Desipramine, other antidepressants

Withdrawal Desipramine Other antidepressants Bromocriptine Amantadine Lithium L-dopa Carbamazepine... 

The serotonergic hypothesis of OCD was initially derived from clinical observations that pointed to the preferential response of patients with OCD to medications possessing a serotonergic profile. CMl and other SRls have been demonstrated to be superior not only to placebo in OCD, but also to other antidepressants, such as the noradrenergic tricyclic antidepressant desipramine [W. K. Goodman et al. 1990b H. L. Leonard et al. 1991 Zohar and Insel 1987] as well as nortriptyline, amitriptyline, and imipramine, with much of the same results [Ananth et al. 1981 Volavka et al. 1985). 

With this caveat in mind, each side of the debate has evidence to support its position. The evidence is first summarized supporting the position that SSRIs are less effective than are some other antidepressants (particularly those with dual effects on both serotonin and NE CNS systems) in patients with more severe depression or who are hospitalized. Danish investigators in two double-blind, active-controlled studies found that clomipramine produced a superior response with either paroxetine or citalopram in the treatment of patients hospitalized for major depression (116, 117). Two double-blind studies also have shown that venlafaxine and mirtazapine were more effective than fluoxetine in patients hospitalized with depression ( 114,118). Finally, there are studies showing that the addition of desipramine (one of the most selective NE reuptake inhibitors) to an SSRI can convert nonresponders or pamal responders to full response ( 119, 119a, 120). 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

As one might expect, virtually every antidepressant has been tried in combination with every other antidepressant with the possible exception of MAOIs ( 384). The combined use of desipramine and an SSRI has the best data to support its usefulness (119, 120). However, other groups have not found as robust an effect as was initially reported. 

The actions of amoxapine and maprotiline resemble those of TCAs such as desipramine. Both are potent NET inhibitors and less potent SERT inhibitors. In addition, both possess anticholinergic properties. Unlike the TCAs or other antidepressants, amoxapine is a moderate inhibitor of the postsynaptic D2 receptor. As such, amoxapine possesses some antipsychotic properties. 

It has been known since the mid-1980s that clomipramine, a potent but nonse-lective serotonin reuptake inhibitor, is effective in reducing OCD symptoms. Since then, numerous studies have confirmed the superiority of clomipramine over placebo in OCD patients, whereas other antidepressant medications with less potent inhibitory effects on serotonin reuptake (e.g., nortripytline, desipramine) seem to be ineffective in OCD. Demonstration of the anti-OCD actions of all five SSRIs, namely, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, also supports the hypothesis that the antiobsessional effects of these various pharmacologic agents is due to their potent serotonergic reuptake blocking activity. 

Stahl, S. M. 1984, Regulation of neurotransmitter receptors by desipramine and other antidepressant drugs the neurotransmitter receptor hypothesis of antidepressant action, J.Clin.Psychiatry, vol. 45, no. 10, Pt 2, pp. 37-45. 

Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing desipramine... 

Nortriptyline appears to be the one antidepressant that has a bell-shaped response curve (or therapeutic window) both doses too low and too high are less effective. Thus blood levels can be very helpful when using nortriptyline. For other antidepressants, blood levels may be helpful to see if the dose needs to be increased. Usually antidepressants are started at a low dose, for example, fluoxetine at 10-20 mg or desipramine at 10-25 mg, and titrated upward. This is because of the wide variability (greater than terifold) in absorption of these medicaitons. 

Irrespective of the mechanism of action of tricyclic antidepressants, antagonists of a2 autoreceptors per se might have a beneficial effect in depressive illness, since they facilitate noradrenergic neurotransmission. Phenoxybenzamine, dihydroergotamine and yohimbine, but not the selective ai adrenoceptor antagonist prazosin, have been shown to be synergistic with several antidepressants in decreasing B-adrenoceptor density in rat cerebral cortex.Thus combined administration of an a2 adrenoceptor blocker with other antidepressants may provide a rapid onset therapy.RS 21361 produces a more rapid onset of B-adrenoceptor desensitization by itself than desipramine. 

Trigclic Antidepressants. Imipramine (38) was introduced in the late 1950s as one of the first pharmacotherapies for depression. At that time, chlorproma2ine [50-53-3] was the first effective antipsychotic treatment to be discovered. Researchers looked for similar chemical stmctures and imipramine was found to be effective in the symptomatic treatment of depression. Over the years, other congeners, such as desipramine (39), amitriptyline (40), and dothiepin (41), were synthesized and shown to be clinically efficacious antidepressant dmgs (121). These substances, known under the general mbric of tricycHc antidepressants, share a basic chemical stmcture comprising... 

Until the introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s, tricyclic antidepressants were the most widely used drugs. The therapeutic effect of amitriptyline and imipramine are related to their ability to inhibit the presynaptic reuptake of both NA and 5-HT. They are referred to as non-selective reuptake inhibitors, whereas many of the other tricyclics are more selective thus, clomipramine is a selective reuptake inhibitor for 5-HT and desipramine and nortriptyline are selective... 

Desipramine has been used to facilitate withdrawal from chronic PCP use. The rationale is that PCP depletes norepinephrine concentrations in brain, and that this tricyclic antidepressant is the most selective blocker of norepinephrine uptake. Consequently, some of the deficiency of the neurotransmitter could be remedied. A dose of 25 to 50 mg was said to reduce craving for several hours. Six of eight patients treated with this drug were successfully withdrawn, while none of the eight offered other types of programs were successful (45). 

Tricyclic Antidepressants (TCAs). The TCAs have been nsed to treat ADHD for 30 or more years. Most often used are imipramine (Tofranil) and desipramine (Norpramin), mainly becanse they are the TCAs that most specihcally increase norepinephrine activity. Remember, boosting norepinephrine activity in the brain shonld improve attention. Other TCAs, namely, amitriptyline (Elavil, Endep) and nortriptyline (Pamelor), have been used, though they also increase norepinephrine activity. TCAs do offer a modest benefit for both the inattention and the hyperactivity of ADHD. In addition, they are often effective at doses mnch lower than those required to treat depression. However, their effectiveness nsnally falls short of the stimulant medications. In addition, TCAs have considerable side effects including dry mouth, constipation, drowsiness, weight gain, and adverse cardiac effects. 

Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the... 

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). 

Other alternatives to the stimulants that have been studied for treatment of ADHD in children and adults include the tricyclic antidepressants desipramine and nortriptyline the newer antidepressants bupropion, venlafaxine, and atomoxetine the beta-blocker pindolol and the selective monoamine oxidase inhibitor, deprenyl. Across these agents, the number of controlled studies varies from none (nortriptyline) to four (bupropion). Only deprenyl and desipramine have been studied in children with ADHD and tic disorders. 

Since that time, many other tricyclic antidepressants have been studied and put into use. They are all structurally related to imipramine. The active metabolite of imipramine is desipramine. This means that imipramine breaks down into desipramine in the body, and the resulting desipramine actually improves mood. Because their structures are so similar, scientists assume that they have a similar action in the body. 

This antidepressant can interact with other drugs via its two mechanisms of action serotonin and NE uptake inhibition. The former action means that the same pharmacodynamic interactions will occur with venlafaxine as with SSRIs, including the serotonin syndrome. At higher doses, venlafaxine is also prone to the same pharmacodynamic interactions as NSRIs such as secondary amine TCAs like desipramine and with newer NSRIs such reboxetine. Thus, the combination of high-dose venlafaxine plus an MAOl could produce a hypertensive crisis as well as the serotonin syndrome. 

Like alprazolam, clonazepam may cause treatment-emergent depression in some patients. Pollack et al. (42) also reported that only 10% of their patients who remained on clonazepam had a history of depression, although 47% lost to follow-up and 30% who eventually required alternate treatment had histories of dysthymia or depression. Of 31 patients without a prior history of affective illness, depression developed in three on low daily dosages (0.75, 1.5, and 2 mg), one was switched to alprazolam, and the others responded to the addition of desipramine or imipramine. These investigators recommend that, until further data are available, PD patients with chronic or concurrent depression should not be given clonazepam alone and that those in whom depression develops during clonazepam therapy should have their dose lowered or an adjunctive antidepressant added. 

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