Selective Serotonin Reuptake Inhibitors SSRIs

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Consistent with the findings described above with TCAs, treatment of depressed patients with the SSRI, fluvoxamine, results in increased PRL responses to TRP present at one week and to an even greater extent at four weeks.86 Probing of 5-HT1A receptor function using ipsapirone, buspirone and gepirone following chronic SSRI treatment gives a consistent picture of blunted cortisol, GH, psychological and hypothermic responses in healthy volunteers and patients with OCD14,101,102 suggesting both pre- and postsynaptic 5-HT1A receptors are desensitized. The blunted GH and psychological responses to buspirone are seen in spite of a three-fold increase in plasma buspirone concentrations.102 These findings are not easily reconciled, but one interpretation is that the balance of effects is enhancement of net 5-HT1A neurotransmission in spite of postsynaptic receptor desensitization.

A further presynaptic mechanism of potential importance is the effect of SSRIs on 5-HT1D receptor function. One study reports no effect of paroxetine on PRL suppression following sumatriptan103 and neither is a significant decrease in GH response seen (PJ Cowen personal communication) suggesting that SSRIs do not desensitize 5-HT1D receptors.

Studies using presynaptic 5-HT2 receptor probes to investigate the effects of SSRIs have not produced entirely consistent findings and are difficult to interpret. The 5-HTP-induced cortisol response, investigated in depressed and OCD patients after 4-12 weeks of treatment with fluoxetine97 and 8 weeks with paroxetine,82 shows an increase. A more complex finding is reported after paroxetine in healthy volunteers with marked enhancement at 1 week which is nearly back to baseline at 3 weeks.82 A reduction in plasma 5-HTP concentration following paroxetine in controls but not patients offers a pharmacokinetic explanation of this finding although it is possible that the effect of SSRIs on depressed subjects and volunteers are not the same. Studies with ^-fenfluramine in depressed patients treated with fluoxetine31 and OCD patients treated with fluvoxamine32 show increased PRL responses following treatment but in both cases the responses appear to 'normalize' rather than show enhancement compared to controls. In contrast Kasper et al98

report non-significantly blunted PRL responses to ¿^-fenfluramine in depressed patients following treatment with fluvoxamine. The cortisol response to d-fenfluramine is reportedly unaltered by fluoxetine treatment.31 Although no relationship is seen between clinical response and degree of PRL enhancement in the ^-fenfluramine studies, as discussed above, it is possible that improvement in the depressed state may at least partly account for these findings.

Results from postsynaptic 5-HT2 receptor probes are inconclusive. Hollander et al104 reports enhanced PRL and cortisol responses to mCPP in OCD patients treated with fluoxetine but plasma mCPP concentrations are increased by the SSRI making interpretation difficult. In contrast Quested et al105 report a blunting of PRL and temperature responses to intravenous mCPP in normal volunteers treated for three weeks with paroxetine. Fluoxetine is reported to enhance cortisol responses to MK-212 in depressed patients97 but no pharmacokinetic data are given.

In summary:

1. In common with TCAs, from the evidence of studies using TRP, SSRIs appear to enhance net neurotransmission through 5-HT1A receptor-mediated pathways.

2. The primary mechanism for this action is probably desensitization of presynaptic 5-HT1A receptors but there is also evidence that SSRIs induce desensitization of postsynaptic 5-HT1A receptors, a property not so far reported for TCAs. It is difficult to fully reconcile this with the overall enhancement suggested by the TRP studies.

3. There is less clarity regarding effects of SSRIs on 5-HT2 receptor-mediated pathways; enhanced neurotransmission is suggested by the studies using 5-HTP but not consistently with fenfluramine or post-synaptic 5-HT2 receptor probes.

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Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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