PubMed · 10173270
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G Cowley, K Springen. 1997-09-29. After fen-phen.. https://pubmed.ncbi.nlm.nih.gov/10173270/
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BACKGROUND: Pharmacologic treatment of emotional disorders in HIV-infected patients can be more easily optimized by understanding of potential interactions of psychotropic drugs with medications used to treat HIV infection and its sequelae. METHODS: Biotransformation of the antidepressant trazodone to its principal metabolite, meta-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. Interactions of trazodone with the azole antifungal agent, ketoconazole, and with human immunodeficiency virus protease inhibitors (HIVPIs) were studied in the same system. RESULTS: Formation of mCPP from trazodone in liver microsomes had a mean (+/- SE) K(m) value of 163 (+/- 21) micromol/L. Ketoconazole, a relatively specific CYP3A inhibitor, impaired mCPP formation consistent with a competitive mechanism, having an inhibition constant (K(i)) of 0.12 (+/- 0.01) micromol/L. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the K(m) was 180 micromol/L, consistent with the value in microsomes. The HIVPI ritonavir was a potent inhibitor of mCPP formation in liver microsomes (K(i) = 0.14 +/- 0.04 micromol/L). The HIVPI indinavir was also a strong inhibitor, whereas saquinavir and nelfinavir were weaker inhibitors. CONCLUSIONS: CYP3A-mediated clearance of trazodone is inhibited by ketoconazole, ritonavir and indinavir, and indicates the likelihood of pharmacokinetic interactions in vivo.
RATIONALE: Previous studies showed that adjunctive paroxetine increases tricyclic antidepressant (TCA) serum levels by inhibiting cytochrome P4502D6. This effect has, however, been examined only in experimental studies using low doses of TCAs in healthy volunteers. OBJECTIVE: The present study investigated TCA serum level changes and side-effects after the addition of paroxetine in depressed patients treated with doses customarily used for inpatients. METHODS: 14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (< or = 25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n = 9) or imipramine (n = 5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady state conditions. RESULTS: After 2 weeks the serum levels of the metabolites nortriptyline (from 88 +/- 49 ng/ml to 176 +/- 57 ng/ml) and desipramine (from 152 +/- 78 ng/ml to 338 +/- 104 ng/ml) had risen to a significantly greater extent than those of the parent compounds amitriptyline (123 +/- 50 ng/ml to 195 +/- 128 ng/ml) and imipramine (from 75 +/- 36 ng/ml to 98 +/- 51 ng/ml). It is noteworthy that, with the exception of one case of incipient delirium, the combination therapy was well tolerated despite high TCA serum level rises. CONCLUSION: The higher increase of the metabolites as compared with the parent compounds can be explained by a paroxetine-induced inhibition of the liver enzyme cytochrome P4502D6, which catalyses the second step of the TCA metabolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine.
BACKGROUND: Previous reports document visual illusions resembling hallucinogen persisting perception disorder (HPPD) after risperidone treatment in patients with histories of previous LSD exposure. METHODS: We report a case with visual disturbances resembling HPPD after each of three consecutive risperidone dose increases. RESULTS: Contrasting with previous reports, our patient lacked any history of substance abuse, particularly hallucinogen exposure. She lacked neurologic or other contributory illnesses. Illusions generally remitted within 48 hours each time. Coadministration of trazodone and clonazepam may have contributed to these phenomena, although clonazepam has been used to treat this condition. She had been unusually sensitive to the side-effects of many psychotropics. CONCLUSIONS: This case is unique due to the absence of substance abuse. This and another report note heightened sensitivity to medication side-effects. Visual phenomena resembling HPPD evidently can occur with risperidone and, possibly, other atypical antipsychotics and certain antidepressants regardless of previous hallucinogen use. Several lines of evidence implicate reduced 5HT2a serotonin receptor stimulation rather than increased 5HT2c stimulation.