Is There a Role for Antidepressant and Antipsychotic Pharmacogenetics in Clinical Practice in 2014?

The recent release of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, has been associated with much hand-wringing and many comments about the lack of progress on the understanding of biological mechanisms underlying mental disorders and their treatment.¹ Publications, both in the general press and in scientific journals, decried psychiatry for being falsely advertised as a science. Among many similar examples, a columnist in The New York Times stated,

The problem is that the behavorial sciences like psychiatry are not really sciences; they are semi-sciences. [ . . . ] Mental diseases are not really understood the way, say, liver diseases are understood, as a pathology of the body and its tissues and cells.²

He went on, quoting Martin Seligman, a past president of the American Psychological Association, in this statement:

I have found that drugs and therapy offer disappointingly little additional help for the mentally ill than they did 25 years ago—despite billions of dollars in funding.

This viewpoint, by the general public and by health professionals, is that the impact of scientific progress in psychiatry has not met up with its promise. Contemporary psychiatric treatments are as efficacious as (or more efficacious than) most other nonsurgical treatments offered by modern medicine. With a number-needed-to-treat typically of 3 to 6, the efficacy of antidepressants (ADs) and antipsychotics (APs) is superior or similar to the efficacy of any medications used to treat general medical conditions except for antibiotics.³ Nevertheless, it can be argued that, except for better tolerability, there has been only incremental progress in the development of newer ADs and APs since the original, serendipitous discoveries of iproniazid, imipramine, and chlorpromazine in the 1950s.

There are many possible reasons for this negative perception regarding progress in psychiatry, including a bias about patients with mental illness. Because of their salience, people are painfully aware of those who are not treated or are not doing well, and they are not aware of those who are successfully treated and are doing well; we see and hear the untreated, acutely psychotic shoeless man screaming in the street or our loved ones who have not yet responded to their medications. By contrast, the mental illnesses of our colleagues or friends who have remitted with treatment are invisible. Another reason for these negative perceptions is that, when used under usual care conditions, psychotropics typically yield mediocre, or even poor, outcomes. For instance, several studies published during the past decade have shown that less than one-half of depressed patients who were treated under usual care conditions by a community psychiatrist or a family physician achieved good outcomes.^4,5

Some of these disappointing outcomes are due to the variable efficacy and the early side effects of ADs and APs. Given the tepid faith in the therapeutic powers of these medications, patients and health professionals are unable or unwilling to stay the course in the face of delays in response or unpleasant side effects, leading to premature discontinuation and, consequently, perceived lack of benefit. Innovative models of care incorporating more intensive education and support for patients, health professionals, and family caregivers (for example, collaborative care for major depressive disorder or assertive community treatment for schizophrenia) can counteract these factors and markedly increase the number of patients who take, tolerate, and respond to psychotropics.⁵ A complementary approach that could increase the number of patients who take and stay the course with currently available psychotropics is to preferentially use medications that are better tolerated. This can be done either by implementing medication algorithms that promote the systematic use of psychotropics that are statistically more likely to be better tolerated (that is, medications with lower overall rates of discontinuation associated with adverse effects) or by trying to match specific patients with specific medications. However, the attempt to match specific patients with specific medications based on symptoms and medication side effect profiles, while an intellectually appealing strategy, is not supported by evidence. For example, a study that assessed this strategy showed that depressed patients with insomnia were not more likely to tolerate or respond to a sedating AD (imipramine) than to an activating one (fluoxetine).⁶ This inability to match patients and medications based on symptoms and adverse effects has been confirmed in a recent meta-analysis.⁷ Is it possible to move beyond existing algorithms and match patients to medications that personally fit them best? In this issue of The Canadian Journal of Psychiatry, 2 systematic In Review papers^8,9 assess whether the new field of pharmacogenetics could lead to a true personalized psychiatry, with specific ADs or APs selected for specific patients based on their genetic predisposition to tolerate and respond to them.

In the first review, Dr Chiara Fabbri, Dr Stefano Porcelli, and Dr Alessandro Serretti⁸ summarize the published evidence supporting the use of pharmacogenetics to improve AD response through the personalization of treatment. They conclude that, to date, despite a large number of relevant findings, our current knowledge is not yet applicable to routine clinical practice. Among the main methodological limitations that have impeded advances in AD pharmacogenetics, they identify the use of diagnostic criteria (that is, phenotypes) that are not based on biological mechanism. They propose that methodological advances, such as the integration of genome-wide association studies, with candidate gene approaches, pathway analyses (which consider genetic variants within several genes involved in the same biological pathway), and the study of new depressive endophenotypes, could overcome the limitations of the first generation of AD pharmacogenetic studies.

In the second review, Dr Eva J Brandl, Dr James L Kennedy, and Dr Daniel J Müller⁹ summarize published evidence relevant to the use of pharmacogenetics to individualize AP pharmacotherapy and improve its outcomes. Like Dr Serretti and colleagues,⁸ they conclude that because of lack of replication and inconsistent results, most findings relevant to variability in treatment response are not robust enough to be applied in clinical practice. However, some genetic associations with polymorphisms of the cytochrome P450 system, and with adverse effects, such as AP-induced weight gain, clozapine-induced agranulocytosis, or tardive dyskinesia, seem to be consistent enough to warrant validation of their use in pharmacogenetic-based algorithms in large clinical studies.

In conclusion, it took only 50 years between the identification of the structure of deoxyribonucleic acid in 1953 and the completion of the sequencing of the entire human genome in 2003. Ten years ago, at the time of this scientific breakthrough, it was hoped that it would lead to rapid progress in the identification, prevention, and treatment of diseases, including mental disorders. However, there are still only a handful of genetic findings that are consistent enough to warrant their application in clinical psychiatry. This lack of progress is, in part, due to the inability, so far, to identify specific biological mechanisms underlying mental disorders and their response to existing treatments. Thus it is unlikely that in the near future a clinician will be able to select ADs or APs based on a patient’s genetic predisposition to respond to the treatment. However, within the next decade, AD and AP pharmacogenetics could guide the selection of medications to avoid specific adverse effects. Funding for the large clinical trials needed to test these predictions appears unlikely, given the current fiscal climate. Nevertheless, real or putative adverse effects of existing medications—including cardiometabolic effects, bone loss, and sedation—have enormous public health significance. Therefore, advances in personalized psychiatry based on minimizing adverse effects of existing medications could greatly advance the practice of psychiatry, as we await the scientific advances necessary to create the next generation of treatments.

The Canadian Journal of Psychiatry / La Revue canadienne de psychiatrie

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