Pharmacotherapy

There is consensus amongst experts that pharmacotherapy (i.e., antidepressants; see Table 38) for comorbid depression and alcohol use disorders is effective, provided an individualised approach is used [424, 432]. Unless there are significant contraindications, it appears clinically appropriate to use medication that has been proven efficacious in the treatment of major depression in those depressed patients with an AOD use disorder.

Thase and colleagues [424] comment on the sometimes over-restrictive attitudes towards pharmacological treatments for depressive disorders among people with AOD use disorders, where clients can present in a state of physical and emotional despair that requires immediate intervention. Considering the safety of most of the newer antidepressants such as SSRIs, such caution as waiting for a minimum number of weeks of abstinence cannot be justified. This would particularly apply where a client has a history of depression during periods of abstinence, or where the person has had successful antidepressant intervention in the past. Clients being commenced on antidepressants should nonetheless be carefully monitored as there have been some well-publicised cases of increased suicidality on commencement of antidepressant treatment [614]. Such incidents are rare and there is much conflicting and contradictory evidence on the clear link between antidepressant-induced suicidality [615, 616]. Thus, although it is suggested that the benefits of antidepressant use outweigh the risks, and appropriate use actually protects depressed patients from suicide [617], it is important to maintain appropriate monitoring of suicidality [618].

Reviews have generally found that among clients with comorbid alcohol and depressive disorders, treatment with tricyclic antidepressants (TCAs) and SSRIs has a significant effect on symptoms of depression, but effects on alcohol use have been equivocal [424, 432, 539]. A more recent review found mixed findings regarding depressive symptoms. Antidepressants were generally found to be effective in treating symptoms of depression however, when the effectiveness of SSRIs were examined separately, there were no significant treatment effects on depressive symptoms, relative to placebo [619]. Ioveno and colleagues [619] speculated that this may be due to high placebo response rates in these trials, and therefore further studies examining the use of SSRIs in this comorbid group are required.

Alcohol use responds well where depressive symptoms have been reduced, but sustained abstinence is not usually achieved [620-623]. There have been some studies which have shown a relatively negative effect on alcohol consumption in alcohol-dependent young men prescribed SSRIs [624-627]. Antidepressants that do not come under the umbrella of SSRIs or TCAs have been found to be effective in single studies [628, 629].

Compared to the newer antidepressants, TCAs are poorly tolerated, potentially lethal in overdose, and cause significant adverse effects when combined with other central nervous system depressants. In contrast, SSRIs are associated with fewer side effects, have better tolerability (resulting in improved compliance) and are safer in overdose [121, 424]. Despite their efficacy, some clients may be reluctant to take SSRIs due to the misconception that they are ‘addictive’. SSRIs are not habit-forming; however, users may experience a discontinuation syndrome if the medication is stopped abruptly [121]. Symptoms are similar to some of those experienced during alcohol or opiate withdrawal (e.g., flu-like symptoms, light-headedness, headache, nausea) [121]. When discontinuing SSRIs, the dose should be gradually tapered.

Although studies of comorbid alcohol dependence and major depression support the use of SSRIs, studies of cocaine and opiate dependent clients do not [263]. At present, there is limited evidence to support the use of antidepressants in treating depressed opioid dependent persons currently receiving opioid agonist treatment. In a recent systematic review, Pani and colleagues [631] noted that the evidence in this area was highly limited due to the small number of studies conducted, and methodological limitations within these studies. Whilst there was some evidence of a trend towards improved outcomes for depression symptoms and AOD use for clients receiving antidepressants as well as opioid agonists, there were no statistically significant differences in outcomes between antidepressant and placebo groups.

Adapted from Australian Government Department of Health [630]. For a full list of generic brands available, see the Therapeutic Goods Administration website (https://www.tga.gov.au/).

Different types of antidepressants seem to be suitable for different types of substance use disorders [416]. In particular, individuals with AOD use disorders tend to respond better to antidepressants that have a similar direct or side effect profile to their substance of abuse. Hence, the more sedating antidepressants such as doxepin or paroxetine are more effective in depressed abusers of alcohol, heroin and sedatives, and the more stimulating antidepressants such as desipramine and bupropion have greater efficacy in depressed abusers of stimulants and nicotine. As there are no guidelines as yet for the treatment of comorbidity with depression in users of psychostimulants such as amphetamines and ecstasy [632], the use of the more stimulating antidepressants for these clients provides the best guidance at this time.

For all AOD clients, extreme caution should be taken when prescribing monoamine oxidase inhibitors (MAOIs). These medications are potentially dangerous because of the dietary and medication restrictions involved [121]. Hypertensive crisis with intracranial bleeding and death can occur if combined with a tyramine-rich diet or contraindicated medications (including opioid and psychostimulant substances, such as over-the-counter cold and flu medications) [121, 263]. For this reason, MAOIs should only be used when other medication options have failed.

It is important to note that it can take up to four weeks for an antidepressant to reach therapeutic levels in the blood. Responses to antidepressants are typically noticeable within two to four weeks, with continued improvement in symptoms for up to 12 weeks [633-635]. If little or no improvement in mood occurs over the induction time specified by the drug manufacturer and the medication is being taken as prescribed, consideration should be given to increasing the dose within the recommended range. If still little or no improvement is observed, switching or augmenting with another antidepressant may be considered. It is recommended that there be at least one within-class switch before considering augmentation or other options, keeping in mind the potential for drug interactions, and the adverse effects of some antidepressants [633-636].

Two medications that have been used for treating alcohol use disorders – naltrexone and acamprosate– have shown moderately positive outcomes in this single disorder [637-641]. Disulfiram can also be an effective treatment for some people with alcohol problems, particularly those who are highly motivated and who can be closely supervised. Research suggests that naltrexone, acamprosate, and disulfiram are all tolerated well in clients with comorbid depression [642].

Naltrexone has been found to be associated with better drinking outcomes in clients being treated with antidepressants for their depression and anxiety [643]. With little support for the use of antidepressants alone to reduce excessive drinking, more recent research indicates that the use of antidepressants combined with naltrexone may lead to improved outcomes. Pettinati and colleagues found that when sertraline and naltrexone were combined in the treatment of co-occurring depression and alcohol dependence, there were better outcomes in terms of abstinence and relapse, relative to either sertraline or naltrexone alone, or placebo [644].

It should also be borne in mind that at least for naltrexone, treatment beyond 12 weeks may not improve drinking outcomes in those with alcohol use disorders alone [645]. While both acamprosate and naltrexone are available on the Pharmaceutical Benefits Scheme for alcohol dependence, disulfiram is expensive and only available with a private prescription. Although only a tentative finding requiring further research, another study found that buprenorphine had better outcomes with opiate abusers with comorbid depression than those who were not depressed [646]. This suggests that buprenorphine may prove to be an especially useful pharmacotherapy for this sub-group.