Is the Juice Worth the Squeeze?

By Andy Mattai M.D.

One of the most memorable moments of my career as a psychiatrist occurred early in my residency training. One of my first patients was a middle-aged woman who had been admitted to the general inpatient unit because of a suicide attempt. During my clinical interview, I determined she was suffering from treatment-resistant depression (TRD), which at the time was an evolving concept.

However, what struck me was that the hospital admission seemed related less to her organic mood disorder than to untoward effects of the medications she had been prescribed. By the time I saw in her in the hospital, the patient had been prescribed several psychotropic medications, to which she attributed to her weight gain of 30 pounds. The weight gain apparently triggered Type 2 diabetes, which led to more medications being prescribed. I distinctly remember her saying, “I’m not sure what is worse, the illness or the seven different medications I need to take because of it.”

Despite the availability of various medications and psychotherapies, it is readily apparent that treatment for depressive disorders continues to be woefully inadequate. There are a multitude of factors that drive this phenomenon. However, the unfortunate truth is that only 30% of patients seeking care meet the aspirational treatment goal of recovery or remission.

When delving into the root causes of why patients do not respond “adequately” to traditional antidepressant medications, many clinicians equate lack of response with lack of efficacy. However, this only highlights a portion of the core problem. The STAR*D study was a large NIMH-funded trial used to assess the effectiveness of depression treatments in patients diagnosed with major depressive disorder. Patients were treated at each of the four levels of the study using a different medication or medication combination. Those who did not become symptom-free could move to the next level of the study.

While the study results indicated that patients with difficult-to-treat depression may achieve remission after trying several medication options, the rate of participant withdrawal would make any clinician wary. The withdrawal rates rose with each level—21% withdrew after level 1, 30% withdrew after level 2, and 42% withdrew after level 3.

The elevated rates of withdrawal are reflective of a fundamental challenge all prescribers of psychopharmacologic agents face —the relative intolerability of many of our medications. While there are some patients who can take antidepressants without issue, this seems to be less and less common, especially in the context of newer antidepressant side-effect profiles.

As a clinician in a small private practice, I find this has tangible and intangible downstream effects on the therapeutic relationship. While being quite diligent about obtaining informed consent and discussing the risk/benefit calculus regarding a medication(s), not a week goes by without multiple calls from patients concerned about somatic and psychologic effects of their antidepressant medication regimen. A typical example is a patient who just began a SSRI medication and is now experiencing intermittent nausea and/or headache.

I occasionally field more urgent calls from patients who have concerns that a medication is exacerbating insomnia or acutely worsening anxiety. When preparing to call a patient back, I must consider numerous factors that can make the decision of how to proceed convoluted:

• How do I distinguish these side effects from primary depressive symptoms?
• Were symptoms present before starting treatment?
• How long has the patient been on the medication?
• Are the side effects expected?
• Has this patient been vulnerable to side effects in the past?

Answers to the questions lead to a litany of further options:

• Waiting to see if the side effect normalizes with time.
• Lowering the dose or changing the dosing paradigm.
• Pursuing an add-on medication (e.g.: bupropion for sexual side effects) that may counteract the primary untoward effect.
• Switching medications to something perceived to be more tolerable.
• Considering non-medication treatment options as a primary treatment. This could involve the use of psychotherapy as a core treatment with selective adjunctive use of psychotropic medications to address specific symptoms.

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Based on my collective experiences with patients, I fully recognize the impact of adverse effects of medications on the physician/patient relationship. Despite my best of intentions to be transparent and proactively inform patients of side effects, there is a great variability to their occurrence that can adversely affect treatment adherence. Lack of adherence is a tangible reason many patients choose to discontinue care (temporarily or permanently).

Freedom to Respond?

While the armamentarium for the treatment of TRD has increased in recent years, the unmet need for effective therapies is striking; depression remains the leading cause of disability. Our goal as mental health practitioners is to find effective therapies tailored to patient needs. We know nothing works for everyone, so it’s a question of finding therapies that work for those who are currently not helped and to figure out who might benefit from what. To this end, much of my job as a psychiatrist involves sometimes thinking out of the box as to ascertain who might benefit from a specific intervention.

One novel therapeutic option on the horizon is psilocybin therapy. As demonstrated in multiple studies, combined use of psilocybin and psychotherapeutic support can lead to clinically significant changes in core depressive symptoms after one dose.

The safety and tolerability of psilocybin has been relatively well characterized with common adverse events such as headache, nausea, hallucinations, and palpitations resolving within eight hours of dosing. It is very rare for any side effects to persist a day after dosing. Furthermore, only a small percentage of patients relate the use of psilocybin as being a negative experience.

While optimum dose and duration of effect are still being determined, it is safe to presume that the frequency of dosing will be significantly less than that required by other treatments currently available. Furthermore, given the mechanism of action of psilocybin (5HT2a agonism), the majority of studies to date have asked patients to taper off their antidepressant medication before trial participation. Psilocybin promises psychiatrists and patients an option that does not involve chronic use of antidepressant medication or frequent visits for continued treatment.

As scientifically rigorous clinical studies of psilocybin read out in the near future, I am one of many psychiatrists watchfully waiting to determine whether the agent could be a therapeutic option for those whose symptoms fail to respond to traditional treatments.

Any psychiatric intervention that allows patients a treatment opportunity unfettered from the challenges related to daily medication administration and polypharmacy would be well received by the mental health community. Time will tell whether this ever comes to fruition, but I look forward to a day where there is less equipoise over whether the reward of treatment is worth the effort.

Andy Mattai, M.D.

Source: Andy Mattai, with permission

Andy Mattai M.D. is Vice-President of Clinical Safety at COMPASS Pathways. He is a graduate of the University of Iowa Carver College of Medicine and completed his psychiatric residency at Creighton University/University of Nebraska College of Medicine. ​ His experience includes completion of a clinical research fellowship at the National Institutes of Mental Health and work at the FDA as a medical officer reviewer in the Division of Psychiatry. Dr Mattai has served as an investigator for numerous clinical trials in both psychiatry and neurology. He maintains a small private practice in Columbia, Maryland.