Heterocyclic antidepressants

The answer is b. (Katzung, pp 504-505.) Amoxapine is a heterocyclic antidepressant that has effects on norepinephrine and serotonin uptake. It is useful in psychotic patients who are depressed. The dopaminergic antagonism caused by amoxapine may lead to the amenorrhea-galactorrhea syndrome. 

Closed-angle glaucoma Topical anticholinergics Topical sympathomimetics Systemic anticholinergics Heterocyclic antidepressants Low-potency phenothiazines Antihistamines Ipratropium... 

Side effects, mainly due to serotonin reuptake inhibition include G1 upset, nervousness, and sexual dysfunction. SSRls are associated with an increased risk of falls. Hyponatraemia due to SIADH is an uncommon, but important side effect in elderly patients. Selective serotonin and norepinephrine reuptake inhibitors (S SNRls) such as venlafaxine and duloxetine are also useful in older patients. Other heterocyclic antidepressants of importance in older patients because of relative safety include bupro-prion and mirtazepine. They are reserved for patients with resistance to or intolerance of SSRls. Currently, trazodone is used mostly for sleep disturbance in depression in doses of 50-100 mg at bedtime. The monoamine oxidase inhibitors phenelzine. 

Maprotiline (Ludiomil) and amoxapine (Asendin) are heterocyclic antidepressant agents that are not members of the tricyclic family. However, their pharmacology is so similar to that of the tricyclic amines that they are included for discussion purposes with this class of agents. Desipramine and nortriptyline are major metabolites of imipramine and amitriptyline, respectively. 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

Classman, A.H. and Preud homme, X.A. (1993) Review of the cardiovascular effects of heterocyclic antidepressants. / Clin Psychiatry 54(suppl) 16-22. 

Mirtazapine is associated with modest anticholinergic side effects, including dry mouth and constipation. Anticholinergic side effects and their management are discussed in the Tricyclic and Heterocyclic Antidepressants section later in this chapter. 

Specific factors to consider are both psychiatric and physical contraindications. For example, bupropion is contraindicated in a depressed patient with a history of seizures due to the increased risk of recurrence while on this agent. Conversely, it may be an appropriate choice for a bipolar disorder with intermittent depressive episodes that is otherwise under good control with standard mood stabilizers. This consideration is based on the limited data suggesting that bupropion is less likely to induce a manic switch in comparison with standard heterocyclic antidepressants. Another example is the avoidance of benzodiazepines for the treatment of panic disorder in a patient with a history of alcohol or sedative-hypnotic abuse due to the increased risk of misuse or dependency. In this situation, a selective serotonin reuptake inhibitor (SSRI) may be more appropriate. 

One noteworthy naturalistic study (43) compared the incidence of suicidal behavior with the prescribed dose of heterocyclic antidepressant (HCA) and found the rate was 22% for low doses (i.e., less than 75 mg per day) but decreased progressively as the HCA dose was increased (i.e., 11% at 75 to 149 mg per day 1% at 150 to 249 mg per day and 0.5% at 250fall+also mg per day). This finding is even more remarkable considering that the more severely ill patients would be receiving the higher doses. 

TABLE 7-5. Summary of controlled double-blind studies of heterocyclic antidepressants... 

Similar to the heterocyclic antidepressants, antipsychotics must be used carefully and sparingly in this physiologically impaired population. In particular, low potency agents (most notably chlorpromazine) may cause extreme hypotension and hypothermia in these patients. 

Other drugs of the depressant, antianxiety, antipyschotic, and anticonvulsive types are being investigated as treatments for cocaine abuse. Those which have been or will be covered in this course include the heterocyclic antidepressants desipramine and imipramine, which diminish cocaine use and craving as well as improve the outcome in the first few months of treatment. Buprenorphine (depressant) may augment the reward system (it has been found to suppress self-administration of cocaine in monkeys). Lithium sometimes works for those who are clinically depressives. Carbamazapine, bromocriptine and mazindol are also used as well as fluphenthixol and buspirone. 

Fluoxetine was the first SSRI to reach general clinical use. Paroxetine and sertraline differ mainly in having shorter half-lives and different potencies as inhibitors of specific P450 isoenzymes. While the SSRIs have not been shown to be more effective overall than prior drugs, they lack many of the toxicities of the tricyclic and heterocyclic antidepressants. Thus, patient acceptance has been high despite adverse effects such as nausea, decreased libido, and even decreased sexual function. 

At about the same time, the drug imipramine was first produced. It was originally developed as a phenothiazine (antipsychotic), but was found to have antidepressant properties. Soon came amitriptyline, followed later by other "tricyclic" and "heterocyclic" antidepressants. 

Pugsley TA, Lippmann W. 1979. Effect of acute and chronic treatment of tandamine, a new heterocyclic antidepressant, on biogenic amine metabolism and related activities. Naunyn Schmiedebergs Arch. Pharmacol. 308 239 17... 

The uses, drug interactions, and adverse effects of the monoamine oxidase inhibitor tricyclic, selective serotonin reuptake inhibitor, and heterocyclic antidepressants are discussed. 

Clomipramine (brand name Anafranil) A heterocyclic antidepressant drug that is also effective in the treatment of obsessive-compulsive disorders. This drug should not be taken with the MAOIs. 

Doxepin (brand name Sinequan) A commonly prescribed heterocyclic antidepressant drug. It is also occasionally used for the treatment of anxiety. This medication should not be used with an MAOI. 

Most antihistamines possess anticholinergic properties that by themselves are of minor intensity but may increase considerably if given together with MAOIs. Interactions of MAOIs with antihypertensives (e.g., reserpine-type drugs) and oral antidiabetic drugs, as well as insulin and L-dopa, have all been encountered. It can be seen why MAO inhibitors are not viewed today as initial therapy except possibly in atypical depression. Certain panic and phobic reactions respond well. An important indication would be in case of therapeutic failures with the tricyclic or other heterocyclic antidepressants. 

Heterocyclic antidepressants antagonize receptors ( heterocyclic receptors) located on serotonergic neurons. This results in an increase in serotonergic outflow. In addition, antagonism of presynaptic ctj-adrenergic receptors in the CNS increases norepinephrine outflow, further contributing to mood elevation. 

Are heterocyclic antidepressants considered first-line therapeutic agents ... 

Do all heterocyclic antidepressant drugs have similar chemical structures ... 

Amoxapine is a heterocyclic antidepressant. It is a metabolite of the antipsychotic drug, loxapine, and thus has the additional action of dopaminergic blockade. This action makes it a potentially useful therapy in depressed psychotic patients. 

Izumi X Inoue T, Kitagawa N et al. Open pergolide treatemtn of tricyclic and heterocyclic antidepressant-resistant depression, j Affect Disord 2000 61 127-132. 

Fluoxetine at a dose of 20-60 mg/day, may cause a 2-4-fold increase in plasma concentration of tricyclic antidepressants (TCAs), possibly associated with signs of toxicity, including decreased energy, psychomotor retardation, sedation, dry mouth, and memory loss. The mechanism of this interaction may be attributed to the potent inhibitory effect of fluoxetine and norfluoxetine on the CYP2D6-mediated hydroxylation of TCAs. When given in combination with the heterocyclic antidepressant trazodone, fluoxetine was found to produce a significant elevation in plasma levels of both trazodone and its metabolite m-cbloropbenylpiperazine (mCPP)... 

Identify the second- and third-generation heterocyclic antidepressants and their distinctive properties. 

---