CATR: Tell us about yourself.

Dr. Tolliver: I’m an addiction psychiatrist at the Medical University of South Carolina. My research and clinical interests are in treating co-occurring mood and substance use disorders (SUDs).

CATR: How do you define substance-induced depression?

Dr. Tolliver: From a DSM perspective, it’s depression that wouldn’t exist if it weren’t for substance use. But that strict definition is a bit simplistic, and unfortunately persists. This definition can lead us astray into thinking that if we could only remove the substance, then everything will be fine. But that’s often not the case. I prefer the term substance-precipitated depression. That may seem like too fine a distinction, but I think that term more accurately acknowledges the nuance that exists between substance use and mood. Many of our patients with depression have an underlying susceptibility to depression; substance use precipitates an acute episode rather than being entirely causal. If we see substance use as precipitating an underlying susceptibility, then we are less likely to delay depression treatment.

CATR: Is it even useful to make a distinction between depression caused by substance use as opposed to depression and substance use that are simply comorbid?

Dr. Tolliver: It’s not a terribly useful distinction to make for an individual patient in front of you. When I came into training, the lore was “Wait until someone has a month of sobriety before diagnosing or treating a mood disturbance.” That seemed fraught at best, if not frankly wrong, even back then. First, it’s very common that a patient just isn’t able to achieve sobriety. So, what do we do then—not treat their depression? Second, our treatment settings often limit our ability to make this distinction anyway. Inpatient stays are much shorter these days; a treatment course needs to be decided on quickly. If the clinical thinking is “This patient just needs a detox, and then we’ll address the depression if it doesn’t remit,” we’re going to miss a lot of treatment opportunities.

CATR: It’s not as cut and dry as we might expect, or hope.

Dr. Tolliver: That’s right. Epidemiologic data are informative here. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) study is a good example; this study is a series of surveys done at discrete points in time. We can get an idea of how these diagnoses progress over time by comparing the first wave from 2001 and the second wave four years later. We see that many people diagnosed with substance-induced mood disorder in the first wave go on to be diagnosed with major depressive disorder by the time the second wave comes around. And this is an epidemiologic sample, not a treatment-seeking sample (Blanco C et al, J Clin Psychiatry 2012;73(6):865–873).

CATR: What is your approach when a patient presents with active substance use and depressive symptoms?

Dr. Tolliver: This may sound trite, but I just start with the history. A careful history is usually the best way to start in pretty much any clinical scenario. I want a timeline of substance use and mood episodes. Can we identify a period of abstinence in which they had depression? Did the depression predate substance use, or did it only come after? But it’s also important to acknowledge that substance use confounds accurate diagnosis. It’s hard to tell if someone has underlying depression if they are drinking a quart of vodka a day or crashing from a run of stimulant use. It’s hard to tell if there is an underlying mood disorder at all, and if there is one, what kind of mood disorder it is. Distinguishing between unipolar and bipolar depression affects treatment greatly.

CATR: Gathering a history may seem straightforward, but in reality it can be challenging to get accurate timelines that stretch back decades.

Dr. Tolliver: It can be enormously difficult, especially as we are pushed to have shorter and shorter appointments. So we do our best. But there are a few helpful clues that I like to look out for. For example, in the case of bipolar disorders, it’s not unusual for patients to have early-onset depression, often in their teens, and often before the onset of heavy substance use (Winokur G et al, Am J Psychiatry 1995;152(3):365–372). That could provide a clue that we’re looking at a patient in a depressed stage of bipolar disorder as opposed to unipolar depression. Family history can be helpful too; bipolar disorder has a very strong heritability. Another piece of history-taking advice that I always emphasize is the value of solid therapeutic rapport.

CATR: How do you go about establishing this trust?

Dr. Tolliver: We need to check our language and remain as free of judgment as possible. Until very recently, addiction treatment has operated under the premise “The patient is the problem. The patient is bad. The patient will be fine if they just toughen up and adhere to our treatment.” And how has that approach worked for us historically? I’d say not so well. So, staying free of judgment is critical. The field of addiction psychiatry has moved to a motivational enhancement approach, which acknowledges that there might be some very understandable reasons why someone started using substances in the first place. That’s a huge shift. And finally, patients are pleasantly surprised not to be stigmatized even further when they come into treatment. Many carry a lot of guilt and shame already. They expect to be shamed further when they see us because that is what the system has done to them so many times. So, we should do whatever we can to reinforce the message “You are not ‘less than.’ You are not broken. You’re here for help and we want to help you.”

CATR: Are there certain substances that are more commonly associated with depression than others?

Dr. Tolliver: It’s no surprise that central nervous system depressants like alcohol and benzos are commonly co-occurring with patients presenting with depression. But we see the opposite as well: patients coming off a period of heavy stimulant use, like cocaine or methamphetamine, can be profoundly depressed. It’s especially striking in those using large amounts of methamphetamines; there’s almost a cognitive impoverishment, particularly if the stimulant was smoked or injected. It can be days before the patient can even really engage in treatment of any kind.

CATR: Are there clinical features that differentiate major depressive disorder, alcohol-precipitated depression, and post-stimulant depression?

Dr. Tolliver: Nothing reliable. If that were the case, it might help us tease apart a mood disorder from substance use much more easily. Anecdotally, patients coming down from recent cocaine or methamphetamine use will do two things after they are hospitalized: sleep in bed all day except for short periods when they’re awake and eating. My explanation is that people using stimulants don’t sleep and don’t eat very much. What we’re seeing is a compensatory increase in these activities. I’m not sure you’d necessarily say that constitutes a depressive episode, but that’s a reliable observation. In general, depressive symptomatology can overlap greatly.

CATR: Let’s move on to treatment. Can you describe your treatment approach to these patients?

Dr. Tolliver: In my experience as an inpatient attending on an addiction unit, pure substance-induced depression, as in the DSM sense, is relatively rare. Many patients are admitted to my service with a presumptive diagnosis of substance-induced mood disorder, but by the time they discharge, they have two separate diagnoses: a SUD and either major depressive disorder or bipolar disorder. This is my admittedly anecdotal experience, and my sample may be a bit skewed, but others have reported similar observations (Blanco et al, 2012). And that goes back to our earlier discussion about substance-induced versus substance-precipitated depression. Typically, these are patients who have an underlying vulnerability to depression, which is exacerbated by addiction. So treatment needs to be a two-pronged approach: depression treatment and SUD treatment.

CATR: That sounds intuitive, but do we have an evidence base to support that?

Dr. Tolliver: We want to practice evidence-based psychiatry whenever we can, but in this case, very few studies exist in which participants have been carefully randomized to receive either treatment for depression, treatment for a co-occurring SUD, or treatment for both, and then outcomes carefully compared. The studies we do have are too small to have a reliable signal. One exception is a 2010 study on alcohol-dependent patients with depression. Nearly 200 participants were detoxed and randomized into one of four groups: naltrexone, sertraline, naltrexone and sertraline, and double placebo. The patients randomized to receive sertraline and naltrexone did the best both in drinking outcomes and mood outcomes (Pettinati HM et al, Am J Psychiatry 2010;167(6):668–675). The results were very clear, at least in the case of alcohol use disorder (AUD) and depression. Given the lack of further studies, we’ve tended to generalize that finding. So, I’d say that treating the SUD and depression simultaneously is intuitive, supported by a modest amount of evidence, and makes the most sense from a pragmatic standpoint.

CATR: How do you tailor medication choice? Will a patient with AUD respond differently to antidepressants than a patient with, say, stimulant use disorder?

Dr. Tolliver: That is an open question, to which we don’t have an answer. There is a bit of evidence that certain people with AUD, the so-called “type A” patients, might respond better to SSRIs (Dundon W et al, Alcohol Clin Exp Res 2004;28(7):1065–1073). But data are pretty limited. So again, I tend to go with an intuitive approach. And this is where a careful history can guide you. For example, if I’m treating a patient who drinks excessively at night to sleep or who struggles with insomnia when they try to stop drinking, I’ll start with a sedating antidepressant like mirtazapine. That’s not an evidence-based decision, it’s a clinical decision that I still think can be helpful.

CATR: What about the flip side—a patient using stimulants?

Dr. Tolliver: If someone is withdrawing from cocaine or methamphetamine, I’ll steer clear of a sedating antidepressant. In that case I’ll use something more stimulant-like, such as bupropion. Although even that is not entirely clear, as there is some limited evidence for mirtazapine for cocaine use disorder (Nanni-Alvarado R et al, Int J Ment Health Addict 2021;20:2770–2786).

CATR: There is evidence that bupropion can be helpful for stimulant use disorders.

Dr. Tolliver: That’s right. In the case of methamphetamine use disorder, bupropion was recently found to be especially helpful if combined with naltrexone (Trivedi MH et al, N Engl J Med 2021;384(2):140–153). The effect size is not large, but it’s one of the most promising pharmacologic options we have. And this returns to my earlier point about intuitive treatment approaches. Treating depression was not an explicit goal in the study, but mood disorders are highly comorbid with stimulant use, and we know that depressive symptoms are commonly part of stimulant withdrawal. So it’s not surprising that combining a medication for addiction, naltrexone, and a stimulating antidepressant, bupropion, turned out to be a successful approach.

CATR: Thank you for your time, Dr. Tolliver.