The findings of the present study suggest that sertraline delays relapse relative to placebo in recently abstinent cocaine-dependent individuals presenting with depressive symptoms. These results are consistent with those of a previous outpatient randomized, placebo-controlled clinical trial, in which the SSRI citalopram reduced cocaine use in cocaine dependent individuals.[78
] In addition, preliminary data with the SSRI paroxetine suggested that it may reduce craving,[79
] although data from well-controlled clinical trials are lacking. Sertraline showed initial promise to decrease craving in an open label pilot study[29
]. However, sertraline administered at one-half the dose used in the present study did not reduce cocaine use relative to placebo in a CREST trial for cocaine dependence[80
] or methamphetamine use relative to placebo in methamphetamine dependent individuals.[81
] Overall, these findings suggest that sertraline at doses higher than 100 mg/day may be necessary for a therapeutic effect.
It has been suggested that SSRI’s are not efficacious for treating psychostimulant dependence. This appears to be mainly due to results of clinical trials with the SSRI fluoxetine that, although initially promising,[82
] were not replicated under rigorous, double-blind, placebo controlled conditions,[24
] even in depressed drug dependent populations.[37
] The reasons for these mixed results are unclear, but may be due to methodological differences such as in study design. The present study used a relapse paradigm in which all participants were abstinent from cocaine for two weeks. Thus, medication was not initially administered during concomitant cocaine use. Indeed, Schmitz et al.[37
] hypothesized that, because chronic cocaine use reduces serotonergic function, the efficacy of SSRI’s are compromised in active cocaine users; however, serotonergic function is restored after cessation of cocaine use. Thus, SSRI’s may have utility in recently abstinent cocaine dependent individuals.
Another reason for the mixed results could be the differing affinities of the SSRI’s for other receptor sites besides the serotonin transporter.[87
] For instance, fluoxetine, a more potent inhibitor of 5-HT2C receptors than other serotonin reuptake inhibitors,[88
] has activating properties that may produce insomnia and agitation in anxious patients[89
] through modulation of NE and DA systems.[91
] In contrast, citalopram is probably the most selective 5-HT reuptake inhibitor among the SSRIs with minimal activity at other receptors, except histamine H1 receptors.[87
] Meanwhile, sertraline has activity as a DA reuptake inhibitor in addition to its potent serotonin reuptake inhibitor properties.[58
] Rothman et al.[94
] recently postulated that agents with both serotonergic and dopaminergic based on evidence of a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine abuse. Thus, sertraline, particularly in the context of recent abstinence from cocaine abuse, may have the type of pharmacological profile that would be efficacious in treating cocaine dependence.
On the other hand, there was no significant difference in the percentage of participants still completely abstinent through the last two weeks of the trial (44% in sertraline vs. 30% in placebo), which has been suggested as a Food and Drug Administration criterion for efficacy. However, a power calculation based on the difference in these two percentages indicated that we would have required a sample size only about 10 subjects larger in order to attain sufficient statistical power for our difference to be significant. Therefore, future studies of this medication might modestly increase the sample size, since a difference in sustained abstinence that is 47% greater than placebo has substantial clinical significance that begs for a sufficient sample size to establish its statistical significance to FDA standards
Sertraline’s effects on drug use did not appear to be related to alleviating depressive symptoms, with symptoms in both groups sharply declining within the first week of the study. This is consistent with results of the fluoxetine clinical trial in depressed cocaine abusers [37
] as well as results in cocaine abusers entering non-medicated outpatient treatment,[95
] suggesting that psychiatric symptoms at study entry may be more indicative of an acute rather than chronic state. Indeed, HAM-D scores were significantly correlated with CSSA scores at study entry (Pearson r=0.30, p=0.02), suggesting that depressive symptoms may reflect cocaine withdrawal severity. Nevertheless, whether co-occurring psychiatric disorders actually arise independent of substance use disorders has been questioned.[96
] Given the report by Schmitz et al.[37
] that those with lower depression ratings during the fluoxetine study were more likely to have cocaine-free urine samples, sertraline may have efficacy for cocaine dependence regardless of depression status.
Self-reported cocaine use results were inconsistent with urinalysis results. This is likely due to participants not reporting or under-reporting their use, with only one-sixth of those with positive cocaine urines reporting having used. In our experience, underreporting use is common in this population. Given that participants were abstinent prior to the outpatient phase, urine results do appear to be a more accurate measure for determining first use of cocaine.
Sertraline was generally well tolerated in this population with few adverse effects, which is consistent with recent reports of sertraline trials for cocaine dependence [80
]. There did appear to be a greater incidence of suicidal ideation (5.3%) than expected in the overall sample. These findings are in contrast with a more recently completed sertraline trial in cocaine dependent participants with depressive symptoms whereby no suicidal ideation occurred [97
]. This result may therefore reflect some sort of sampling bias.
Almost one-third of participants dropped out during the residential stay, so the lack of outcome data with these individuals cannot inform our overall results. The majority of these dropouts occurred during the first part of the study when procedures with the residential milieu were still being clarified; however, no compensation was available during this portion of the study and, given the general difficulty retaining stimulant users, using some form of contingency for attendance may have increased retention during this time. Nevertheless, that only data from those who participated beyond week 2 were analyzed limits the generalizability of these findings to individuals who are abstinent and receiving sertraline for at least two weeks.
Of those who were retained past the residential stay, more than one-third maintained abstinence for the entire 10-wk outpatient phase. This is a striking finding suggesting that initiating two weeks of abstinence followed by manual-guided CBT can facilitate delayed relapse in such a difficult-to-treat population. More research is needed to determine the reproducibility of these findings. Nevertheless, the results of this study suggest that sertraline should be investigated further as a relapse prevention agent for cocaine dependence.