Tricyclic Antidepressants TCAs

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Although TCAs are traditionally considered as a group, individual drugs differ in important properties and receptor binding profiles. Clomipramine and, to a lesser extent, amitriptyline and imipramine have greater 5-HT reuptake inhibiting properties than other TCAs. Sedative and non-sedative TCAs differ in H1 receptor antagonism and 5-HT2 receptor antagonism varies between drugs.83 The property most shared is their ability to inhibit noradrenaline reuptake.83

TRP challenge generally reveals a consistent picture of enhanced PRL responses by TCAs. This is seen in normal volunteers with acute clomipramine15 and chronic desipramine.84 In depressed patients similar findings occur with desipramine85,86 and amitriptyline.85,87 In the study using amitriptyline by Cowen et al87 this effect was only evident if three patients with pretreatment weight loss were excluded, probably because weight loss is itself associated with increased PRL responses to TRP in women.88 The enhancement with clomipramine occurs acutely (presumably related to acute 5-HT reuptake inhibition; see also: SSRIs, below) whereas chronic treatment is required with desipramine86 suggesting that a different mechanism is involved (possibly pre- or postsynaptic 5-HTiA receptor changes, but see below). The increase in PRL responses is not related to clinical response.85-87 Changes in GH responses after TCAs have been less consistent (where reported) with increases seen with acute clomipramine15 but not with chronic amitriptyline87 or desipramine.84

These results suggest that 5-HTiA receptor-mediated neurotransmission may be enhanced by TCAs, at least in some pathways, and that this is not just a consequence of 5-HT reuptake inhibition (which is unlikely by itself to account for antidepressant effects given the time lag in onset of antidepressant action). A possible mechanism for this, as suggested by the 5-HTiA enhancement model, is increased postsynaptic 5-HTiA receptor sensitivity but studies with 5-HT1A receptor agonists do not support this:

1. a normal volunteer study with lofepramine found no alteration in the GH (or PRL) response to buspirone89 and

2. Lesch et al90 report no alteration in the ACTH/cortisol response to ipsapirone in depressed patients treated with amitriptyline.

An alternative explanation is increased serotonergic neuronal firing due to the desensitization of 5-HTiA autoreceptors and studies using the hypothermic response to azapirones, a possible index of presynaptic 5-HTiA receptor function (but see page 116), provide some support for this in that amitriptyline causes blunted hypothermic response to ipsapirone90 and buspirone.91 However, desensitization of 5-HTiA autoreceptors (also seen with the SSRIs, see page 119) is not found with lofepramine, a selective noradrenaline reuptake inhibitor, as measured by buspirone-induced hypothermia in one volunteer study89 suggesting that 5-HTiA autoreceptor desensitization may depend on 5-HT reuptake inhibition and that noradrenaline reuptake inhibitors increase presynaptic 5-HT neuronal function by a different mechanism. One way this could occur is through sensitization of 5-HT cell body ai-adrenoceptors or desensitization of terminal a2-heteroreceptors.41,92-95 This would result in increased 5-HT neuronal firing or terminal release of 5-HT and is consistent with the observation that TCA treatment results in blunted GH responses to the a2-adrenoceptor agonist, clonidine.96

With regard to the effect of TCAs on putative 5-HT2-mediated responses to presynaptic pharmacological challenge, Meltzer97 reports that three to six weeks treatment of 14 patients with depressive illness or OCD with a mixed group of TCAs (including 1 patient on maprotiline) has no effect on the cortisol response to 5-HTP. Studies using fenfluramine challenge give inconsistent findings in depressed patients with enhanced PRL responses following treatment with clomipramine, imipramine and amitriptyline29-31 but non-significantly lower responses to a mixed group of antidepressants (mostly TCAs) in another a study.98 In studies using the more noradrenaline-specific reuptake inhibitors, nortriptyline and maprotiline, decreased PRL responses are reported98,99 although only the study with nortriptyline reached statistical significance, and then at five, but not three, weeks treatment. One possible interpretation is that TCAs with 5-HT reuptake properties result in enhanced 5-HT2-mediated function but noradrenaline-specific drugs are associated with reduced function. Caution is needed in the interpretation of these results because of the potential confound of alterations in mood state and the lack of studies using healthy volunteers, e.g., in the study by O'Keane et al31 the PRL responses are reported to 'normalize' and there is no effect of treatment on cortisol responses. This is consistent with the study by Leatherman et al100 reporting that clomipramine-induced PRL responses increase after mixed antidepressant treatment in responders, but not non-responders, suggesting a state-dependent rather than pharmacological explanation. There are few data on the effects of TCAs on putative 5-HT2-mediated responses to postsynaptic pharmacological challenge; surprisingly there appear to be no studies using mCPP and only one study using MK-21297 which reports no alteration in cortisol responses after three to six weeks treatment of nine patients with depressive disorder or OCD using an unspecified range of TCAs.

In summary:

1. TCAs appear to enhance 5-HT1A neurotransmission by an action on the presynaptic 5-HT neuron without altering postsynaptic 5-HT1A receptor sensitivity.

2. TCAs, with and without 5-HT reuptake inhibitor properties, may enhance 5-HT1A neurotransmission by different mechanisms. This suggestion however rests on the findings of one study.89

3. Effects on 5-HT2 receptor pathways are somewhat conflicting and potentially confounded by changes in illness condition. While no consistent overall effects emerge, it is possible that noradrenaline-specific TCAs decrease 5-HT2 function while those with 5-HT reuptake inhibition result in enhanced function.

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