Фармакогенетика СИОЗС, ассоциации между полиморфизмом CYP2D6 и CYP2C19 и ответом на терапию антидепрессантом

An investigation of MEDLINE and other database resources was carried out to summarize the research conducted between 1970 and 2003 in the role of CYP2D6 genetics on SSRI dose exposure.^[2] Area-under-the-concentration curve (AUC) values of 5 SSRIs in poor metabolizers, intermediate metabolizers, and extensive metabolizers as a measure of bioavailability were collected. Dose adjustments were then calculated to compensate for variability in CYP2D6 metabolizer status in white patients. On the basis of metabolizer phenotype, the following dose adjustments were extrapolated for extensive vs poor metabolizers: 33%-129% for fluvoxamine, 66%-114% for paroxetine, 56%-119% for fluoxetine (including the AUC of its active metabolite), 98%-101% for citalopram, and 99-100% for sertraline. A dose adjustment of 130% for paroxetine was extrapolated for ultrarapid metabolizers.

However, the study authors concluded that dose adjustments that are based on CYP2D6 could not be recommended for SSRIs for various reasons. They noted the limited data from multiple dosing, which more accurately reflects the clinical situation; the unknown effect of saturation kinetics of some SSRIs (eg, paroxetine and fluvoxamine); and the long-term effect of inhibition of CYP2D6 by some SSRIs (eg, fluoxetine, fluvoxamine, and paroxetine) when given in chronic treatment regimens. Thus, basic human pharmacokinetic data do not strongly support routine clinical use of CYP2D6 testing.

Another study scanning 1200 Web-based articles between 1966 and 2006 for treatment of major depression found no consistent association between CYP2D6 genotype and SSRI metabolism, efficacy, or risk for side effects.^[3]Although 2 studies showed greater nonresponse to SSRIs among ultrarapid metabolizers relative to the general population, the data were inconsistent across other studies. The study authors concluded that there is no established association between plasma drug concentration and SSRI drug response at standard doses.

Finally, a study of SSRI drug response and tolerability in 1953 patients enrolled in the Sequenced Treatment of Alternatives to Relieve Depression (STAR*D) study also showed no significant association between CYP2D6 variants and citalopram response, remission, or tolerability when comparing extensive metabolizers with poor metabolizers. However, the study design included numerous concomitant medications with unknown confounding effects.^[4]

The complexity derived from interaction between multiple CYP enzymes was highlighted in a study of the impact of extensive and poor metabolizer status for CYP2D6 and CYP2C19 on the SSRI citalopram. Researchers showed that the AUC for citalopram correlated with the combined CYP2D6/CYP2C19 metabolizer status.^[5] For example, individuals with CYP2D6 extensive metabolizer/CYP2C19 poor metabolizer status showed significantly higher citalopram AUC compared with extensive/extensive metabolizer or poor/extensive metabolizer carriers. Because citalopram metabolism is preferentially catalyzed by CYP2C19 over CYP2D6, consideration of more than 1 genetic variant may be necessary to guide medication dosing decisions.

Pharmacogenomics of SSRIs: Clinical Implications

Особенности воздействия пароксетина тревожную и депрессивную симптоматику

This is rather remarkable. Everyone calls paroxetine "an antidepressant", yet at least in one important sense it works better against OCD and social anxiety than it does against depression!

In fact, is paroxetine an antidepressant at all? It works better on MADRS and very poorly on the HAMD; is this because the HAMD is a better scale of depression, and the MADRS actually measures anxiety or OCD symptoms?

That's a lovely neat theory... but in fact the HAMD-17 has two questions about anxiety, scoring 0-4 points each, so you can score up to 8 (or 12 if you count "hypochondriasis", which is basically health anxiety, so you probably should), out of a total maximum of 52. The MADRS has one anxiety item with a max score of 6 on a total of 60. So the HAMD is more "anxious" than the MADRS.

This is more than just a curiosity. Paroxetine's antidepressant effect was tiny in those aged 25 or under on the HAMD - treatment just 9% of the placebo effect - but on the MADRS in the same age group, the benefit was 35%! So what is the HAMD measuring and why is it different to the MADRS?

Honestly, it's hard to tell because the Hamilton scale is so messy. It measures depression and the other distressing symptoms which commonly go along with it. The idea, I think, was that it was meant to be a scale of the patient's overall clinical severity - how seriously they were suffering - rather than a measure of depression per se.

Paxil: The Whole Truth?

Терапия генерализованного тревожного расстройства

Studies comparing antidepressants with benzodiazepines in the treatment of GAD showed that although benzodiazepines work quickly, the antidepressants lower anxiety more effectively in the long term.[11] Antidepressants that have been approved by the United States Food and Drug Administration (FDA) for the treatment of GAD are extended-release venlafaxine,[12] duloxetine,[13] escitalopram,[14] and paroxetine.[15] Although not FDA approved, citalopram has also been found to be effective for the treatment of GAD.[16] Whereas benzodiazepines have been shown effective for shortterm anxiety, they may worsen depression, a common comorbidity of GAD, and cause other cognitive adverse effects such as sedation and anterograde amnesia. Individuals with a history of substance abuse or dependence should not use benzodiazepines, but patients with no such history rarely abuse these agents and can use them safely.[17] Buspirone and pregabalin also have proven efficacy for GAD.[18–21]

Table 1. Summary of Clinical Trials of Adjunctive Use of Atypical Antipsychotics for Treatment-Resistant Generalized Anxiety Disorder^a

Agent	Study Design	No. of Patients	Study Duration (wks)	Mean Daily Dose (mg)	Change in Assessment Score	Mean Weight Gain (lbs)b
Aripiprazole[30]	Open label	17	4.9	16.9	CGI-S: −1.6	NR
Aripiprazole[31]	Open label	10	9	NR	HAM-A: −20.6	7.1
Aripiprazole[32]	Open label	9	6	13.9	HAM-A: −12 CGI-I: 8 of 9 patients rated as much improved or very much improved	NR
Aripiprazole[33]	Open label	23	8	10.5	HAM-A: −6.7 CGI-S: −1	2.5
Olanzapine[34]	Randomized, controlled	21	6	8.7	HAM-A: olanzapine −7 vs placebo −3.9 (p=0.4) CGI-S: 67% of patients rated as not at all ill or borderline ill	11
Quetiapine[35]	Randomized, controlled	58	8	182	HAM-A: quetiapine −12.5 vs placebo −5.9 (p=0.002)	5.2
Quetiapine[36]	Randomized, controlled	22	8	120	HAM-A: quetiapine −2.6 vs placebo −0.3 (p=0.98)	2.7
Quetiapine[37]	Open label	40	12	386	HAM-A: −20.6	1.1
Risperidone[38]	Open label	16	8	1.12	HAM-A: −6.75 CGI-S: −1.53	3.9
Risperidone[39]	Randomized, controlled	40	5	1.1	HAM-A: risperidone −9.8 vs placebo −6.2 (p=0.034)	2.3
Risperidone[40]	Randomized, controlled	390	4	0.86	HAM-A: risperidone −9.26 vs placebo −9.12 (p=0.858) PaRTS-A: risperidone −8.54 vs placebo −7.61 (p=0.265)	2.65
Ziprasidone[41]	Open label	13	7	40	HAM-A: −11.2	0.2

HAM-A = Hamilton Rating Scale for Anxiety (lower scores indicate less severe symptoms of anxiety); CGI-S = Clinical Global Impressions-Severity (lower scores indicate less severe illness); CGI-I = Clinical Global Impression–Improvement; NR = not reported; PaRTS-A = Patient-Rated TroublingSymptoms for Anxiety.
^aAll atypical antipsychotic treatment was added to current antidepressant therapy.
^bIn patients who received the atypical antipsychotic.

Adjunctive Use of Atypical Antipsychotics for Treatment-resistant Generalized Anxiety Disorder

Anxiety Disorders in Children and Adolescents. Early Identification and Evidence-Based Treatment

Anxiety Disorders in Children and Adolescents

рисперидон и паксил в терапии тревожных расстройств с паническими атаками

We can identify no difference in the efficacy of paroxetine and low-dose risperidone in the treatment of panic attacks. Low-dose risperidone appears to be tolerated equally well as paroxetine. Low-dose risperidone may be an effective treatment for anxiety disorders in which panic attacks are a significant component.
A comparison of low-dose risperidone to paroxetine in the treatment of panic attacks: a randomized single-blind study.