate the neural response to NMDA. The adaptive changes in NMDA receptors induced by antidepressants could be connected with this binding to sigma receptors. All antidepressants which have as yet been examined lead to a significant increase in the density of receptors in the cortex and in various subcortical regions after long term dosage. The hypothalamus-pituitary-Adrenal Axis One of the molecular targets of the TCAs and SSRIs haas been identified as the glucocorticoid receptor, of which the mRNA is formed in increased quantities during treatment.(Barden,1996) It is possible that increased density or better functioning of glucocorticioid receptors leads to normalization of the feedback mechanisms in the hypothalamus-pituitary adrenal axis which is disturbed in depressive patients.(Young et al.1991) The time course of these adaptive changes in the glucocorticoid receptors also corresponds to the time course of clinical improvement. The changes in central receptors are responsible for the decreases in circulating ACTH and cortisol. In animal experiments, antidepressants have also been found to decrease the mRNA for CRH in the hyppthalamus. Neurotropins In animal experiments, stress leads to a decrease in 'brain derived neurotrophic factor' (BDNF). In contrast, antidepressants and anticonvulsive therapy cause an increase in BDNF in the hippocampus. BDNF increases the axonal transport of 5-HT and apparently possesses inherent antidepressive activity.

Immune processes In recent years, several immunological changes have been found in patients suffering from major depression(Maes et al.1995). In one of these studies a significant correlation was found between reduction in tryptophan availability and immunological abnormalities. Both noradrenergic and serotonergic receptors could be identified on immunocompetent cells. The immune hypothesis was encouraged by the finding that a high percentage of patients with bipolar affective disorder are carriers of the Borna virus.(Bode et al.1997 This is of particular clinical relevance, as amantadine is an antiviral drug which has been shown to possess efficacy in both case studies and, more recently, in larger trials. Apart from its antiviral potency, amantadine also inhibits MAO-A and 5-HT reuptake. Intracellular Mechanisms It is possible that the mechanisms responsible for antidepressive activity are not primarily related to neurotransmitter metabolism, but are connected with intracellular processes, which can also be influenced by monoamine(Duman et al.1997). Aldenhoff et al. examined intracellular homeostasis in T cells during severe depression and after treatment with interpersonal psychotherapy (IPT). In the depressed state there was a pathological lowering in the Ca response after stimulation with PHA (phytohaemagglutinin). During treatment with IPT the Ca response was fully normalized. Newer Antidepressants in comparison to classical antidepressants Pharmacodynamics MAO Inhibitors The novel RIMAs bind reversibly only to MAO-A, resulting in a lower degradation of 5HT and nor adrenaline, while MAO-B is not inhibited (Amrein et al., 1989) SSRI The mechanism of action of SSRIs is usually explained simply by selective inhibition of the serotonin transporter (Barker & Blakely, 1995). However, a more precise statement of SSRI therapeutic action is delayed disinhibition of serotonin neurotransmission in at least four key pathways (Blier et al.1987). When an SSRI is administered, it indeed blocks the serotonin reuptake pump, and this happens immediately. However, this action causes a sudden increase in serotonin predominately in the somatodendritic area, and not at the axon terminals where serotonin is presumably needed in order to exert therapeutic actions. If SSRIs are administered chronically, the sustained increases of serotonin in the somatodendritic area of the serotonin neuron cause the somatodendritic serotonin 1A atutoreceptors to desensitize(Stahl,1996). Once the somatodendritic autoreceptors desensitize, neuronal impulse flow is no longer as readily inhibited by serotonin. Thus neuronal impulse flow is turned on, i.e., serotonergic neurotransmisson is disinhibited, and more serotonin is released from the axon terminal. Since different 5-HT pathways are known to mediate different CNS functions, the various therapeutic effects of SSRIs may be mediated by disinhibition on different pathways. Thus disinhibition of serotonergic neurotransmission in the pathway from midbrain raphe to prefrontal cortex could hypothetically help mediate the antidepressant effects of SSRIs(Palacious et al. 1991,Mann et al.1996). Similarly, disinhibition of the pathway from midbrain raphe to basal ganglia could hypothetically mediate therapeutic actions of SSRIs in OCD (Barter et al.1992), disinhibition of the pathway to limbic cortex and hippocampus, therapeutic actions in panic disorders, and disinhibition of the pathway to hypothalamus, therapeutic action in bulimia and binge eating disorder (Casper, 1995). Differences in the potency of inhibition of various neurotransmitter uptake and the secondary pharmacological mechanism of each of the five SSRIs may explain the intraclass differences. Sertraline is the most potent and citalopram the most selective serotonin reuptake inhibitor than the other SSRIs. In addition paroxetine has higher affinity for cholinergic muscarinic receptors than the other SSRIs (suggesting some anticholinergic effects), while citalopram has a slight affinity for histamine H1 receptors (suggesting some sedative effects). Selective Noradrenergic reuptake inhibitors These act by increasing norepinephrine at desirable synapses and at desirable noradrenergic receptors. The first truly selective noradrenergic reuptake inhibitor (NRI) is reboxetine, which lacks the undesirable binding properties as of tricyclics (Alpha 1, histamine 1, and muscarinic cholinergic receptor). Norepinephrine and dopamine reuptake blockers Bupropion is the prototypical agent of the norepinephrine and dopamine reuptake inhibitors. Bupropion itself has weak reuptake properties for dopamine, and weaker yet reuptake properties for norepinephrine. The action of the drug on norepinephrine and dopamine neurotransmission, however, has always appeared to be more powerful than these weak properties could explain, which has led to proposals that bupropion acts rather vaguely as an adrenergic modulator of some type. Dual serotonin and norepinephrine reuptake inhibitors These serotonin/norepinephrine reuptake inhibitors are called SNRIs or dual inhibitors. A small amount of dopamine reuptake inhibition DRI is also present in some of these agents, especially at high doses. The both reuptake pumps are (norepinephrine reuptake and serotonin reuptake) blocked, and the drug mediates an antidepressant effect. This is analogous to two of the dimensions of the tricyclic antidepressants (TCAs) and analogous to the single action of SSRIs added to the single action of the selective NRIs. Dual serotonin and norepinephrine actions via alpha 2 antagonism Alpha 2 antagonist actions yield dual enhancement of both serotonin and norepinephrine release. Mirtazapine a prototype of this group does not block any monoamine transporter, but in addition to its potent antagonist action on alpha2 receptors it also has antagonist actions at serotonin 2A, 2C and 3 receptors and histamine 1 receptors. The 5-HT2A antagonist properties may contribute to mirtazapine's antidepressant action, and these serotonin 2A antagonist properties as well serotonin 2C antagonist and H1 antihistamine properties may contribute to its anxiolytic and sedative hypnotic properties. Dual serotonin 2 antagonists/serotonin reuptake inhibitors Nefazodone is the prototypical member of the SARI class of antidepressants. It is a powerful reuptake inhibitor. Nefazodone also blocks alpha-1 receptors, but the clinical consequences of this are generally not important.

Pharmacokinetics There are several known CYP450 systems. Five of the most important enzymes for antidepressant drug metabolism are 1A2, 2D6, 2C9, 2C19 and 3A4 (Stahl, 1997). Inhibition potential of antidepressants at CYP450 enzyme systems Relative rank 1A2 2C9/19 2D6 3A4 High Fluvoxamine fluvoxamine paroxetine fluvoxamine fluoxetine fluoxetine nefazodone fluoxetine Moderate to low tertiary TCAs fluoxetine sertraline fluoxetine Secondary TCAs sertraline TCAs paroxetine venlafaxine bupropion citalopram reboxetine mirtazapine

Low to minimal

venlafaxine bupropion citalopram reboxetine mirtazapine sertraline nefazodone

venlafaxine bupropion citalopram reboxetine mirtazapine nefazodone

venlafaxine bupropion citalopram reboxetine mirtazapine sertraline nefazodone fluvoxamine

Citalopram, Citalopram is a racemic drug whose enantiomers stereoselectively inhibit reuptake (the S-form is more potent). Both CYP2 19 and CYP2D6 appear to be involved in its metabolism (Baumann, 1996) although a recent report using human liver microsomes to study the N demethylations of citalopram found CYP3A4 to be the major enzyme involved, with CYP2C19 playing a minor role and CYP2D6 having no detectable activity (Koyayashi et al.1997). With regard to enzyme inhibition, citalopram is a minor player among the SSRIs. It is a weak inhibitor of CYP2D6 (weaker than sertraline, stronger than fluvoxamine) and has little or no effect on CYP1A2 or CYP2C19 (Jeppesen et al. 1997). Fluvoxamine. A recent study suggests that both CYP1A2 and CYP2D6 are involved(Carrillo et al.1996). Fluvoxamine is the only SSRI that inhibits CYP1A2 very potently. For example, 100 mg daily of fluvoxamine increased the half life of caffeine from 5 to 31 hours. In case reports, blood clozapine levels were reported to increase 5 to 10 fold in the presence of fluvoxamine(Koponen et al.1996). Finally, because fluvoxamine decreases the clearance of theophylline by a factor of 3, theophylline dose should be reduced to1/3 of usual if it is coadminsitered with fluvoxamine. Fluvoxamine also inhibits CYP2C19 and CYp3A4 to moderate degrees, which may be enough to produce clinically meaningful increases in blood levels of benzodiazepines such as diazepam, alprazolam, and triazolam. On the other hand, the degree of CYP3A4 inhibition does not appear sufficient to justify the package insert contraindication to the coadminsitration of fluvoxamine with terfenadine, astemizole, or cisapride. Reboxetine is characterized by the absence of inhibitory properties towards the major CYP isoforms involved in drug metabolism in humans. In additions, repeated administration of reboxetine does not cause induction of CYP3A4, which is responsible for the metabolism of a majority of drugs. At therapeutic doses reboxetine neither inhibits nor is metabolized (at least not a significant extent), by CYP2D6, which is also strongly involved in the metabolism of drugs. Venlafaxine- It is oxidized to its major active metabolite O-desmethyl venlafaxine (ODV) by CYP2D6. A lesser metabolic pathway is N-demethylation to N-desmethylvenlafaxine by CYP3A4. Venlafaxine and ODV have similar neurotransmitter reuptake inhibitory potencies; therefore, the inhibition of CYP2D6 should not be particularly problematic since the total concentration of venlafaxine plus ODV would remain roughly the same. Venlafaxine does not have pronounced inhibitory effects on the P450 system. It does not inhibit human microsomal CYPIA2, 2CP, or 3A4, and it is a relatively weak inhibitor of CYP2D6. Nefazodone Its effects on CYP1A2, 2C19, and 2D6 are not of clinical consequences while inhibition of CYP3A4 by nefazodone is important clinically. Co-administration with terfenadine, astemizole, or cisapride is contraindicated because of cardiac arrythmias. Serum levels of alprazolam and trizaolam are increased substantially in the presence of nefazodone, and oversedation is quite likely,however nefazodone does not alter the pharmacokinetics of lorazepam, because the latter does not require oxidative metabolism(Greene et al .1995) Bupropion. In vitro studies indicate that CYP2B6 is responsible for converting bupropion to hydroxybupropion, with the other known P450 enzymes having minor roles. In an open, single-dose study of the sustained release (SR) form of bupropion, no significant differences in pharmacokinetic were noted between smokers and nonsmokers, suggesting that CYP1A2 (induced in smokers) is not involved in bupropion metabolism. On the other hand, the major role of CYP2B6 in nicotine metabolism and bupropion's effectiveness as a smoking cessation agent suggest some interesting but as yet unexplored possibilities of interactions at these levels. The observation that carbamazepine decreased blood bupropion levels and increased hydroxybupropion concentration suggests that the drug is an inducer of CYP2B6(Ketter et al.1995). Valproate did not alter bupropion concentrations, but did increase hydroxybupropion levels, suggesting inhibition of the metabolism of the latter. Mirtazapine. It is metabolized extensively by CYP1A2 receptor and CYP2D6 to an 8-hydroxy metabolite and by CYP3A4 to N-desmethyl and N-oxide metabolites. Mirtazapine is a competitive inhibitor of CYP1A2, 2D6, and 3A4, but it is a relatively weak inhibitor and, consequently, not likely to cause clinically significant interactions with P450 substrates. Mirtazapine has an additive effect on the impairment of motor skills caused by diazepam or alcohol. Speed of onset of action In general, antidepressants take 2-3 weeks to work. The development of dual-action antidepressants raised the important possibility that they may have a more rapid onset of action than tricyclic antidepressants or SSRIs (Montgomery, 1995a). The early onset of action of venlafaxine in comparison with fluoxetine has been illustrated in a study by Rudolph et al. (1998) in outpatients. This showed that there was an earlier cumulative probability of response or of improvement in patients treated with venlafaxine rather than with fluoxetine. Early onset of action has also been observed in some studies with milancipran; for example, there was a significant advantage of milnacipran at the end of the first week in a comparative trial with fluvoxamine (Clerc et al. 2001)

as well as in a comparative trial with imipramine (Kasper et al. 1996). A meta-analysis of five comparative studies of mirtazapine and SSRIs showed that 2 weeks after treatment initiation, there was a marginal advantage of mirtazapine in terms of relative risk of treatment response with respect to SSRIs, whereas at the study end the two treatments were similar (Anderson, 1999). This study may suggest that mirtazapine has an earlier onset of action than SSRIs. Reboxetine is likely to have a similar onset of action to other antidepressants (2-3weeks) (Holm et al.1999). Greater efficacy SNRIs in general, and both venlafaxine (Anderson, 2001) and milnacipran (Lopez-Ibor et al. 1996), in particular, have been found to be more effective than SSRIs. In contrast the overall efficacy of milnacipran does not differ from that of tricyclic antidepressants (Kasper et al. 1996). The data for mirtazapine suggest an earlier treatment response, but no absolute difference in efficacy later in the treatment (Anderson, 1999). No comparative meta-analytic data are available for nefazodone. In some individual studies, impressive differences in efficacy between single-action and dual action drugs have been found. A series of studies by the Danish University Antidepressant Group have been influential in the development of this concept. The first of these studies compared clomipramine and citalopram (Danish University Antidepressant Group, 1986). The study found response rates twice as high in patients treated with clomipramine than in those treated with citalopram. A second study compared clomipramine and paroxetine and reached the same conclusions (Danish University Antidepressant group, 1990). A meta-analysis of all comparative studies between clomipramine and SSRIs has not found a significant difference in efficacy between the two treatments (Anderson, 2000). Dose response relationship A frequent observation in dose ranging clinical studies with SSRIs is that these drugs appear to have an all-ornone antidepressant response (Preskorn, 1997). In a study of fluoxetine by Dornseif et al. (1989), it was demonstrated that in patients who did not respond to 20 mg fluoxetine, increasing the dose to 60 mg did not trigger a treatment response. This ceiling effect on the efficacy of SSRIs may be caused by the non selective activation of post-synaptic serotonin receptors by increased extracellular serotonin. While activation of the 5-HT1A receptor pathway is probably responsible for the beneficial effects of the antidepressant, the 5-HT2 receptor pathway may act as a brake, counteracting the antidepressant effect (Deakin, 1988). This suggestion is supported by two observations. First, several effective antidepressants (notably mianserin, mirtazapine and nefazodone), are 5-HT2 receptor antagonists, while some selective 5-HT2 receptor antagonists, such as deramciclane (Montgomery, 2001) and ritanserin (Lapierre, 1994) have antidepressant properties in dysthymia. Second, the antidepressant effect of SSRIs can be enhanced by co-adminsitration of 5-HT2 receptor antagonists including mianserin (Ferreri et al. 2001), olanzapine and trazodone (Deakin et al. 1999). Unlike SSRIs, a clear dose response relationship has been observed with venlafaxine (Rudolph et al. 1998). This means that the dose can be tailored to optimize the therapeutic benefit, and that dose escalation is useful in non responders. The superior efficacy of higher doses of venlafaxine may be a result of the noradrenergic effect at doses over 200 mg day. In the case of milnacipran, there is also some evidence for a dose response relationship. A dose ranging study comparing doses of 25, 50, 100 mg twice daily has been described by Lecrubir et al. (1996). This showed that the 50 and 100 mg twice daily doses were superior to the 25 mg dose twice daily, although the 50 and 100 gm twice daily doses were equivalent. Therapeutic profile With the advent of so many antidepressants, the therapeutic implications of antidepressants have broadened. Serotonergic antidepressant are efficacious not only in depression but also in obsessive compulsive disorder, eating disorders, panic, social phobia and even posttraumatic stress disorder, whereas noradrenergic antidepressants may improve overall social functioning and work capacity by targeting psychomotor retardation, fatigue, and apathy. Noradrenergic enhancement might even boost cognitive functioning in disorders other than depression that are characterized by deficits in attention and memory, such as A1zheimer's disease, attention deficit disorder, and the cognitive disturbances associated with schizophrenia. The dual mechanism antidepressant may be of help in patients with so called apathetic response to the SSRI. Table: Matching patient profiles with antidepressant drug profiles Patient profiles Antidepressant drug profiles Examples Atypical (weight gain hypersomnia; Activating by 5HT or DA/NE SSRIs, MAOs, bupropion hyperphagia; anergia) Anxious 5HT2 antagonist nefazodone mirtazapine Agitated 5HT2 antagonist nefazodone mirtazapine Insomnia 5HT2 antagonist nefazodone mirtazapine Sexual dysfunction 5HT2 antagonist nefazodone Non-5HT mirtazapine bupropion Pain 5HT2 antagonist/5HT reuptake amitriptyline nefazodone? mirtazapine?? Migraine prophylaxis 5HT2 antagonist/5HT reuptake amitriptyline nefazodone? mirtazapine?? Panic disorder 5HT SSRI Obsessive compulsive disorder 5HT SSRI Bulimia/binge eating disorder 5HT SSRI (Stahl, 1997)

Tolerability The tolerability of classical tricylic antidepressants is, in general, poor, and a reason for poor compliance (Anderson and Tomeson, 1995; Maddox et al. 1994; Montgomery and Kasper, 1995) and the use for suboptimal doses (Donoghue and Tylee, 1996). The poor tolerability of tricyclic antidepressants can in large part, be attributed to antagonist activity of these drugs at monoamine receptors (acetylcholine, noradrenaline, histamine and serotonin receptors) (De Jonghe and Swinkels, 1992). In this respect, SSRIs and SNRIs are better tolerated because they are devoid of affinity for monoamine receptors. Effects on peripheral acetylcholine and noradrenaline receptors and on sodium channels lead to disturbances of the autonomic nervous system. Resulting cardiovascular effects (in particular orthostatic hypotension and disturbances of cardiac rhythm) are potentially life threatening. Venlafaxine and milnacipran have little effect on cardiovascular function,although high doses of venlafaxine (>300 mg) have been associated with hypertension (Thase, 1998; Fantaskey and Burkhart, 1995). Milancipran has been taken in overdose at 2800 mg, without any detrimental effect on the cardiovascular system being observed (Montgomery et al. 1996). Other side effects of tricyclic antidpressant resulting from autonomic disturbances include constipation and dry mouth and sweating, all caused by anticholinergic action; these are rarely seen with SSRIs, or dual action drugs. On the other hand, dysuria has been reported, albeit rarely, with venlafaxine and milnacipran (Montgomery et al. 1996; Horst and Preskorn, 1998). This effect can probably be explained by facilitation of sympathetic neurotransmission caused by noradrenaline reuptake blockade in the periphery, and is also observed for the selective noradrenaline reuptake inhibitor reboxetine (Mucci, 1997). Central anticholinergic effects may cause sedation, impaired psychomotor performance and poor cognitive function. Activity at 1 adrenoceptors and H1 histamine receptors may also contribute to the sedative effects of tricyclic antidepressants. Other side effects of these drugs include weight gain (Bernstein, 1988.) and sexual dysfunction (Baldwin and Birtwistle, 1998). These may be due to interactions with serotonin or histamine receptors. Such side effects are less frequent with the dual action drugs. In contrast, the receptor antagonist properties of mirtazapine and nefazodone have their own side effects. Sedation is especially prominent with mirtazapine (Montgomery, 1995b) and can probably be attributed to the antihistamine properties of this drug, as it is with certain tricyclic antidepressants. The other important side effect of mirtazapine is weight gain, which may be very significant in certain patients (Montgomery, 1995b). This could be related to antagonist activity at H1 histamine receptors or 5-HT2 receptors (Bernstein, 1988). The use of nefazonone, which is also a 5-HT2 receptor antagonist, is not associated with significant weight (Robinson et al. 1996). The adverse event profile of nefazodone includes autonomic symptoms (dry mouth, constipation, dizziness and blurred vision) frequently seen with tricyclic antidepressants and attributed to antocholinergic effects (Robinson et al. 1996). This is somewhat surprising given that, in vitro, nefazodone has very low affinity for muscarinic cholinergic receptors (Eison et al. 1990). These findings may be explained by the presence in vivo of a metabolite with anticholinergic activity. The principal side effects of SSRIs are nausea and sexual dysfunction (Baldwin and Birtwistle, 1998; Baldwin et al. 1998; Mackay et al. 1999; Rosen et al. 1999). These are thought to be the result of stimulation of serotonergic neurotransmission in parts of the central nervous system unrelated to depression. The receptor subtype involved in sexual dysfunction has not been identified, although some animal data have implicated the 5-HT2 receptor (Baldwin and Birtwistle, 1998). On the other hand, nausea and vomiting are probably attributable to stimulation of 5-HT3 receptors in the brainstem. Both velafaxine and milnacipran appear to produce less sexual dysfunction that SSRIs (Baldwin et al. 1998; Baldwin and Birtwistle, 1998; Hirschfeld, 1999 It would also be expected that antidepressant drugs blocking 5-HT2 receptors should produce less impairment of sexual function, and this has indeed been demonstrated for both mirtazapine and nefazodone (Robinson et al. 1996; Baldwin et al. 1998; Boyarsky et al. 1999). The incidence of nausea in patients treated with venlafaxine is also lower than in patients treated with SSRIs (Holliday and Benfield, 1995; Mackay et al. 1999), and even lower with milnacipran(Lopez-Ibor et al. 1996). The propensity for producing nausea may this be correlated with the selectivity of these drugs for serotonin over noradrenaline reuptake. Although the incidence of nausea with venlafaxine and milnacipran is low compared to SSRIs, it should be noted that this is still the most prevalent adverse event reported with these drugs. Mirtazapine, which is an antagonist at 5-HT3 receptor, also produces little nausea (Montgomery, 1995b; Holm and Markham, 1999). However, the prevalence of nausea in patients treated with nefazodone, which is inactive at 5-HT3 receptors, is similar to that seen with SSRIs (Robinson et al. 1996; Davis et al. 1997). Reports of switch with Venlafaxine, Reboxetine, Mirtazapine are there, though conclusive reports are yet not available. Serotonin syndrome It has attained greater prominence recently because of the widespread use of potent serotonin reuptake inhibitor antidepressants.The big offender appears to be combinations of MAOIs with potent serotonergic drugs such as tryptophan, SSRIs, venlafaxine, and tricyclics. Serotonin reuptake inhibitors Although the TCAs were the dominant class of antidepressants worldwide for more than 30 years, the SSRIs have overtaken them in popularity in just 10 years. Currently, this class includes fluoxetine, paroxetine, setraline, fluvoxamine, and citalopram. Fluvoxamine does not have an FDA-approved indication for the treatment of depression. However, the drug is marketed in many countries as an antidepressant. Indications The SSRIs are indicated primarily for the treatment of major depression, and numerous studies have supported this use. The SSRIs are effective in atypical depression, in combination with standard antipsychotics in the treatment of psychotic depression, and in the maintenance therapy of recurrent depression. The SSRIs are also useful in the treatment of chronic major depression with dysthymia. The second indications for the SSRIs is the treatment of OCD. Fluvoxamine, fluoxetine, sertraline, and paroxetine all have an FDA indication for the treating the disorder. SSRI doses for the treatment of OCD are usually higher than those required for the treatment of depression, and the latency to response is usually longer. A third indication for the SSRIs is the treatment of eating disorders, particularly bulimia nervosa. Fluoxetine has been shown to have a positive effect on the binge-purgecycle in some bulimic patients (Fluoxetine Bulimia Nervosa Collaborative study Group 1992). The SSRIs may also ameliorate the carbohydrate craving and mood disturbance associated with bulimia nervosa and obesity. Fluoxetine and sertraline have been shown to have a modest effect on weight and food intake in obese patients. There are few data on the use of the SSRIs to treat classic anorexia nervosa, but one report suggested that fluoxetine may be useful for this condition (Kaye et al. 1991).

Finally, there appears to be a role for the SSRIs in the treatment of other anxiety disorders, including panic disorder, social phobia, GAD and PTSD. Although patients with panic disorder may be sensitive to the activating effects of some SSRIs, most are able to tolerate a slow titration of dosage upward. For example, some reports indicate that although some patients do not tolerate an initial dosage of 20 mg/day day of fluoxetine, many patients are able to benefit if the starting dosage is 5 mg/day (Schneier et al. 1990). The SSRIs, including citalopram and fluvoxamine, all appear, on the basis of published data, to be effective in treatment panic disorder. Paroxetine and sertraline have received an FDA approved indication for the treatment of panic disorder. In 1999, paroxetine received an FDA approved indication for treatment of social phobia. A number of double blind studies indicate that paroxetine at dosages of 20-50 mg/day is more effective than placebo in alleviating symptoms, including undue fear and avoidance of interpersonal interaction. Further, paroxetine appears to reduce the significant disability associated with more severe forms of this disorder (Stein et al. 1998). Posttraumatic stress disorder is associated with a variety of comorbid conditions, especially depression and substance abuse. SSRIs have been used since the late 1980s to treat some of the symptoms of PTSD, including depression, insomnia hyperarousal, and agitation. There is substantial evidence that fluoxetine, paroxetine, and sertraline help alleviate these symptoms and may even impact comorbid substance use. In 1999, sertraline became the first drug to be approved by the FDA for the treatment of PTSD. Many PTSD patients treated with sertraline appear to require doses above 100 mg/day of sertraline for maximum effects. With paroxetine, a dosage of 20 mg/day appears to be about as effective as 40 mg/day in treating PTSD. The SSRIs should help with GAD, and paroxetine has now received FDA approval for this indication. Paroxetine, at dosages of 20-50 mg/day, was effective in reducing anxiety by 60% on the Hamilton Anxiety Scale. Large-scale studies of escitalopram have also shown benefit in the treatment of generalized anxiety. A number of studies have supported the use of SSRIs, especially fluoxetine and sertraline, in treatment of premenstrual dysphoric disorder. Both of these drugs have also been used as intermittent treatment in the luteal phase of the cycle and appear to be effective (Jermain et al. 1999). In 1999, fluoxetine (Sarafem) became the first medication approved for the treatment of PMDD. The SSRIs appear to be useful in treating the anger or impulsive aggression associated with some personality disorders (Kavoussi et al. 1994; Salzman et al. 1995) and certain pain disorders such as diabetic neuropathy and fibromyalgia (Wolfe et al. 1994), although here the mixed norepinephrine serotonin reuptake blockers appear to be far more effective. Side effects The SSRIs are largely devoid of the anticholinergic side effects that plague the TCAs. Furthermore, orthostatic hypotension does not typically occur with SSRI use. The most common reasons patients discontinue the SSRIs early in treatment are gastrointestinal (GI) side effects. These include nausea, diarrhea, cramping, heartburn, and other symptoms of GI distress. 5-HT3 appears to be responsible for SSRI-induced GI distress. The earliest reports suggested that approximately 20%-30% of patients treated with fluoxetine developed GI side effects, the incidence in clinical practice has been much lower. In clinical practice, the starting dosage of 20 mg/day is maintained for 3 weeks, and nausea is both less common and less severe. Furthermore, the GI side effects tend to diminish over the first 2-4 weeks of treatment. Instructing patients to take medicines with meals, slow titration of dose may help. 5-HT3 antagonist can be used if the problem is intolerable. Another group of side effects commonly encountered with SSRIs is related to CNS activation. At least 15 20% of patients receiving SSRI therapy complain of insomnia, jitteriness, and agitation in the course of treatment. For this reason, fluoxetine, which has activating properties, should be taken in the morning, when it is less likely to interfere with sleep. Likewise, if patients develop insomnia with other SSRIs, it is often effective to have the patients take the dose earlier in the day. Occasionally, patients require modest doses of a benzodiazepine (e.g., clonazepam 0.5mg bid, lorazepam 0.5 mg bid, alprazolam 0.25 mg bid) early in the course of therapy. A number of case reports also suggest that trazodone may augment response in the SSRIs. Treatment emergent sexual dysfunction is a big problem with SSRIs. Reports suggest that the incidence may be 30-40% for all SSRIs. Though tolerance occurs to these side effect, holding the dose of shorter acting SSRIs, such as paroxetine and sertraline, for 24 hours prior to anticipated sexual activity has been anecdotally reported to be helpful in some 50% of patients. Adjunctive agents buspirone (20-60 mg/day), bupropion (75-150 mg/day), sildenafil (50-100 mg prn), ginkgo biloba (60-240 mg/day), amantadine (100-300 mg/day), cyproheptadine (4-12 mg prn), yohimbine (5.4 mg tid) can be used. Headache, akathisia have also been commonly reported. Dosage and administration Fluoxetine is usually initiated at 20 mg/day, and the maximum recommended dosage is 80 mg/day. Recently, a 90 mg, once weekly form of fluoxetine was introduced. This form is designed to be an alternative to daily treatment with fluoxetine at 20 mg/day and is meant for use in the maintenance phase of treatment only. Paroxetine is usually initiated at 20 mg/day. If no response is seen, the dosage may then be increased each week by 10-20 mg/day until a maximum dosage of 50 mg/day is achieved. Citalopram is dosed at 20-60 mg/day. Escitalopram is more potent and is generally dosed at 10-20 mg/day. Sertraline is initiated at 50mg/day this may be continued for 2 weeks if no response is seen doses may be increased weekly by 50mg/day till maximum dose of 200 mg/day is achieved. Fluoxamine is usually initiated at 50-100 mg/day. However some patients may require as high a dose as 300mg/day. Some of the newer antidepressant Venlafaxine is a phenylethylamine that was released to the US market in 1994. In 1998, it became available in an extended release form. Pharmacological profile of venlafaxine The pharmacology of venlafaxine is dose dependent At low doses only serotonin reuptake blockade At medium to high doses, both serotonin and norepinephrine reuptake blockade At very high doses, three monoamine reuptake blocked; namely dopamine as well as serotonin and norepinephrine (Muth, 1986)

Therapeutic profile of venlafaxine At medium to high doses, used for melancholic, severely depressed, inpatients and those refractory to other antidepressants. Venlafaxine was shown to be effective in some 35% of patients with treatment refractory depression (Nierenberg et al. 1994). At low doses indications same as SSRIs Used in retarded, hypersomnic, weight gaining, atypical depressives Along with its FDA indication to the treatment of depression, venlafaxine has also obtained FDA approval for the treatment of GAD. Low doses of venlafaxine (75-150 mg/day) are useful in the treatment of GAD, and most patients obtain some benefit within 2 weeks, with additional improvement seen over the next 6 weeks of treatment. Venlafaxine appears to be effective in pain conditions (Davis and Smith, 1999; Kiayias et al. 2000; Prien et al. 2000). It appears to be as useful as the TCAs and superior to the SSRIs for chronic pain. Dosages over 150 mg/day are often required. A number of studies suggest that venlafaxine may be effective in both childhood and adult attention deficit/hyperactivity disorder (ADHD) at dosages of 150-300 mg/day. Several case reports and open label studies have suggested that venlafaxine is effective in the treatment of social anxiety (Altamura et al. 1999; Lenderking et al., 1999). Likewise, venlafaxine has some demonstrated efficacy in the treatment of PTSD, including PTSD that has failed to respond to an SSRI (Hamner and Frueh, 1998). Side effects Venlafaxine side effects at low doses: (same as SSRIs) Nausea (Somewhat greater propensity for causing nausea than SSRIs, but adaptation to this side effect occurs rapidly, in the first 3 weeks of therapy). Agitation Sexual dysfunction Insomnia Venlafaxine side effects at medium to high doses: (mediated by norepinephrine and dopamine as well as serotonin) Hypertension* Severe insomnia Severe nausea Headache * This noradrenergically mediated side effect occurs in about 5% of patients at dosages less than 200 mg/day and in 13% of patients at dosages greater than 300 mg/day. The increase in blood pressure is usually modest, and only 1% of patients have to discontinue the drug because of the hypertension. Nonetheless, it is important to monitor blood pressure, particularly in the first 2 months of treatment. Reducing the dose is often helpful, can consider adding a -blocker or an -blocker. Dosage and administration Venlafaxine is available in 37.5 mg and 75 mg tablets. The usual recommended starting dosage is 75 mg a day, divided in two or three doses, to be taken with food. If there is no clinical improvement after 4 weeks, the dose can be increased by a maximum of 75 mg a day at an interval of 4 days. For moderately depressed outpatients, there is no evidence of usefulness of dosages above 225 mg a day. However, more severely depressed patients responded to higher dosages, between 350 and 375 mg a day. The maximum dose is 375 mg a day. It is recommended that the total daily dose be decreased by 50 percent for patients with hepatic or renal impairment. Elderly patients who were healthy require no dose modification. Discontinuation The relatively short half life of venlafaxine may predispose patients to an increased risk of discontinuation symptoms when the drug is stopped suddenly. Decreasing the dosage by 37.5 mg every 3 days or 75 mg per week circumvents withdrawal symptoms in many patients. Mirtazapine Mirtazapine which was released in the United States in 1996, chemically related to mianserin has FDA approval for the treatment of depression. It is useful in Depression associated with Anxiety Agitation Insomnia SSRI-induced; o Sexual dysfunction o Nausea o GI disturbance Panic Weight loss Severe depression Other subtypes of depression including atypical depression and seasonal depression, may also be responsive to mirtazapine (Falkai, 1999). Compared with the SSRIs, mirtazapine may have more rapid anxiolytic and antidepressant effects (Thompson, 1999). Mirtazapine may be useful in the treatment of panic disorder, with or without concurrent depression (Carpenter et al. 1999b). Pilot studies of mirtazapine for PTSD also appear promising (Connor et al. 1999). Side effects

Sedation (Somnolence is more evident at lower doses than at higher doses because antihistaminic effects predominate at dosage below 15 mg/day. Thus, vis-a-vis sedation, a starting dosage of 30mg/ day is often better). Weight gain Increased appetite

About 15% of patients demonstrate a significant (>20%) increase in cholesterol, and 6% of patients experience a significant increase in triglycerides. It is thus worthwhile to obtain fasting triglyceride and cholesterol levels at baseline and periodically with treatment, for patients with known hypercholesterolemia or who have a history of high triglyceride levels. Concurrent use of an HMG-CoA (3-hydroxy-3-methylgulutaryl-coenzyme A) reductase inhibitor such as atorvastatin has been anecedotally reported to reduce the cholesterol and lipid effects of mirtazapine at dosages of 10-80 mg/day. Orthostatic hypotension, or conversely hypertension, is occasionally seen in patients treated with mirtazapine. About 7% of patients experience significant dizziness, and some of this may be from postural changes. Dosage and administration The average adult starting dosage of mirtazapine is 15 mg a day administered as a single oral dose, preferably at bedtime. Controlled clinical trials have established an effective dosage range of 15 to 45 mg a day. The pharmacokinetics of mirtazapine indicate that once daily dosing is sufficient and that dose increases can be made at 4- to 5- day intervals. Elderly patients or those with renal or hepatic disease may develop higher serum concentrations than younger patients; no specific dosage appears necessary, but dosage should be increased with caution. Bupropion Bupropion is a unicyclic antidepressant which became available in a sustained release form in 1998. Therapeutic profile Bupropion appears to be effective in many types of depression including retarded depression, is safe in cardiac patients. For the treatment of bipolar depression Bupropion is a reasonable first line agent. The second FDA indication for bupropion is in smoking cessation, administered at 300 mg/day (Goldstein, 1998). Bupropion appears to be effective in the treatment of ADHD in both adults and children (Cantwell, 1998). In adolescents who have comorbid substance abuse problems, bupropion might be the first line treatment (Riggs et al. 1998). Two important uses of Bupropion are as an adjunct to SSRI treatment to augment the antidepressant effect and to counteract the sexual side effects of SSRIs. Hypersomnia Nonresponders to serotonergic agents Nontolerators of serotonergic agents Cognitive slowing/pseudodementia Side effect Bupropion has a favourable side effect profile. Common side effects are Stimulating Agitation Nausea Insomnia Seizures (4/1000): Seizures for the immediate release formulation of the drug have been reported at the rate of 4 per 1,000 at dosages less than 450 mg/day; this risk increased to 4 per 100 when the dosage was increased above 450 mg/day. The sustained release formulation appears to carry a seizure risk about 1 per 1,000 patients at dosages less than 400 mg/day. Single dose of the drug should never exceed 150 mg for the immediate release formulation and 200mg for the sustained release preparation. Dosage and administration Bupropion has a wide dosage range (i.e., 200-450 mg/day). The optimum dosage range has been 300 to 400 mg/day. Bupropion is available in 75 mg and 100mg tablets; Bupropion in a sustained release preparation is available in 100 mg and 150 mg tablets. Moclobemide Moclobemide is the best studied RIMA, it has been found to be effective in a wide spectrum of depressive illnesses, including melancholic, endogenous, atypical, psychotic (in combination with a neuroleptic), and bipolar subtypes (Fitton et al. 1992). Moclobemide appears to be effective in elderly as well as younger patients and may be effective in the treatment of social phobia. Nausea is the only side effect reported more commonly for Moclobemide than for placebo. Because Moclobemide does not increase tyramine sensitivity, the risk of dietary interactions appears low. Dosages Moclobemide is available as oral 100 or 150 mg tablets. Usual doses 300-600 mg/day. Usual maximum dose is 600 mg/day. It is usually given after meals or at bed time to minimize dietary interactions. Reboxetine Reboxetine, derivative of morpholine is a selective norepinephrine antidepressant. Therapeutic indications The only FDA approved indication for reboxetine is for the treatment of major depression. Reboxetine, appears to be superior to fluoxetine in improving social functioning. Side effects Some common side effects of Reboxetine are dry mouth, constipation, urinary hesitancy, and hypotension. Hypertension has been reported in 3% of patients. Dosages and administration The starting adult dosage is 4 mg bid. For most patients, the starting dose will be the therapeutic dose. If no response is seen by 3-4 weeks, the dosage may be increased to the maximum dosage of 10 mg/day. The half life of the drug suggests bid dosing, although qd dosing can be tried. In elderly patients, the typical starting dosage is 2 mg bid, with the maximum dosage of 6 mg/day.

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St. Jone's Wort St. Jone's Wort is the popular name for the plant Hypericum perforatum, a member of the Hypericaceae family. Manufacturers of St. Jone's Wort are pursuing an FDA indication for their preparation to treat mild to moderate depression. Mechanism of action Hypericum performatum contains many active constituents. Standard hypericin and hyperforan extracts of St. Jones Wort have been shown to have mild serotonin reuptake blocking properties. There is little evidence that St. Jones Wort produces any significant inhibition of monoamine ixidase (MAO) in vitro, although such an effect is commonly attributed to the herb. Hypericin also has affinity for sigma receptors, may inhibit COMT (catchol-O-methyltransferase), and may enhance GABA (gamma-aminobutyric acid) receptors. Side effects The common side effects of St. Jones Wort are gastrointestinal upset, photodermatitis, and fatigue. Reports of reversible neuropathy and reduced fertility are available. It has also been associated with inducing mania or hypomania less commonly. Drug interaction Recent findings suggest that St. Jones Wort is a inducer of the cytochrome P450 3A3/4 enzyme. Dosage and administration The typical dose is 0.2-1 mg of the hypericin or 900-1800 mg/day of the whole herb taken in two or three divided doses. Conclusion The therapeutic needs will continue to stimulate the development of new antidepressant drugs. During the last 15 years there has been substantial improvement in the possibilities for treatment. The development of new antidepressants has resulted in great progress with respect to side effects and toxicity, although the clinical efficacy has not yet been adequately documented for all the newer agents. Apart from the costs, this may be the reason that these drugs have not yet been able to displace the classical TCAs from the market. With the availability of so many drugs differential diagnosis of different types of depressive disorders should be investigated carefully, with a view to differential treatment. The decision of the clinical psychiatrist to use a certain antidepressant drug for a given patient may be influenced in a complex manner by many factors, which go beyond the advantages and disadvantages of the drugs discussed above. For example, the comorbidity, the age of the patient, the previous drug history and the current concomitant medication may all be considered. Even in the future, we cannot expect that there will be an ideal antidepressive agent for all cases. It will still be a question of selecting the best drug for an individual patient. DISCUSSION FISCAL CONCERNS: COST-EFFECTIVENESS OF NEWER ANTIDEPRESSANTS Depressive disorders place a significant economic burden on every society. The costs incurred could be calculated in terms of direct and indirect medical costs. Direct costs are related to the disease itself and include money spent on general practitioners, pharmacotherapy, etc. Indirect costs include the impact on productivity, days lost from work, forgone leisure time, and increased mortality (Rosenbaum and Hylan, 2002). Cost of illness studies on depression have found that direct costs comprised less than 50% of the overall burden of illness with the majority of costs being indirect (Stoudemire et al, 1986; Greenberg et al, 1993; Jonsson and Bebbington, 1993; Kind and Sorenson, 1993). Studies have also shown that depressed patients in primary care generally have 2-4 disability days per month (Ormel et al, 1994; Spitzer et al, 1995). Decision-analytic models provide the most reliable estimates of cost-effectivity of antidepressant management strategies. Economic comparisons of newer antidepressants to TCAs and SSRIs have found that the use of the former results in total direct health care expenditures that are equal to or lower than those of other antidepressants. These studies include decision-analytic models comparing the cost-effectiveness of venlafaxine compared with TCAs and SSRIs (Einarson et al, 1995) and a small hospital-based study comparing venlafaxine with TCAs and SSRIs. Two decision-analytic models in France and Austria compared mirtazapine with fluoxetine or amitriptyline and projected mirtazapine to be more cost-effective than the comparators (Brown et al, 1998). A good way of assessing cost benefit is to look at treatment cost per successfully treated patient, which obviously benefits drugs with lower rate of treatment failure, i.e SSRIs and newer antidepressants. Montgomery and Kasper (1995) performed an economic analysis of the costs of treating patients with nefazodone or imipramine for 1 year and found lower overall treatment costs for nefazodone and also lower costs per successfully treated patient. However, it is important to conduct naturalistic studies of antidepressant use in clinical practice to assess how the outcomes compare with those predicted by the decision-analytic model. Besides, prices for health care resources and decision making structures vary in different countries which puts a question mark to the generalizability of these findings to other countries, especially developing countries like India where similar evaluative studies are lacking. OLD AGE BLUES: NEWER ANTIDEPRESSANTS IN THE ELDERLY Various problems are encountered in treating depression in the elderly. Levels of circulating serum albumin are lower resulting in elevated unbound drug concentrations, and the rates of both hepatic metabolism of the drugs and renal excretion of the metabolites are lower. Pharmacokinetics of antidepressants differ in the elderly with increase in interindividual variability making dose prediction difficult. Frequent associations with physical illnesses cause considerable risks of adverse interactions with drugs for medical disorders (Aitken and Baldwin, 1998). Besides, older patients may respond more slowly, relapse is more common among elderly and its consequences more severe. In this backdrop, newer antidepressants with their highly focused pharmacodynamic profile resulting in improved safety and tolerability have a pivotal role. Some of the newer antidepressants used in older populations are: Bupropion: it is well tolerated in low to moderate doses (37.5-200mg/day). Higher doses may be associated with unwanted activation, agitation and sleep disturbance (Salzman, 1998). Its use should be avoided in patients having CNS focal disease because of increased seizure rate (Aitken and Baldwin, 1998).

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Nefazodone: Should be started in low doses (50-100 mg/day) with slow increase based on response. Higher doses may be associated with sedation. Venlafaxine: It has several advantages like low plasma protein binding and minimal effect on hepatic cytochromes. It should be started on very low doses (12.5-18.75 mg/day) to minimize nausea and headache. Some anticholinergic side-effects (Dunner, 1994) and systolic hypertension at high doses are other disadvantages. Newer antidepressants also have minimal effect on cognitive functioning in the elderly. Thus, newer antidepressants are emerging as an important choice in treatment of elderly depressives. However, they have to undergo several trials in this subgroup to dethrone the SSRIs which are still recommended for first line pharmacotherapy (Chiu et al, 2002). TOWARDS A NEW HORIZON: ANTIDEPRESSANTS OF THE FUTURE As the newer antidepressants are in the process of establishing their place in the market, the search for novel antidepressants continues targeting yet unexplored mechanisms. Some of them are on the anvil while others are in the embryonic stage. Some of the novel antidepressants are: Cleaned up imipramine like drugs Lofepramine Ipsapirone, gepirone, zalospirone, 5HT1A agonists Flibanserin 5HT1A agonist,5HT 2A antagonist Ritanserin 5HT2 antagonist Levoprotiline, Oxaprotiline NA reuptake inhibitors Flerobuterol agonist drugs Fluparoxan 2 adrenoceptor antagonists Rolipram Phosphodiesterase inhibitors MK-869 NK-1 (Substance P) antagonists R12 1919 CRF antagonists Igmesine Sigma- receptor antagonists Nemifitide Novel injectable pentapeptide Deramciclane 5HT2C inverse agonist Agomelatin Blockage of melatonin receptors BDNF replacement therapy (Stahl et al, 2003; Kasper and Schatzberg, 2003)

MYTH Vs REALITY: WHAT HAVE WE REALLY GAINED Newer antidepressants, having in them the capacity to affect diverse yet specific neurotransmitter mechanisms, came with the promise of efficacy sans adverse effects. After several years of use, the time has come to take stock of how we have really benefited from them-- Antidepressant medications which, as late as 1980s, was the exclusive domain of psychiatrists, have been increasingly embraced by primary care physicians with the advent of SSRIs and newer antidepressants. Safety, tolerability and ease of administration have popularized their use in all medical specialities. Venlafaxine has shown superiority to SSRIs in terms of response and remission rates (Thase et al, 2001). The recent meta-analysis by Smith et al (2002) extends these findings to a larger group of studies. There is also some evidence pertaining to duloxetine and milnacipram suggesting superior efficacy to SSRIs in attaining remission from depression (Puech et al, 1997; Goldstein et al, 2002; Nemeroff, 2002). There is also some evidence that SNRIs may be effective in treating the physical symptoms of depression, which may prove to be an advantage over SSRIs (Detke et al, 2002; Nemeroff, 2002). There are venlafaxine and duloxetine data suggesting effects in painful conditions comorbid with depression. An abstract of the American College of Neuropsychopharmacology (2002) by Gendreau et al. reported unpublished data on milnacipram, a highly potent dual-uptake blocker, that suggested efficacy in fibromyalgia. Newer antidepressants score significantly over TCAs in adverse-effect profile, including life-threatening cardiotoxicity. Nefazodone and mirtazapine are free from sexual dysfunction characteristic of SSRIs. MAO-B specific inhibitors and RIMAs do not require dietary restrictions. Escitalopram, the newest SSRI, has shown greater efficacy and tolerability in comparison to its predecessors (Burke, 2004). Newer antidepressants have been found to affect cognitive functions minimally, which has special relevance to elder depressives (Ravizza et al, 1998). These developments have also facilitated the study and adoption of long term maintenance treatment with antidepressants as a means of preventing recurrence. However, many of these studies have been criticized on methodological issues. Moreover, clinical experience with these drugs is limited. Thus, experts opine, the data available so far is not convincing enough to win the case for the newer drugs. More definitive and well-designed studies need to be conducted to come to firm conclusions and resolve ambiguity. FUTURE DIRECTIONS The use of combination or augmentation treatment should be evaluated to a greater degree, both in terms of early onset of actions and in therapy-resistant depression (Bech, 2002). Role of newer antidepressants in children and adolescents, pregnant and postpartum women need to be explored. Cost-effectivity analyses should be carried out in developing countries on a large scale. These could be pathfinders to correct treatment decisions. Further studies on newer antidepressants should be well-designed clinical trials: randomized, double blind, parallel group and superiority trials with larger sample size (Leon, 2004). Intracellular signal transduction cascades offer a broad variety of interesting targets for future antidepressant therapy (e.g., BDNF replacement). This should be explored further. Identification of brain regions and novel target genes of antidepressant medications may shed light on therapeutic mechanisms of action of antidepressants and the pathophysiology of depression. Search for medications that regulate mechanisms leading to mood disorders rather than having a symptomatic effect.

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