“First line” treatments for OCD (treatments that multiple research studies have shown to be effective in
reducing symptoms for a significant number of patients) include medication and cognitive behaviorial therapy,
specifically Exposure and Response Prevention.
For many people, one of these treatments, or a combination of the
two, have been extremely effective in reducing OCD symptoms. And for those individuals who have found relief via those
treatments, there is no need to change course.
However, one of the most common phone calls or emails we receive at the International OCD Foundation concerns medication treatment options for OCD, and how to treat OCD that has not responded to the treatment options mentioned above. Though there are a handful of “first line” medications a psychiatrist may use to treat OCD symptoms (mostly serotonin-targeting medications), as you will see in the two articles below, as many as 1 in 4 individuals do not respond to these first-line treatments or have intolerable side effects. So, what do you do if you are someone who has not responded to the “first line” treatments? For this issue of
the OCD Newsletter, we reached out to some of the leading researchers in the area of “what’s next” for OCD medications.
The first article takes a look at a new family of medications that target glutamate levels in the brain rather than serotonin.
We also often receive questions from members about using “herbal supplements” or “neutraceuticals” as possible options for individuals who have had a minimal or poor response to serotonin-based drugs. The second article examines research about these alternative treatment options, to determine if there really is benefit to be had from supplements.
As you will see in both articles, more research needs to be done. We encourage individuals in the OCD and related
disorders community to help advance our understanding of effective treatments for OCD by participating in these studies.
You can find a list of recent studies currently recruiting participants on page 21 of this newsletter, and a more extensive list
of OCD and related disorders research projects on our website at: www.iocdf.org/Participants.aspx. In some cases, these
research studies offer an opportunity to receive free treatment as well.
– Jeff Szymanski, PhD, Executive Director, International OCD Foundation Towards New Medications for Refractory OCD
by Christopher Pittenger, MD, PhD1,2 & Wayne Goodman, MD3 1. Yale OCD Research Clinic, Department of Psychiatry (Celexa), and escitalopram (Lexapro) — are the standard 2. Department of Psychology, Child Study Center, and Interdepartmental “first line” medications used for OCD pharmacotherapy. (The Neuroscience Program, Yale University School of Medicine first four of these have been approved by the FDA for the 3. Mount Sinai School of Medicine, New York, NY treatment of OCD; the last two have not, but research shows Current psychotherapy and medication treatments for them to be just as effective, and they are often prescribed “off OCD can be of help to many who suffer from the disorder. label.”) Many patients find that their OCD symptoms get a lot Unfortunately, as many as a quarter of patients do not better within 8–12 weeks of taking one of these medications. experience much benefit from these standard treatments, (For more information about these medications, please visit such as selective serotonin reuptake inhibitors (SSRIs) or the IOCDF website at www.iocdf.org/MedSummary.aspx.)
Exposure and Response Prevention (ERP), even when they are However, some patients do not respond to or tolerate the first used well. The development of new treatment options for medication they are prescribed, and thus may be prescribed a these individuals is an urgent clinical and research need. This different SSRI or the older antidepressant clomipramine. If this article looks at up-and-coming research on medications that fails, a “second-line” medication may be recommended, such affect the brain’s glutamate system as a strategy for treating as a low dose “antipsychotic” medication like risperidone. refractory OCD (also known as “treatment-resistant” OCD).
These first- and second-line medications target the The SSRI antidepressants — fluoxetine (Prozac), fluvoxamine neurotransmitters serotonin and dopamine, and they provide (Luvox), sertraline (Zoloft), paroxetine (Paxil), citalopram some benefit in a majority of OCD cases. Unfortunately, many Towards New Medications for Refractory OCD (continued)
patients — up to 30–40% — do not get much benefit. And first- and second-line treatments, these other medications are many of those who are considered ‘responders’ still have becoming reasonable options. For more information about significant symptoms, or have difficulty with side effects, over-the-counter alternative treatments, please see the article especially with the second-line medications.
“Over-the-Counter Supplements in the Treatment of Obsessive Compulsive Disorder” on page 17 of this newsletter.
Because of the clear need to develop treatment options for the many people who do not benefit much from these The way glutamate works in the brain is by attaching to standard treatments, there has been great interest recently several different receptor proteins, which are essentially in the use of medications that target other neurotransmitter the “On/Off” switches for neurons. Thus, glutamate affects systems in the brain. In particular, there has been a lot of electrical communication (or “signaling”) in the brain. interest in the neurotransmitter glutamate, an important One specific receptor, the NMDA receptor, has become a part of the central nervous system.1 If glutamate imbalance major focus of attention in OCD and other neuropsychiatric contributes to OCD, then medications that target the conditions, including major depressive disorder. The NMDA glutamate neurotransmitter system in a variety of ways receptor is the target of the drug memantine, which is being may hold promise for individuals with otherwise treatment- used by some psychiatrists in treatment-resistant cases of resistant OCD. This is a major focus of current research, both OCD. It is also the target of the drug ketamine, which has in academic settings and in the pharmaceutical industry.
been shown in recent studies to have a remarkable, rapid antidepressant effect.6 The effect of ketamine in treatment- Several lines of evidence suggest that changes in glutamate resistant OCD remains unclear, with one study suggesting contribute to OCD, in at least some cases. First, genetic that it is not effective (though it can benefit depression in abnormalities in a brain protein responsible for maintaining patients who suffer from both conditions), and a more recent normal glutamate levels have been associated with OCD one suggesting that it is.7, 8 This is an interesting and important 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 There are other, more indirect ways to affect the NMDA therefore most accepted, genetic finding in OCD to date.2 receptor, which is a receptor for both glutamate and the Second, examination of cerebrospinal fluid from individuals related small molecule glycine. Changing brain levels of with OCD has revealed increased levels of glutamate in some glycine indirectly adjusts the effects of glutamate; this is an of them.3, 4 Third, some studies using magnetic resonance exciting area of recent focus in OCD research. A placebo- spectroscopy (MRS), a brain imaging method that makes controlled trial of glycine itself suggested that it can be of it possible to measure certain molecules in the brain, have benefit in treatment-resistant OCD. Unfortunately, the very shown changes in normal glutamate levels, with the nature large doses of glycine needed in order to have an effect in the of the change depending on the brain region studied.5 Less brain resulted in unpleasant side effects, especially nausea.9 direct evidence for glutamate changes come from findings in animal studies, changes in brain electrical response that are The indirect effect of glycine using sarcosine, which is an similar to an altered glutamate state, and other research.1 amino acid that comes from glycine and is available over the counter, showed some evidence of benefit in an uncontrolled The theory that glutamate imbalance contributes to OCD trial.10 Sarcosine works in the brain by blocking the reuptake has led to studies of a number of drugs and over-the-counter of glycine, much as SSRI antidepressants block the reuptake (OTC) supplements that are already widely available, of serotonin, and therefore increasing its levels without the either with or without a prescription. Small studies, most problems associated with taking large amounts of glycine of which have not had a placebo control group, have itself. This has led to the idea that a more powerful and provided interesting preliminary evidence of benefit from specific blocker of glycine reuptake may represent a new riluzole, memantine, N-acetylcysteine, and topiramate, all frontier in OCD treatment. Such drugs are not yet approved of which have an effect on glutamate.1 In none of these by the FDA or widely available by prescription, but they cases is the data strong enough for any of these drugs to have been developed by several different pharmaceutical 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 Towards New Medications for Refractory OCD (continued)
An investigation of one of these drugs for individuals with Institute of Mental Health. Both authors are recruiting refractory OCD, sponsored by the pharmaceutical company patients for the SkyLyte study, funded by F. Hoffman La Roche, F. Hoffman La Roche, Ltd., is currently underway at research Ltd., at their research sites, and have received compensation sites across the country. The drug, called bitopertin, was (< $5000) from Roche for consultative input during the design originally developed as a new treatment for schizophrenia, especially for “negative symptoms” such as reduced motivation11; it is completely distinct from traditional REFERENCES
antipsychotics like risperidone and haloperidol. While 1. Pittenger, C., Bloch, M.H., & Williams, K. (2011) Glutamate
bitopertin is not yet clinically available, it has been used in abnormalities in obsessive compulsive disorder: neurobiology, hundreds of people in earlier studies. This trial is important pathophysiology, and treatment. Pharmacology & Therapeutics, for the field of OCD research for two reasons. First, it should provide us with important information about a completely 2. Stewart, S.E., et al. (2013). Meta-analysis of association between
new type of medication that may be of benefit to refractory obsessive-compulsive disorder and the 3’ region of neuronal patients. Second, it is the first time since the 1980s that a glutamate transporter gene SLC1A1. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 162B(4), 367–79.
major trial of a new medication for OCD has been undertaken by the pharmaceutical industry. Collaborations of this sort are 3. Bhattacharyya, S., et al. (2009). Anti-brain autoantibodies and
altered excitatory neurotransmitters in obsessive-compulsive very important for turning our growing understanding of the disorder. Neuropsychopharmacology, 34(12), 2489–96.
neurobiology underlying OCD symptoms into innovative new 4. Chakrabarty, K., et al. (2005). Glutamatergic dysfunction in OCD.
Neuropsychopharmacology, 30(9), 1735–40.
This trial, which goes by the name of Skylyte, is currently 5. Brennan, B.P., et al. (2013). A critical review of magnetic resonance
looking for individuals with OCD symptoms that have not spectroscopy studies of obsessive-compulsive disorder. Biological Psychiatry, 73(1), 24–31.
responded to SSRI treatment to participate. More information
can be found at www.skylytestudy.com.
6. Aan Het Rot, M., et al. (2012). Ketamine for depression: where do we
go from here? Biological Psychiatry, 72(7), 537–47.
The needs of OCD sufferers whose symptoms are refractory to 7. Bloch, M.H., et al., (2012). Effects of ketamine in treatment-refractory
the best psychotherapy and pharmacotherapy that we have obsessive-compulsive disorder. Biological Psychiatry, 72(11), 964–70. to offer are great. However, we are in an exciting time for OCD 8. Rodriguez, C.I., et al. (2013). Randomized Controlled Crossover Trial
research, and new hope may be on the horizon. The idea that of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept. chemicals that have an effect on glutamate can benefit some Neuropsychopharmacology. doi: 10.1038/npp.2013.150. [Epub ahead of print] patients has driven a great deal of research in recent years.1 And a major treatment trial of a new medication, Skylyte, 9. Greenberg, W.M., et al. (2009). Adjunctive glycine in the treatment
of obsessive-compulsive disorder in adults. Journal of Psychiatric may indicate new interest by the pharmaceutical industry in the development of new treatment strategies — an interest 10. Wu, P.L., et al. (2011). Sarcosine therapy for obsessive compulsive
that has been unfortunately lacking for many years. We are disorder: a prospective, open-label study. Journal of Clinical hopeful that these research efforts will lead to new hope in Psychopharmacology, 31(3), 369–74.
11. Javitt, D.C. (2012). Glycine transport inhibitors in the treatment of
schizophrenia. Handbook of Experimental Pharmacology, (213), ACKNOWLEDGEMENTS & DISCLOSURES
Dr. Pittenger is the 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. Dr. Goodman 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

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