Treatment Resistance: Challenges and Solutions

Treatment resistance occurs in a variety of psychiatric disorders and presents an ongoing challenge as we attempt to optimize treatments for our patients. The manifestations and sources of treatment resistance are attracting increasing attention as research provides a growing understanding of the mechanisms of resistance and as newer treatments are explored. This Special Report on treatment resistance examines a variety of difficulties that arise in the treatment of different psychiatric disturbances, the sources of these difficulties, and the treatment solutions.

The role of genetic factors, acting through neurotransmitters and neuromodulators, is examined by Dr Francisco Moreno. While genetic factors are key in determining responsiveness to treatment, as well as adverse effects of antidepressant medications, their interaction with environmental factors complicates the picture and must always be kept in mind, since those factors can contribute to, maintain, or worsen existing mood disorders.

The article by Dr Richard Shelton focuses on results of the NIMH's STAR*D program, which showed that remission is difficult to achieve in patients with clinical depression despite multiple trials of antidepressants. Pharmacokinetic differences may help explain treatment resistance in depression, including polymorphisms of various cytochrome P-450 enzymes that affect metabolism and subsequent drug levels. In addition, neuroanatomical connectivity issues can lead to a poor treatment response in those with resistant forms of depression.

Another factor that may influence psychotropic drug effects is P-glycoprotein (P-gp), which is produced by the multidrug-resistance gene ABCB1 (ABCB1 encodes for P-gp). Animal studies that manipulate the expression of such proteins or gene products provide some insight into the complex mechanisms of the genetic components of responsiveness to treatment.

Drs Vural Ozdemir and Béatrice Godard describe the difficulty of understanding the multitude of drug transporters in the brain with their variability and selectivity, as well as their expressions and connection to drug interaction phenomena. Their article also provides a fascinating introduction to preemptive or predictive medicine as it applies to psychiatry. Issues of interest include informed consent, disclosure of potential adverse effects and genetic information to patients, patient privacy and its relationship to insurance coverage, and the inadequacy of genetics training in psychiatry.

Finally, Dr Michael Poyurovsky's article on subtypes of obsessive-compulsive disorders (OCDs) includes consideration of tic-related OCD (eg, Tourette syndrome), schizotypal personality characteristics or schizophrenia, hoarding, and poor insight. The identification of this wide variety of phenotypic expressions can help predict treatment response and resistance, and the identification of psychiatric comorbidities can help establish the pharmacological treatment plan.

These excellent articles provide a helpful review of the issues to be considered in understanding and addressing treatment resistance in psychiatric disorders. I hope you enjoy and benefit from reading these articles as much as I did.