For many adults, depression and chronic medical conditions are inextricably linked.
In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.
“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”
Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.
“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.
An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.
“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”
Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline.
As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.
“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Alpert, who is also chair of the American Psychiatric Association’s Council on Research.
Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.
“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact — hours to just a few days,” Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B — which induces the enzymes that usually metabolize drug A — the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”
Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.
On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.
“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”
He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.
“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”
Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.