Concerns over the depressive effects of drugs are well established. More than 50 years ago, researchers pointed to the antihypertensive drug reserpine as a possible offender. Although there are few randomized-controlled studies concerning the depressive effects of drugs, the FDA keeps vigilant watch over drug-induced depression (DID). In the past, it has issued alerts over the smoking cessation drug varenicline (Chantix) and various antiepileptic drugs for concerns over suicidal ideation. Similarly, it also gave the antiobesity drug rimonabant (Accomplia), an inverse agonist for the cannabinoid receptor CB1. “In our own time, numerous medications and classes of medications have been implicated in DID, sometimes called substance-induced depression or drug-related depression. DID has important medical, medicolegal, and commercial implications. Any physician who has observed steroid-related mood swings—either mania or depression—knows that DID can drastically affect a patient’s clinical course,” wrote the authors of an insightful review of different depressogenic agents published in Psychiatry. The following are drugs that have been linked to depressive side effects. Antivirals Alpha interferons are used to treat hepatitis C and different types of cancer and have been linked to depressive effects based on the research. On a related note, beta interferons, which are used to treat multiple sclerosis, are not strongly linked to depression, according to the authors of the aforementioned review. The frequency of depression in hepatitis C patients treated with interferon, for instance, ranges from 3%-50%, with the wide range dependent on the type of clinician doing the screening (ie, psychiatrist vs gastroenterologist). Some studies have shown that about 33% of those started on alpha interferon developed new-onset depression within 12 weeks. The proposed mechanism involves neurotransmission interference in the basal ganglia and limbic system caused by alpha-interferon therapy. Ultimately, screening for depression by a psychiatrist before and during alpha-interferon therapy is probably a good idea, experts say. 5α-reductase inhibitors Finasteride is a 5α-reductase inhibitor (5ARI) used to treat androgenic alopecia in lower doses and benign prostatic hypertrophy (BPH) in higher doses. Per the authors of the review, clinical trials have demonstrated increases in depressive symptom scores on the Beck Depression Inventory (BDI) and the Hospital Anxiety Depression Scale (HADS) in adults taking the drug for alopecia. Such concerns are likely pronounced in those taking the drug for BPH because this patient population skews older and doses of 5α-reductase inhibitors taken, including finasteride and dutasteride, are usually five times greater than those taken for hair loss. Indeed, results from a population-based study published in JAMA Internal Medicine demonstrated that although rates of suicidal ideation are not any greater in those taking the drug for BPH, risks of self-harm and depression were greater—particularly during the first 18 months of treatment. The authors concluded, “The risk of self-harm and depression should be considered when prescribing 5α-reductase inhibitors. In patients presenting with thoughts or evidence of self-harm, or with a new diagnosis of depression, the continued use of this medication should be reevaluated.” As for a proposed mechanism underlying the depressive effects of 5ARIs, these drugs block the conversion of progesterone to dihydroprogesterone, which is then converted to allopregnanolone, a neurosteroid with anxiolytic and antiepileptic properties, along with antidepressant effects. Antiepileptic drugs The use of antiepileptic drugs (AEDs) can lead to a broad range of psychiatric effects, including depression in some. In general, although sedating AEDs, including valproic acid and carbamazepine, harbor anxiolytic, antimanic, and sleep-promoting effects, they may lead to mood depression, impaired attention, and fatigue, according to the authors of a review published in Epilepsy Currents. On the other hand, activating AEDs, including felbamate and lamotrigine, may have antidepressant and attention-enhancing efficacy, but may cause anxiety, agitation, and insomnia. “Epilepsy patients, in general, may be more susceptible to the adverse behavioral effects of AEDs than are other populations, possibly resulting from structural or functional changes that increase their risk of psychiatric disorders,” noted the authors. “For example, affective and psychotic symptoms exhibited with levetiracetam administration are significantly more common among patients with epilepsy than among patients with cognitive or anxiety disorders. For other medications, such as ethosuximide, vigabatrin, and topiramate, a forced normalization-like process may contribute to behavioral changes, such as psychosis. A hypothesis relating to this phenomenon posits that epileptiform discharges may mimic electroconvulsive therapy in a focal area, and discharge suppression may lead to psychopathology. However, multiple other mechanisms are likely,” they added. Birth control Adding progesterone to hormone therapy has been linked to adverse mood effects, per the literature. For instance, results from a nationwide prospective cohort study published in JAMA Psychiatry indicated that in more than 1 million women living in Denmark, there was heightened risk for antidepressant use and first diagnosis of depression in users of hormonal contraception. This risk was highest among adolescents. According to the authors, “Likely mechanisms also include the action of progesterone metabolites on the γ-aminobutyric acid A receptor complex, which is the major inhibitory system in the human central nervous system. Levels of neuroactive metabolites of progesterone increase during the luteal phase of the menstrual cycle in fertile women, and some experience negative mood symptoms. They added, “External progestins, probably more than natural progesterone, increase levels of monoamine oxidase, which degrades serotonin concentrations and thus potentially produces depression and irritability. Clinical studies have indicated that changes in estrogen levels may trigger depressive episodes among women at risk for depression and that women with major depression generally have lower estradiol levels than do control individuals.” Steroids Lastly, time to address the elephant in the room. It will come as no surprise to the seasoned physician that steroids lead to mood disturbances. According to the authors of a study published in the Journal of Pharmacology & Pharmacotherapeutics, the incidence of DID due to steroids is 40.5%. Moreover, the incidence of mania, psychosis, and delirium are 27.8%, 13.9%, and 10.1%, respectively. Other common symptoms include emotional lability and irritability, with auditory hallucinations and paranoia also possible. Resultant altered consciousness and disorientation, however, are rare. Although the psychiatric effects of steroids are well recognized, the mechanisms underlying these changes remain to be elucidated, per the authors. “The mechanism by which the corticosteroid induces symptoms such as mania, depression, and psychosis is not clear,” they wrote. “The administration of prednisone is associated with decreased levels of corticotrophin, norepinephrine, and beta-endorphin in the cerebrospinal fluid. Furthermore, corticosteroids induce an increased release of glutamate that induces neuronal toxicity due to accumulation effect,” they concluded. Source
