Towards New Medications for Refractory OCD

by Christopher Pittenger, MD, PhD, & Wayne Goodman, MD

This article was initially published in the Summer 2013 edition of the OCD Newsletter

Current psychotherapy and medication treatments for OCD can be of help to many who suffer from the disorder.  Unfortunately, as many as a quarter of patients do not experience much benefit from these standard treatments, such as selective serotonin reuptake inhibitors (SSRIs) or Exposure and Response Prevention (ERP), even when they are used well.  The development of new treatment options for these individuals is an urgent clinical and research need. This article looks at up-and-coming research on medications that affect the brain’s glutamate system as a strategy for treating refractory OCD (also known as “treatment-resistant” OCD).

The SSRI antidepressants — fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro) — are the standard “first line” medications used for OCD pharmacotherapy. (The first four of these have been approved by the FDA for the treatment of OCD; the last two have not, but research shows them to be just as effective, and they are often prescribed ‘off label’.) Many patients find that their OCD symptoms get a lot better within 8–12 weeks of taking one of these medications.  [For more information about these medications, please visit the IOCDF website page on medication here.] However, some patients do not respond to or tolerate the first medication they are prescribed, and thus may be prescribed a different SSRI or the older antidepressant clomipramine. If this fails, a “second-line” medication may be recommended, such as a low dose “antipsychotic” medication like risperidone.

These first- and second-line medications target the neurotransmitters serotonin and dopamine, and they provide some benefit in a majority of OCD cases. Unfortunately, many patients — up to 30–40% — do not get much benefit.  And many of those who are considered ‘responders’ still have significant symptoms, or have difficulty with side effects, especially with the second-line medications.

Because of the clear need to develop treatment options for the many people who do not benefit much from these standard treatments, there has been great interest recently in the use of medications that target other neurotransmitter systems in the brain.  In particular, there has been a lot of interest in the neurotransmitter glutamate, an important part of the central nervous system [1].  If glutamate imbalance contributes to OCD, then medications that target the glutamate neurotransmitter system in a variety of ways may hold promise for individuals with otherwise treatment-resistant OCD.  This is a major focus of current research, both in academic settings and in the pharmaceutical industry.

Several lines of evidence suggest that changes in glutamate contribute to OCD, in at least some cases.  First, genetic abnormalities in a brain protein responsible for maintaining normal glutamate levels have been associated with OCD in numerous studies. While this association has not been proven beyond a doubt and is likely to explain only a minority of OCD cases, it is still the most repeated, and therefore most accepted, genetic finding in OCD to date [2].  Second, examination of cerebrospinal fluid from individuals with OCD has revealed increased levels of glutamate in some of them [3, 4].  Third, some studies using magnetic resonance spectroscopy (MRS), a brain imaging method that makes it possible to measure certain molecules in the brain, have shown changes in normal glutamate levels, with the nature of the change depending on the brain region studied [5].  Less direct evidence for glutamate changes come from findings in animal studies, changes in brain electrical response that are similar to an altered glutamate state, and more [1].

The theory that glutamate imbalance contributes to OCD has led to studies of a number of drugs and over-the-counter (OTC) supplements that are already widely available, either with or without a prescription.  Small studies, most of which have not had a placebo control group, have provided interesting preliminary evidence of benefit from riluzole, memantine, N-acetylcysteine, and topiramate, all of which have an effect on glutamate [1].  In none of these cases is the data strong enough for any of these drugs to be considered part of standard treatment; certainly they are not appropriate in place of a trial of one of the better-proven SSRIs.  But in individuals who do not respond to first- and second-line treatments, these other medications are becoming reasonable options. For more information about over-the-counter alternative treatments, please see the article “Title TK” on page TK of this newsletter.

The way glutamate works in the brain is by attaching to several different receptor proteins, which are essentially the “On/Off” switches for neurons.  Thus, glutamate affects electrical communication (or “signaling”) in the brain. One specific receptor, the NMDA receptor, has become a major focus of attention in OCD and other neuropsychiatric conditions, including major depressive disorder.  The NMDA receptor is the target of the drug memantine, which is being used by some psychiatrists in refractory cases of OCD.  It is also the target of the drug ketamine, which has been shown in recent studies to have a remarkable, rapid antidepressant effect [6].  The effect of ketamine in refractory OCD remains unclear, with one study suggesting that it is not effective (though it can benefit depression in patients who suffer from both conditions), and a more recent one suggesting that it is [7, 8].  This is an interesting and important area of ongoing work.

There are other, more indirect ways to affect the NMDA receptor, which is a receptor for both glutamate and the related small molecule glycine.  Changing brain levels of glycine indirectly adjusts the effects of glutamate; this is an exciting area of recent focus in OCD research.  A placebo-controlled trial of glycine itself suggested that it can be of benefit in treatment-resistant OCD.  Unfortunately, the very large doses of glycine needed in order to have an effect in the brain resulted in unpleasant side effects, especially nausea [9].

The indirect effect of glycine using sarcosine, which is an amino acid that comes from glycine and is available over the counter, showed some evidence of benefit in an uncontrolled trial [10]. Sarcosine works in the brain by blocking the reuptake of glycine, much as SSRI antidepressants block the reuptake of serotonin, and therefore increasing its levels without the problems associated with taking large amounts of glycine itself.  This has led to the idea that a more powerful and specific blocker of glycine reuptake may represent a new frontier in OCD treatment.  Such drugs are not yet approved by the FDA or widely available by prescription, but they have been developed by several different pharmaceutical companies for a variety of uses.

An investigation of one of these drugs for individuals with refractory OCD, sponsored by the pharmaceutical company F. Hoffman La Roche, Ltd., is currently underway at research sites across the country. The drug, called bitopertin, was originally developed as a new treatment for schizophrenia, especially for “negative symptoms” (when a person is lacking a typical emotional response or thought process) such as reduced motivation [11]; it is completely distinct from traditional antipsychotics like risperidone and haloperidol.  While bitopertin is not yet clinically available, it has been used in hundreds of people in earlier studies.  This trial is important for the field of OCD research for two reasons.  First, it should provide us with important information about a completely new type of medication that may be of benefit to refractory patients.  Second, it is the first time since the 1980s that a major trial of a new medication for OCD has been undertaken by the pharmaceutical industry.  Collaborations of this sort are very important for turning our growing understanding of the neurobiology underlying OCD symptoms into innovative new treatments.

This trial, which goes by the name of Skylyte, is currently looking for individuals with OCD symptoms that have not responded to SSRI treatment to participate. 

The needs of OCD sufferers whose symptoms are refractory to the best psychotherapy and pharmacotherapy that we have to offer are great.  However, we are in an exciting time for OCD research, and new hope may be on the horizon.  The idea that chemicals that have an effect on glutamate can benefit some patients has driven a great deal of research in recent years [1].  And a major treatment trial of a new medication, Skylyte, may indicate new interest by the pharmaceutical industry in the development of new treatment strategies — an interest that has been unfortunately lacking for many years.  We are hopeful that these research efforts will lead to new hope in the coming years.

Acknowledgements & Disclosures:  CP is Associate Professor of Psychiatry, Psychology, and in the Child Study Center and Director of the OCD Research Clinic at Yale University in New Haven, Connecticut.  His work is funded by the NIMH, the Doris Duke Charitable Foundation, and the State of Connecticut through its support of the Ribicoff Research Facilities at the Connecticut Mental Health Center.  WG is Chair of Psychiatry at the Mount Sinai School of Medicine in New York City and is co-founder of the IOCDF.  His work is funded by National Institute of Mental Health.  Both authors are recruiting patients for the SkyLyte study, funded by F. Hoffman La Roche, Ltd., at their research sites, and have received compensation (< $5000) from Roche for consultative input during the design phases of this trial.


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