Tricyclic antidepressants with stimulants

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

The atypical tricyclic antidepressant amineptine (Survector) is an indirect dopamine agonist, which selectively inhibits dopamine uptake and induces its release, with additional stimulation of the adrenergic system. Its antidepressant effects are similar to those of other tricyclic antidepressant drugs. However, it acts more rapidly, is better... 

The prevalence of concurrent prescriptions raises concern regarding drug interactions with stimulants. Stimulants, especially MPH, have been used to augment the effects of tricyclic antidepressants in the treatment of refractory depression. Although one early report claimed that circulating levels of imipramine can rise seven fold when taken concurrently with MPH (Wharton et al., 1971), a more recent study found that combining stimulants with desipramine (DMI) did not increase the plasma level of DMI relative to children treated with DMI alone (Cohen et al., 1999). 

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. 

Glucagon has also been used to stimulate insulin and C-peptide secretion, to see whether the islets still produce insulin, as a stimulatory test during pheochromocytoma, hyperinsulinism, and Zollinger-Ellison syndrome, or as an additive in upper gastrointestinal X-ray investigations (0.5-1 mg). It has been used in myocardial infarction, although its inotropic effects may present a risk. It has also been used to treat overdoses with beta-blockers (3) and calcium channel blockers (4), although its efficacy in such cases has only been demonstrated in animals (5) and to treat overdose with tricyclic antidepressants (6,7). 

Prolactin concentrations are very rarely altered during treatment with tricyclic antidepressants, but this is more likely to occur and to produce galactorrhea or amenorrhea with clomipramine and amoxapine and when there are other contributory factors that may stimulate prolactin secretion, such as stress or electroconvulsive therapy (1139). 

MAO inhibitors are indicated for depressed patients who are unresponsive or allergic to tricyclic antidepressants or who experience strong anxiety. Patients with low psychomotor activity may benefit from the stimulant properties of MAO inhibitors. These drugs are also useful in the treatment of phobic states. A special subcategory of depression, called atypical depression, may respond to MAOIs. Atypical depresssion is characterized by labile mood, rejection sensitivity and appetite disorders. 

Many patients with mild to moderate depression are aware of the potential benefits of the herbal remedy St. John s Wort (Hypericum perforatum). The active ingredients in the h3rpericum extract have yet to be identified and their mode of action is unclear, although it has been postulated that several of the known mechanisms of existing antidepressants are incorporated (inhibition of monoamine reuptake and the monoamine oxidase enzyme, as well as a stimulation of GABA receptors). Much of the original research into the efficacy of St. John s Wort was performed in Germany where its use is well established. Several direct comparisons with tricyclic antidepressants have shown equivalent rates of response but these studies should be interpreted with caution since many trials failed to... 

Medications play an important part in the treatment of ADD. Stimulants are the mainstay of the treatment of ADD methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and pemoline (Cylert). These differ in their half-lives, with Ritalin having the shortest and Cylert the longest. A warning has recently been issued about Cylert because of reports of sometimes fatal liver toxicity. Thus, it is recommended that it be used only if methylphenidate and dextroamphetamine are ineffective. There is individual variability in resporise, so that a person who does not respond to one may respond well to another. Other medications can also be effective in the treatment of ADD and may be useful, especially in residual ADD, where substance abuse may be an issue. These include tricyclic antidepressants (especially desipramine and imi-pramine) SSRIs, bupropion, venlafaxine, and clonidine. There are reports of antipsy-chotics and lithium being helpful in selected cases, as well. 

Some studies have implied that several tricyclic antidepressants may be able to stimulate tumor growth in animals or humans with existing tumors. However, recent research using human and murine in vitro models have not been able to support these findings. 

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