Based on theoretical consideration a complex interaction between genotype, behavioral or syndromal dimensions, and drug response has been predicted
(Catalano 1999). A given genetic predisposition, such as allelic variation in 5HTT function, may lead to both increased susceptibility to anxious or depressive features and less favorable antidepressant responses in patients affected by mood disorders. Impaired 5HTT function confers, if any, only a very modest susceptibility to depressed states, because adaptive mechanisms are likely to compensate for the deficiency, while more robust alterations of 5HT turnover observed during antidepressant treatment revealed robust effects of allelic variation of 5HTT function, 7-20% of variance of treatment effect) that lead to variable SSRI efficacy. Pharmacogenetic and other treatment response studies of the serotonin transporter gene are summarized in the following sections and in Table 1.
Smeraldi and associates (1998) investigated whether the 5HTTLPR genotype is related to the antidepressant response to the SSRI fluvoxamine and/or augmentation with the 5HT1A receptor antagonist pindolol in patients with major depression with psychotic features who had been randomly assigned to treatment with a fixed dose of fluvoxamine and either placebo or pindolol for 6 weeks. Both homozygotes for the l variant (l/l genotype) of the 5HTTLPR and heterozygotes (l/s) showed a better response to fluvoxamine than patients homozygous for the s variant (s/s). Interestingly, in the group treated with fluvoxamine plus pindolol all the genotypes acted like l/l treated with fluvoxamine alone and the genetic effect could not be detected. Thus, SSRI efficacy in delusional depression seems to be related, in part, to genetic variation of 5HTT function that in the subjects with s/s genotype pindolol may have compensated for the altered transcriptional activity of the 5HTT gene.
The effect of the 5HTTLPR genotype on antidepressant response was replicated in an independent sample of depressed patients treated with the SSRI paroxetine (Zanardi et al. 2000). In a study of elderly patients treated for depression, Pollock and associates (2000) found that patients with a l/l genotype displayed a faster response to paroxetine. The association appeared specific to paroxetine, as there was no genotypic difference with respect to the antidepressant response to nortriptyline, a predominantly noradrenergic drug. The same group also demonstrated an influence of the 5HTTLPR on platelet activation in geriatric depression (Whyte et al. 2001). More recently, Rausch and coworkers (2002) reported an association between the 5HTTLPR l/l genotype and improved response to fluoxetine and a placebo-controlled study confirmed a significant increase in response to the SSRI sertraline in elderly depressed patients homozygous for the l allele of 5HTTLPR compared with patients carrying one or two copies of the s variant. No significant difference was observed in the placebo group (Durham et al. 2003). Arias et al. (2003) confirmed the results of previous studies demonstrating a similar association between 5HTTLPR genotype and an therapeutic effect of the most selective SSRI citalopram. In patients with depression, the remission in the course of treatment was less likely in subjects with the s/s genotype.
Table 1. Pharmacogenetic and other treatment response studies of the serotonin transporter gene
Smeraldi et al.1998 Major depression (n=56)
Major depression (n=46)
Zanardi et al. 2000 Pollock et al. 2000
Kim et al. 2000
Yu et al. 2002 Yoshida et al. 2002 Durham et al. 2003
Perlis et al. 2003 Joyce et al. 2003
Arias et al. 2003
Major depression (n=58)
Major depression (n=95), elderly patients
Major depression (n=120), controls (n=252), Koreans
Major depression (n=121), Chinese Major depression (n=66), Japanese Major depression (n=206), elderly patients, placebo-controlled Major depression (n=36)
Major depression (n=169)
Major depression (n=131)
Response to fluvoxamine Response to fluvoxamine
pindolol Response to paroxetine Response to paroxetine or nortriptyline Response to paroxetine or fluoxetine
Response to fluoxetine Response to fluvoxamine Response time to sertraline
Adverse effects of fluoxetine
Response to fluoxetine or nortriptyline
Remission during citalopram
Better response in l/l and l/s subjects compared to s/s No difference in response to combination
Better response in l/l and l/s subjects compared to s/s More rapid response to paroxetine in l/l subjects, no effect on nortriptyline response Better response in s/s subjects, intron 2 VNTR also associated with response)
Better response in l/l subjects, l/l genotype less common Better response in s/s subjects, l/l genotype rare
Shortened response delay in l/l subjects at week 1 and 2 compared to l/s and s/s; no difference in placebo group Higher rate of insomnia and agitation in s/s subjects compared to l/s and l/l
Better response to both fluoxetine and nortriptyline in l/l and l/s subjects older than 25 years compared to s/s Higher rate of s/s in nonremission group compared to remission group
These findings may, however, apply primarily to European populations. Treatment of Korean and Japanese patient samples with fluoxetine, paroxetine, and fluvoxamine showed contradictory results as a better response was found in patients with a s/s genotype (Kim et al. 2000; Yoshida et al. 2002), whereas Yu and coworkers (2002) reported a superior response to fluoxetine in l/l in depressed patients from China. Possible explanations for these discrepancies are manifold. For example, allele frequencies of the 5HTTLPR l variant between European populations and both the Korean and the Japanese population differ significantly (54% vs. 25% and 26%). A low frequency of the l allele in both of these studies resulted in a small number of homozygous l/l patients. Furthermore, ethnic as well as environmental differences could also influence the genotypic response to SSRIs.
Table 1 (continued): Pharmacogenetic and other treatment response studies of the serotonin transporter gene.
Sleep deprivation/ Sample light therapy
Benedetti et al. 1999
Benedetti et al. 2003
Del Zompo et al. 1999
Bipolar disorder, depressed (n=68) Bipolar disorder, depressed (n=22)
Bipolar disorder (n=67), controls (n=103)
Serretti et al. 2001 Bipolar disorder (n=167), unipolar depression
Switch, rapid cycling
Mundo et al. 2001 Bipolar disorder, antidepressant-induced mania, IM+( n=27), bipolar disorder, IM-( n=29) Rousseva et al. Bipolar disorder 2003 (n=305)
Arranz et al. 2000 Schizophrenic disorder (n=200)
Whale et al. 2000
Antidepressant effect of Better effect in l/l subjects sleep deprivation compared to l/s and s/s Antidepressant effect of Effect more marked in l/l light therapy combined subjects compared to l/s and with sleep deprivation s/s
Response to lithium, 49 responders,
Effect of prophylactic lithium treatment (episode frequency)
Healthy females (n=7, l/l genotype), Healthy females, (n=7, s/s genotype) Male alcohol dependence (n=14), healthy (n=13)
Higher frequency of l allele in nonresponders compared to controls
Fewer episodes before lithium treatment, but less reduction of episodes in s/s patients
Presence/absence of mania (IM+/IM-) during antidepressant treatment
Lifetime history of antidepressant-induced mania/rapid cycling
Response to clozapine
Clomipramine-induced prolactin response
Increased frequency of s allele in IM+ compared to IM-; no effect of intron 2 VNTR
Increased frequency of s allele in subjects with rapid cycling but not with antidepressant-induced mania
Higher rate of s/s in non-response group; five other primarily serotonergic genotypes contribute to the prediction of response
Higher response in l/l subjects
Fenfluramine-induced Higher response in l/l subjects prolactin response
Furthermore, an interaction between 5HTTLPR genotype and therapeutic efficacy of the antimanic/antibipolar agent lithium, which is assumed to act via serotonergic mechanisms, was demonstrated. Del Zompo and coworkers (1999)
reported a trend towards higher frequency of the l allele among lithium nonresponders compared to controls. Serretti et al. (2001) found an opposite result: the group homozygous for the s variant showed poorer response. However, this association appears to have been mainly due to a difference in pre-lithium frequency of episodes; there was no difference in episode frequency during lithium treatment.
Benedetti and coworkers (1998) reported that drug-free patients with bipolar depression who were homozygous for the l variant of 5HTTLPR show superior mood improvement after total sleep deprivation (TSD) than those with the s/l and s/s genotype. However, relapse following restoration of night sleep led to similar depression ratings in all genotype groups at the end of treatment. In a follow-up study the same group demonstrated that short-term relapse following acute response to TSD may be prevented by a combination of TSD with light therapy given during the TSD night and in the morning after recovery sleep and that the response is influenced by the 5HTTLPR with more marked effects in homozygotes for the l variant (Benedetti et al. 2003). These findings suggest that 5HTT function is critical for the antidepressant mechanism of action of sleep deprivation and light therapy, that presence of the l allele is associated with an increased reactivity of serotonergic system to a variety of stimuli, and support the notion that 5HTTLPR genotyping may represent a useful pharmacogenetic tool to individualize treatment of depression.
Finally, Mundo et al. (2001) found that 63% bipolar patients with a history of antidepressant-induced mania had the s allele compared to 29% in bipolar subjects who had been exposed to antidepressants, but did not develop mania. A role of the 5HTTLPR in rapid cycling, though not in antidepressant-induced mania, was supported in an independent cohort of patients with bipolar affective disorder, further supporting the notion that the low-activity s allele of the 5HTTLPR contributes to a pattern of affective instability (Rousseva et al. 2003). The role of allelic variation of 5HTT function in the development of adverse effects of SSRI treatment in patients with major depression was investigated by Perlis and coworkers (2003). A higher rate of fluoxetine-induced insomnia and agitation was found in s/s subjects compared to patients carrying the l/s and l/l genotypes. Although no antidepressant-induced mania was observed in this patient sample, these results seem plausible in the context of the findings that sleep disruption is a risk factor for the switch from depression to mania.
In addition to treatment response studies, 5HT system responsivity following pharmacologic challenge has been investigated with respect to genetic variability of the 5HTT function. Individuals with the l/l genotype exhibited greater prolactin response to either clomipramine or fenfluramine (Reist et al. 2001; Whale et al. 2000). Since the 5HTTLPR is likely to influence 5HT concentrations at all synapses, allelic variation in 5HTT function may affect the response to almost any agent affecting the 5HT system. This assumption would also explain an association between the s/s genotype and poor response to clozapine, an anxiolytically active antipsychotic displaying also a serotonergic mechanism of action (Arranz et al. 2000).
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