To prevent lost time: on using the most effective medication first, not last

Joseph Goldberg has written an important article for clinicians who treat patients with mood disorders. Goldberg JF. Should we reserve big gun antimanic drugs for only big gun manias? Bipolar Disord. 2018; 20:7–8.

He suggests, writing primarily about olanzapine, that following the guidelines (use the big gun drugs last, because of their side effects) can harm patients, while using the big guns first can rapidly improve them, even for patients with “mild or moderate symptom severity on a baseline mania rating scale”.

In my outpatient practice, using it primarily for patients with treatment-resistant or “mixed features” depression (most of whom failed to respond to several previous antidepressant trials of adequate dose and duration), it is amazing how fast it works, often within 3 days. (Antidepressants usually take 2-3 weeks to begin to work, and 4-6 weeks to have their full effect).

The big side effect with olanzapine is weight gain. But this is slow to develop, taking weeks to months. And there are ways to combat it, such as using low carbohydrate diets, and metformin.

As an “atypical” or “second generation” antipsychotic, or “serotonin dopamine antagonist”, olanzapine has the usual list of antipsychotic side effects, including tardive dyskinesia: again, slow to develop.

In the meantime, the patient and physician get a quick answer to the question of ‘does this medication work?’

Here’s some key points Dr Goldberg makes in his paper:

1. He cites the paper by Samara et al, which used “individual participant-level data” to determine that “high baseline symptom severity strongly moderated treatment outcome” (i.e. the sickest patients did the best, a common finding in psychiatric drug trials, since most trials have placebo response rates around 30%; “High baseline severity typically lowers placebo responsivity.”). In a fascinating aside, he notes that using mildly ill patients helped delay recognition of lamotrigine’s efficacy, since it appeared ineffective due to the high placebo response rate.
2. But “side effect burden was unsparing of lower severity patients”. So, Samara et al and the treatment guidelines recommend use of olanzapine mainly in severe presentations of mania.
3. Goldberg notes that “the concept of examining participant-level data is more than just a data analytic nuance; as a practical strategy for transforming group-based findings into more tailored, individualized treatment, it is a quantum leap toward the goal of personalized medicine.” This is the holy grail of psychopharmacology: customizing the treatment to the patient, and the psychopharmacologist’s work with a patient resembles a Savile Row tailor creating a bespoke suit. Goldberg suggests that at present, participant level data is more helpful in this endeavor than pharmacogenomics. One can use “individual participant-level data to broker a more bespoke fit”
4. One can also use “pairwise post hoc comparisons—statistical power permitting—between clinical subgroups of interest. For example, post hoc analyses have demonstrated olanzapine’s comparable antimanic efficacy in men and women, psychotic and nonpsychotic patients, manic and mixed episode patients, rapid cyclers and non-rapid
cyclers, patients with early and later age at onset, and subjects with and without comorbid substance use disorders.” These comparisons usually suggest, however, what patient characteristics worsen response rather than telling us who will respond. What is striking here is olanzapine’s broad spectrum of efficacy.
5. Goldberg argues that we may be mistaking a mistake by withholding big gun drugs like olanzapine from all but the most severely ill patients. “Because some high-risk/
high-gain medications have fast onset and robust breadth of spectrum, even their short-term use at potentially low doses has been shown to reliably temporize an evolving subsyndromal deterioration” (I recently saw this in a treatment-resistant depression patient, who had a dramatic response after 2 days of 2.5 mg olanzapine, which has persisted for several weeks after he discontinued it.) “Brief initial pulsed dosing with a “big gun”/high-risk agent might thus forestall hospitalization or prevent work or other role functions being jeopardized.”
6. Finally, often the alternative to using one high-risk, high gain medication is to cobble together, over time, a multi-drug combination, which combines limited efficacy with additive side effects. “Given that about 20% of “real world” bipolar patients receive extensive polypharmacy regimens (at least four medications)…. consider the potential hazards that low-efficacy/low-risk agents may pose with respect to incomplete remissions, relapse risk, cumulative adverse effects and poorer adherence in complex multi-drug regimens, and prolonged morbidity with psychosocial sequelae—despite the presence of only mild or moderate symptom severity on a baseline mania rating scale.”

Goldberg is writing about olanzapine use for manic patients. But I think the same arguments hold for patients with treatment-resistant depressions (who often turn out to have mixed states, or some form of bipolar disorder).

His article gives the clinician the intellectual rationale for trying the most efficacious intervention first, in appropriately selected patients, rather than last. Time is important, and a rapid response diminishes the time a patient remains ill.

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