Antidepressants atypical

Maprotiline has relatively minor anticholinergic properties compared to amitriptyline. It has a very large elimination half-life of 36 to 48 h and in large doses produces convulsions. 

Amoxapine has neuroleptic properties that stem from its dopamine receptor-binding affinity. Similar to the neuroleptics, it may produce movement disorders. In toxic doses, amoxapine may provoke difficult-to-control convulsions. 

Fluoxetine selectively blocks the uptake of serotonin. It is devoid of anticholinergic properties and hence has little or no effect on the cardiovascular system, including orthostatic hypotension or arrhythmias. 

Trazodone is perhaps the most sedative antidepressant available. It is devoid of anticholinergic effects and causes postural hypotension as well as rarely serious priapism. 

Bupropion is free of anticholinergic, antiadrenergic, and cardiotoxic properties. Its structure is related to that of amphetamine and it possesses stimulating effects hence it may be useful in hyperphagic or obese individuals. 

---

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Atypical Antidepressants. StmcturaHy diverse dmgs such as the tetracyclic mianserin (46) and various bicyclic and tricyclic compounds such as trazodone (47), venlafaxine (48), nefazodone (49), and amfebutamone (50) are atypical antidepressants. The exact mechanism of action is unclear but probably... 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

Despite public misconceptions, there is little firm evidence that the typical and atypical antidepressants produce dependence in clinical users. A review of 21 case reports of antidepressant addiction revealed that 12 were associated with tranylcypromine, although 8 of these 12 had a previous history of substance misuse (Haddad, 1999). Tranylcypromine s structural similarity to amphetamine may account for the significant number of reports of its addictive potential, but even here the term (mild) discontinuation reaction rather than withdrawal reaction should be used to allay any concerns patients might have (Haddad, 1999). 

Venlafaxine An atypical antidepressant that inhibits the reuptake of both serotonin and noradrenaline. 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

There are numerous antidepressant medications on the market (table 7.1). Following development of monoamine oxidase (MAO) inhibitors were tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and several atypical antidepressants (Baldessarini 1996). Successive generations of antidepressants have not necessarily become more effective in treating depression, but rather offer more favorable side-effect profiles—a crucial factor in effective clinical pharmacotherapy. An effective medication is not useful if its side effects are intolerable. 

Future directions for research on hypericum may continue the work done in clinical efficacy. More specifically, studies may be of interest that examine its effects in treatment of more severe depression and different subtypes of depression. The comparative efficacy of different hypericum preparations could be further investigated, and optimum dosages need to be established (Linde et al. 1996). Further work is needed to compare hypericum s efficacy and side effects with those of the SSRIs or atypical antidepressants, because published studies to date have only compared it with tricyclics. 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

Atypical antidepressants Bupropion Duloxetine Mianserin Mirtazapine Nefazodone Reboxetine Trazodone Venlafaxine... 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

When starting a SSRI, the abrupt increase in serotonin may cause side effects. In the brain, the short-term effects include headache, sleep disturbance, nervousness, anxiety, and tremulousness. The digestive system effects include nausea, loose stools, decreased appetite, and indigestion. Most of these effects are mild and shortlived or can be managed with over-the-counter remedies. Nausea, for example, can be minimized by taking a SSRI after meals. These effects are also commonly seen with venlafaxine and duloxetine, atypical antidepressants that block serotonin reuptake like the SSRIs. 

Atypical Antidepressants. The atypical antidepressants are not a true class in the same sense as SSRIs or TCAs. There is no unifying property to these antidepressants. Each of these antidepressants is actually a class unto itself that is structurally and functionally different from all other antidepressants. The atypical antidepressants include trazodone (Desyrel), bupropion (Wellbutrin), venlafaxine (Effexor), duloxetine (Cymbalta), nefazodone (Serzone), and mirtazapine (Remeron). 

Trazodone (Desyrel). Trazodone was the first of the atypical antidepressants and was actually introduced prior to the SSRIs. It does not have the serious cardiac toxicity or anticholinergic side effects of the TCAs and was the most popular antidepressant until the arrival of the SSRIs. It is approved for the treatment of depression and is also commonly used in low doses to treat agitation in demented patients and insomnia. 

Mirtazapine (Remeron). Mirtazapine is the newest of the atypical antidepressants. It mainly works by blocking the alpha-2 negative feedback receptor and thus increases norepinephrine and serotonin activity. In addition, mirtazapine blocks serotonin-2 and serotonin-3 receptors to produce a specific serotonin action like nefazodone. Mirtazapine is approved for the treatment of depression. Its use in the anxiety disorders is being studied. 

The fourth factor influencing medication choice is the safety of the medication. This is especially important given the snicide potential of depressed patients. The newer antidepressants, inclnding the SSRls and so-called atypical antidepressants, are mnch safer in overdose than the older TCAs and MAOIs. In the case of the TCAs, ingestion of a 1-2 week snpply is lethal 50% of the time. 

Atypical Antidepressants. Preliminary open label studies suggested that ven-lafaxine and trazodone might be effective for OCD. However, controlled studies have not yet been completed for venlafaxine, and a controlled study of trazodone (100-200 mg/day) did not find it an effective treatment for OCD. 

Atypical Antidepressants. Initial open label studies of nefazodone and mir-tazapine have been conducted and offer promise, though one negative controlled study with the former has been reported. Further studies are needed. 

Atypical Antidepressants. None of the so-called atypical antidepressants have been tested in the treatment of AN. However, mianserin, an antidepressant available in Europe, has been found to increase body weight in patients with various depressive disorders. Although bupropion (Wellbutrin, Zyban) has not been tested in the treatment of AN, it is effective in the treatment of BN. However, immediate-release bupropion is associated with an especially high risk for seizures in these patients and is therefore contraindicated in those with eating disorders. The seizure risk associated with sustained-release bupropion remains unclear at this time, as the doses studied have not been as high as those for immediate-release bupropion. 

Antidepressants. In the early 1980s, the recognition that depression is a frequent comorbid feature of BN coupled with the observation that appetite changes are a common feature of depression led researchers to evaluate antidepressant treatment for BN. Since that time, a series of controlled studies have demonstrated efficacy for a wide assortment of antidepressants including the TCAs imipramine (Tofranil) and desipramine (Norpramin), the MAOl phenelzine (Nardil), the SSRl fluoxetine (Prozac), and the atypical antidepressants trazodone (Desyrel) and bupropion (Wellbutrin). Overall, approximately two-thirds of antidepressant-treated patients with bulimia experience symptomatic improvement while nearly one-third achieves complete remission of binging and purging. In addition, the improvement in the symptoms of BN is not dependent on the presence of comorbid depression. 

Bupropion (Wellbutrin, Zyban). Bupropion is a newer atypical antidepressant that was initially suggested to increase both norepinephrine and dopamine activity in the brain, though controversy surrounds this hypothesis. Although bupropion has not been studied extensively in ADHD, early evidence does indeed indicate that it may be effective for both inattention and hyperactivity/impulsivity. Its effectiveness for ADHD does not appear to rival the stimulant medications, though a recent controlled study for adult ADHD showed that bupropiou outperformed placebo. 

The so-called atypical antidepressants such as venlafaxine and bupropion can be tried, but their safety and efficacy in treating patients with dementia have not been well studied. The older tricyclic antidepressants and monoamine oxidase inhibitors are not tolerated well by demented patients and should be avoided. Two possible exceptions are nortriptyline (Pamelor) and desipramine (Norpramin), but even these should be tried only after the newer antidepressants have proved ineffective. 

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

Blocking the norepinephrine alpha-2 receptor can also increase norepinephrine activity. The alpha-2 receptor provides feedback to the neurons to stop releasing norepinephrine and, for that matter, serotonin. By blocking the alpha-2 receptor, norepinephrine and serotonin are more readily released. The atypical antidepressant mirtazapine (Remeron) acts in part in this manner (see Table 13.2). 

Serendipity has played a major role in the discovery of most classes of psychotropic drugs. For example, the observation that the first antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors, impeded the reuptake of biogenic amines into brain slices, or inhibited their metabolism, following their acute administration to rats, provided the experimenter with a mechanism that could be easily investigated in vitro. Such methods led to the development of numerous antidepressants that differed in their potency, and to some extent in their side effects (for example, the selective serotonin reuptake inhibitors) but did little to further the development of novel antidepressants showing greater therapeutic efficacy. The accidental discovery of atypical antidepressants such as mianserin led to the broadening of the basis of the animal models... 

There are four classes of antidepressants tricyclic antidepressants (imipramine, trimipramine, amitriptyline, doxepin, desipramine, protriptyline, nortriptyline, amoxapine, maprotiline) monoaminooxidase (MAO) inhibitors (phenelzine, isocarboxazid, tranylcypromine) second-generation antidepressants or atypical antidepressants, which are a chemically dissimilar group of recently proposed drugs (bupropion, trazodone, fluoxetine) and amphetamines and other stimulators of the CNS (dextroamphetamine, methylphenidate). 

Bupropion belongs to the chemical class of aminoketones. It is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist. Initially developed and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. If given to lactating women it can trigger convulsions in the newborn. 

Popoli M, Zanotti S, RadaeUi R, Gaggianesi C, Verona M, Brunello N, Racagni G (1997b) The neurotransmitter release machinery as a site of action for psychotropic drugs effect of typical and atypical antidepressants. Soc Neurosci Abstr 2325 Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64 51-68... 

Atypical antidepressants such as Wellbutrin simultaneously target the neurotransmitters dopamine and norepinephrine. 

This chapter will review available atypical antidepressants and will specifically discuss their uses in children and adolescents. At this time, it is important to note that none of the agents discussed in the chapter have an FDA indication for use in children and adolescents however, the use of these agents in children and adolescents is increasing, and knowledge of these agents is critical for both research and clinical practice. 

In this chapter the basics of the available atypical antidepressants and those that may soon to come on the market have been reviewed. The atypical antidepressants are less readily used, and their benefits for treating depression and anxiety are not fully appreciated. The atypical antidepressants may provide benefit for conditions such as ADHD or offer an alternative to other antidepressants with problematic side effects (i.e., activation on SSRIs). They may also provide specific relief for troublesome symptoms (i.e., nefazodone s normalization of sleep architecture). 

The future of atypical antidepressants in the treatment of psychiatric disorders is bright. Advances in neuroscience are being followed closely by those involved in drug development. It is likely that in the future more unique, novel agents will be developed. Such collaborative efforts will make safer and more effective medications for childhood psychiatric disorders possible. 

Pteskotn, S.H., and Othmet, S.C. (1984) Evaluation of bupropion hydrochloride the fitst of a new class of atypical antidepressants. Pharmacotherapy 4 20-34. 

Manier DH, Gillespie DD, Sulser E Dual aminergic regulation of central beta adrenoceptors effect of atypical antidepressants and 5-hydroxytryptophan. Neuropsychopharmacology 2 89-95, 1989... 

Nalepa I, Vetulani J Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram. J Neurochem 60 2029-2035, 1993 Nalepa I, Vetulani J The responsiveness of cerebral cortical adrenergic receptors after chronic administration of atypical antidepressant mianserin. J Psychiatry Neurosci 19 (2) 120, 1994... 

---