- Treatment-resistant OCD: There’s more we can do
- N-A-C for Depression and Anxiety
- Testosterone levels
- Cholesterol levels
- Fasting Glucose
- Vitamin D
- Misc blood work / lab results
- 5 Supplements for OCD | Dr. Roseann & Associates
- N-Acetylcysteine (NAC)
- Milk Thistle
- N-Acetylcysteine for Pediatric Obsessive-Compulsive Disorder: A Small Pilot Study
- International OCD Foundation | New Horizons in OCD Research and the Potential Importance of Glutamate. Can We Develop Treatments That Work Better and Faster?
- Glutamate in OCD
- Glutamate-targeting Medications
- Glutamate in Depression and the Possibility of a Rapidly-acting Anti-obsessional Drug
Treatment-resistant OCD: There’s more we can do
Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains.
In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d22 and with escitalopram after an increase of dose up to 50 mg/d.
23 However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.
24 A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.25 As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.26
Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment.
Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.
27 On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.28 To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.29-31
Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),32 they have not been shown to be effective for OCD33 or as augmentation to an SSRI.34
Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.
35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.37 No follow-up information is available, however.
In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.38 However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.39
Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.40-43 A small study suggests that patients with OCD may be more ly to respond to memantine than patients with generalized anxiety disorder.44 Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.45
Continue to: Topiramate
N-A-C for Depression and Anxiety
Women live longer than men because women go to the doctor. Sure there is more to it than that, but it’s also true that if a woman sees a mole or something, she’s calling the dermatologist. Men accept “aches and pains” as sign they are growing old and never see a doctor until it’s too late.
Part of taking care of yourself is getting regular blood work done (at least once a year) and knowing how to read your own blood work. The most important tests for men health are testosterone levels, cholesterol levels, fasting glucose levels, and Vitamin D.
- As always, never undergo a diet or exercise regime without a doctor’s supervision!
Yes, you have to learn how to read your own labs because most doctors won’t order the full male anti-aging lab work you need (insurance companies often won’t cover a full panel), and if when doctors do order full labs, they only look to see if you’re with “range.”
Take testosterone levels for example. My own recent blood works shows I am within range, and even have a healthy overall testosterone level. But I’m at the bottom 20% percentile for free testosterone. (Isn’t it funny that people often accuse me of having ‘roid rage. I’m actually low T!)
Let’s go into my own blood work.
Here is what the lab work looks . Does it sound confusing? Fret not.
This testosterone lab result shows my testosterone levels are 538.8 ng/dL.
500 ng/DL is considered a healthy level by most general physicians who tell you to eat according to the Food Pyramid. It’s also the magic number to get TRT.
- See, “Testosterone Replacement Therapy: Playing Catch-up With Patients“
- Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products. Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.
Even though my testosterone is within the average range, but the biological marker that matters is free testosterone.
- Free Testosterone(Direct) 9.5 NORMAL
The range for free testosterone is 6.8-21.5 pg/mL. A level of 9.5 pg/mL is in the low range of testosterone.
Of course if you go to the doctor and get labs ordered, it’s unly he or she will even order a test for free testosterone.
And unless you ask for your results, the doctor is only going to look to see if you’re within range.
You can have low testosterone or have other issues even if you’re within range.
The scientific consensus on cholesterol levels and heart attack risk is a mess. First they said high cholesterol would lead to a heart attack. Then they said your HDL (high density lipoprotein) levels should be used to offset your overall levels. Now…. They don’t know.
Here is the latest on cholesterol and heart attack risk according to the Mayo Clinic:
For predicting your risk of heart disease, many doctors now believe that determining your non-HDL cholesterol level may be more useful than calculating your cholesterol ratio.
And either option appears to be a better risk predictor than your total cholesterol level or even your low-density lipoprotein (LDL, or “bad”) cholesterol level. Non-HDL cholesterol, as its name implies, simply subtracts your high-density lipoprotein (HDL, or “good”) cholesterol number from your total cholesterol number. So it contains all the “bad” types of cholesterol.
An optimal level of non-HDL cholesterol is less than 130 milligrams per deciliter (mg/dL), or 3.37 millimoles per liter (mmol/L). Higher numbers mean a higher risk of heart disease.
To calculate your cholesterol ratio, divide your total cholesterol number by your HDL cholesterol number. So if your total cholesterol is 200 mg/dL (5.2 mmol/L) and your HDL is 50 mg/dL (1.3 mmol/L), your ratio would be 4-to-1. Higher ratios mean a higher risk of heart disease.
My HDL level is 65 and my total cholesterol level is 199.
According to available consensus, I have a less than half the risk of a heart attack:
The Framingham Heart Study states that the following cholesterol ratios roughly signal different degrees of heart disease risk:
5.0 = average risk
3.4 = half the average risk
9.6 = twice the average risk
Because I have had my labs measured for years, I see that my LDL levels increased.
2013 cholesterol levels:
- Total 132
- Triglycerides 41
- HDL cholesterol 45
- VLDL cholesterol 8
- LDL cholesterol 79
Because I’ve tracked my blood work since 2013, I see that my LDL went up, spiking my total cholesterol level. Basically because I’ve eaten a fat ass all year while still exercising.
HDL levels go up when you exercise aggressively.
Fasting glucose levels (measured in two ways) are more important that cholesterol levels. Your fasting glucose levels on a blood test will show you your risk for diabetes.
- Glucose 89 ….. NORMAL 65-99 mg/dL
89 is good, especially as my levels in 2013 were 84.
According to the Mayo Clinic:
- A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it’s 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.
I also had my Hemoglobin A1c labs done:
That’s a freaking good number according to Mayo:
- Glycated hemoglobin (A1C) test. This blood test, which doesn’t require fasting, indicates your average blood sugar level for the past two to three months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. The higher your blood sugar levels, the more hemoglobin you’ll have with sugar attached. An A1C level of 6.5 percent or higher on two separate tests indicates that you have diabetes. An A1C between 5.7 and 6.4 percent indicates prediabetes. Below 5.7 is considered normal.
I’ve still cut the carbs down largely because my diet is a disaster as anyone who follows my Instagram knows.
Vitamin D levels should be in the 50 ng/mL range.
My result was 40.1 ng/mL range.
No big deal, I’ll start taking 5,000 iu’s of Vitamin D a day for a month or two and also make sure to get some more sunshine.
Misc blood work / lab results
Each person is different and your blood will tell the tale.
A full lab shows more than just tesosterone levels, and looks this:
5 Supplements for OCD | Dr. Roseann & Associates
Obsessive-Compulsive Disorder (OCD) is a disorder that afflicts 2.3 percent of the US population.
While most people associate the disorder with OCD cleaning, the uncontrollable and recurring obsessions people feel the urge to repeat over and over also include thoughts and other compulsive behaviors It is a mental health issue that can affect someone for their lifetime and benefits from a form of psychotherapy that combines cognitive behavior therapy (CBT) and exposure therapy called Exposure Response and Prevention Therapy (E/RP). OCD can also be severe with high nonresponse and relapse rates, as well as poor response to pharmacological interventions. Promising research into complementary and alternative medicine indicates these 5 supplements for OCD should be considered to reduce symptoms.
NAC is an amino acid derivative of cysteine that has antioxidant effects and supports brain function, as well as has anti-inflammatory properties. NAC helps the body synthesize glutathione, an important antioxidant necessary for detoxification of the liver.
Moreover, because of the organic compounds of the sulfhydryl groups, NAC protects the body from different toxins as it can bind and inactivate toxic heavy metals, drugs acetaminophen, environmental pollutants, herbicides, mercury, cadmium, lead, microbes, etc.
High toxin loads create an inflammatory response in the brain and body and can lead to a variety of mental health issues, including OCD.
NAC modulates the expression of genes that affect the inflammatory process. WiIth OCD, inflammation and excess neurotransmitter activity has been implicated in the occurrence of OCD.
Research supports that NAC is an effective dietary supplement for those with OCD, as NAC reduces inflammation and inhibits the release of excitatory neurotransmitters.
It inhibits the expression of pro-inflammatory cytokines and, suppresses pro-inflammatory signaling pathway NF-kappa B, and regulates the gene for cyclooxygenase-2 (COX-2), which promotes carcinogenesis, thereby preventing inflammation and pain.
NAC also targets the glutamatergic system. Research suggests that the excitatory neurotransmitter glutamate is dysregulated in OCD patients and that this dysregulation may contribute to the behaviors.
NAC stimulates inhibitory metabotropic glutamate receptors, which then reduces the synaptic release of glutamate.
The restoration of the extracellular glutamate concentration in the nucleus accumbens seems to block reinstitution of compulsive behaviors.
Glycine is a naturally occurring amino acid that supports nerve and neurotransmitter functions.
It helps support the detoxification process, assists with cellular energy, and supports intestinal and brain health, all important factors in OCD.
It is made in small amounts by the human body but is also acquired through food and supplements. The highest sources of glycine are found in collagen, gelatin, and high protein meats, as well as can also be found in bone broth.
This amino acid is important for different muscle, cognitive, and metabolic functions. Strong gut health is important for brain health. Glycine inhibits oxidative stress, which can interfere with intestinal health.
Glycine enables the production of collagen, a protein that is an essential component of muscles, tendon, skin, and bones. It also facilitates the production of creatine, a nutrient stored in and used by the brain for energy.
Glycine helps break down and transport nutrients glycogen and fat to be used by cells for energy thus supporting the brain and in the process, it supports a strong immune, digestive, and nervous system.
We know from research that bacteria can be a source of obsessive-compulsive behaviors, which results in a disorder called PANDAS when from a streptococcus infection and is called PANS when from other infectious sources. With the detoxification process, Glycine is necessary for the synthesis of bile salts, which is needed for the excretion of toxins from the body and inhibiting pathogenic bacterial overgrowth.
Glycine is involved in the transmission of chemical signals in the brain with both inhibitory and excitatory functions within the central nervous system (CNS). Glycine works with other amino acids, including taurine and gamma-aminobutyric acid GABA, as an inhibitory neurotransmitter.
Also, it binds to the NMDA receptor, which is an excitatory receptor site for glutamate, thus inducing a sedative or inhibitory effect, while also being capable of improving mood and cognition. Moreover, research indicates that it may be effective as one of the supplements for OCD patients.
Milk thistle is a plant whose fruit and seeds have been used for more than 2,000 years to support the liver.
One of the active ingredients in milk thistle is silymarin, which is extracted from the plant’s seeds and fruits. Silymarin is a complex mixture of flavonolignans that have antioxidant properties.
Research demonstrates that silymarin stabilizes cellular membranes and regulates permeability to stimulate detoxification pathways
Using milk thistle, OCD patients enable detoxification which promotes better mental health. Milk Thistle is a strong liver detoxifier. As we learn more about mental health, we know that poor detoxification can lead to issues.
When toxins build up in the brain or body, these toxins can create or contribute to significant psychiatric symptoms OCD. Specifically, it supports phase 2 liver detoxification, which is needed to remove toxins from the body.
Milk Thistle increases serotonin and those with OCD may have abnormalities in their serotonin (5-HT) system. Research studies indicate that Milk Thistle lowers obsessions and compulsions in as little as four weeks.
L-Theanine is an amino acid found in green tea and is widely used in Asian countries. It is known for its calming and relaxing properties and used to treat both anxiety and depression.
L-Theanine supports neurocognitive functioning in several ways, supporting both neurotransmitter functioning and brainwave activity and in the case of OCD, helping to calm the brain. L-theanine modulates aspects of brain function in humans by increasing Alpha brainwave activity, which calms the brain.
L-theanine increases levels of the brain neurotransmitters serotonin, dopamine, and gamma-aminobutyric acid (GABA) (an important inhibitory neurotransmitter). L-theanine produces its anti-anxiety effects by increasing GABA without producing sleepiness or impairing motor behavior common to prescription anti-anxiety drugs.
L-Theanine reduces anxiety by blocking the excitatory neurotransmitter glutamate. By inhibiting the overstimulating glutamate, the brain learns to calm and one feels more relaxed, which helps to reduce symptoms associated with OCD.
For those chronic stress, studies demonstrate that L-theanine can specifically reduce the molecular impacts of acute stress, and the resulting excitotoxicity, on brain cells, which can result in cognitive decline.
It has been found to support healthy neurotransmitter activity to reduce behaviors associated with OCD. It can be directly taken in capsule or powder form.
L-Theanine is considered safe and no negative effects have been found in research making green tea one of the primary herbs for OCD patients.
Inositol is a naturally occurring substance that is also called Vitamin B8 but isn’t categorized as a B vitamin. The B vitamin- substance can be found naturally in plants and animals or can be man-made.
It can be found in fruits oranges, cantaloupe, and bananas, as well as in wheat germ, brewer’s yeast, liver, brown rice, oat flakes, nuts, unrefined molasses, raisins, and vegetables. It is necessary for proper cell formation, nerve transmission and transportation of fats in the body.
Inositol may affect the action of the neurotransmitters serotonin and GABA metabolism and therefore has a role in many psychiatric disorders.
Inositol is a nutrient used to promote brain wellness, relaxation, and restful sleep. Research has found positive effects in reducing anxiety, depression, and obsessions and compulsions. In a 1996 study researching Inositol for OCD patients, the subjects had significantly lower scores on the Yale-Brown Obsessive Compulsive Scale when taking inositol.
There have been no documented cases of drug interactions in studies. Some gastrointestinal bloating may be a side effect for some people but inositol is generally well tolerated and reportedly safe.
As patients seek OCD treatment without medication, they seek complementary and alternative treatments. Coupled with Exposure and Response Therapy (E/RP), supplements can be an effective treatment. Patients should begin asking their providers for additional resources to support their therapies.
*Disclaimer: This article is not intended to give health advice and it is recommended to consult with a physician before beginning any new supplement regime and on specific dosages or possible drug interactions.
To make an appointment with Dr.
Roseann to discuss how one of our clinically effective and natural therapies for ADHD, anxiety, depression, such as Neurofeedback, Biofeedback, Executive Functioning coaching, parent coaching or behavioral support can help you or your child, or to meet with one of our psychotherapists call 203.438.4848 or email us at email@example.com. Live state? We work with children, individuals, and families through our intensive therapies program The 360° Reboot® Program.
Dr. Roseann is a Psychologist and Therapist and our center provides expert-level care for children, adults, and families from all over the US, supporting them with research-based and holistic therapies that are bridged with neuroscience. She is a Dr.
Roseann is a Board Certified Neurofeedback (BCN) Practitioner, a Board Member of the Northeast Region Biofeedback Society (NRBS) and Epidemic Answers, Certified Integrative Medicine Mental Health Provider (CMHIMP) and an Amen Clinic Certified Brain Health Coach.
She is also a member of the American Psychological Association (APA), National Association of School Psychologists (NASP), Connecticut Counseling Association (CCA), International OCD Foundation (IOCDF) International Society for Neurofeedback and Research (ISNR) and The Association of Applied Psychophysiology and Biofeedback (AAPB).
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N-Acetylcysteine for Pediatric Obsessive-Compulsive Disorder: A Small Pilot Study
Obsessive-compulsive disorder (OCD) is characterized by time-consuming obsessions and compulsions that cause disruptions in functioning and significant distress (American Psychiatric Association 2013).
Studies show that the prevalence of pediatric OCD is between 1% and 3% (Flament et al. 1988; Douglass et al. 1995). OCD frequently has a major negative impact on quality of life in children (Coluccia et al. 2017).
First-line therapy for moderate to severe pediatric OCD involves the combination of serotonin reuptake inhibitors (SRIs) and cognitive behavioral therapy (Geller et al. 2012).
Although most children with OCD experience improvement with these treatments, approximately half of children with OCD do not experience clinical remission after combination treatment (Pediatric OCD Treatment Study (POTS) Team 2004).
Many individuals with OCD who do respond to treatment still experience significant residual symptoms. Hence, novel treatment options are needed for children with OCD.
Current evidence suggests that glutamate dysfunction may contribute to the pathophysiology of OCD (Pittenger et al. 2011; Kariuki-Nyuthe et al. 2014).
N-acetylcysteine (NAC), a glutamate-modulating drug, has shown to be a promising agent in adults with OCD (Lafleur et al. 2006; Afshar et al. 2012; Paydary et al. 2016).
Trials examining the efficacy of NAC in adults with OCD have revealed mixed results (Lafleur et al. 2006; Afshar et al. 2012; Sarris et al. 2015; Paydary et al. 2016; Costa et al. 2017).
To the best of our knowledge, no randomized controlled trial has investigated the effect of NAC exclusively for pediatric OCD.
Pediatric NAC trials for other psychiatric conditions have demonstrated that NAC is safe and well tolerated in children (Hardan et al. 2012; Bloch et al. 2013, 2016; Nikoo et al. 2015; Wink et al. 2016).
We hypothesized that NAC is safe and effective in improving OCD symptom severity in children. To test this hypothesis, we conducted a double-blind, placebo-controlled clinical trial.
Children ages 8 to 17 years with a primary diagnosis of OCD were recruited through Yale Child Study Center from July 2012 to January 2017.
Children were included in the study if they had OCD for more than 6 months and their Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score was ≥16 at the time of enrollment.
Children were recruited through targeted outreach to local providers and through posted study flyers around the Tourette syndrome (TS)/OCD Clinic and Yale Child Study Centers. Recruitment methods were similar to our two previous studies examining NAC in the treatment of trichotillomania and TS (Bloch et al. 2013, 2016).
Exclusion criteria included a comorbid psychotic disorder, bipolar disorder, developmental disorder, intellectual disability (IQ 600 mg of NAC for longer than 2 weeks.
Finally, children with a proven or suspected diagnosis of cystinuria were not allowed to participate in the study since NAC might increase the risk of forming kidney stones in children with cystinuria.
Study medication could be taken as either a stand-alone medication or added to stable existing treatments for OCD.
The Institutional Review Board approved protocol was explained to eligible participants and their parents before enrollment in the study. Written informed assent was obtained from the child and written informed consent from the parents. This trial was registered in the National Institutes of Health Registry of Clinical Trials (identifier: NCT01172275).
An investigational pharmacist randomized participants on a 1:1 basis. One arm received NAC (Bioadvantex Brand) effervescent tablets and the other arm received matching placebo effervescent tablets. The tablets were indistinguishable in appearance, odor, and flavor.
Children, parents, and investigators were blind to which arm the child was assigned until after assessments were completed at week 12. To determine efficacy of blinding, children and investigators were asked whether they thought the child received NAC or placebo.
The target NAC dosage was 2700 mg/day. Children received one 900 mg tablet (either NAC or placebo) once a day during the first week of the trial.
The second week children received one 900 mg tablet twice a day and during week 3 to the end of the study (week 12) they received one 900 mg tablet three times a day and continued on this dose through week 12. After study completion, NAC was offered to children in the placebo arm.
At each visit, the participants and their parent(s) were asked about medication compliance. Participants were asked whether they were still taking the medication and whether they had missed any doses. The numbers of remaining tablets were not recorded.
Baseline data (age, gender, ethnicity, comorbid psychiatric diagnosis, current use of medication, and ongoing or past behavioral therapy) were collected at enrollment. A physical examination, including vital signs, was performed and urine was collected for a drug screening and pregnancy test.
The primary outcome, OCD symptom severity, was measured using the CY-BOCS. The CY-BOCS contains a 5-item subscale for obsessions and a 5-item subscale for compulsions. A score from 0 (no symptoms) to 4 (extreme symptoms) was assigned for each item.
Scores from the items were then combined to calculate the subscale scores and the total CY-BOCS score (Goodman et al. 1989). Overall improvement from baseline was assessed using the Clinical Global Impression (CGI) scale. The scale ranges from 1 (very much improved) to 7 (very much worse).
A score of 4 indicates no change (Guy 1976). Adverse events were assessed with the Pediatric Adverse Events Rating scale. The Pediatric Adverse Events Rating scale contains 45 questions related to adverse events experienced.
A number indicating severity from 0 (not present) to 4 (extreme) was assigned to each question (Shapiro et al. 2009).
CY-BOCS scores were determined at baseline, weeks 2, 4, 8, and 12. Global improvement subscale score and Pediatric Adverse Events Rating scale scores were determined at weeks 2, 4, 8, and 12.
our sample size calculation (α = 0.05, β = 0.2, Δ = 0.9, dropout rate = 10%), we intended to include 40 children.
Due to poor recruitment and eventual expiration of the study medication, enrollment was stopped at 11 children.
We believe presentation and publication of negative pediatric NAC trials from our group in related conditions significantly hampered our ability to recruit for this study (Bloch et al. 2013, 2016).
We performed descriptive analyses to summarize data collected at enrollment. We computed frequencies with percentages for categorical variables and means with standard deviations for normally distributed continuous variables.
To analyze the effect of NAC on CY-BOCS total score and CGI scores, we conducted intention-to-treat analyses. We used linear mixed models with an unstructured covariance matrix and restricted maximum lihood. In this model, we explored intervention, time (repeated assessments within subjects), and intervention by time interaction.
When there were missing values, a linear mixed model only excluded these particular missing values from the analysis instead of excluding the whole case. Linear mixed models maximized the use of the available data. Adverse events between groups were compared with Fisher's exact test. All analyses were conducted with the R language 3.
Of the 40 children screened, 19 children declined participation and 10 were not eligible inclusion and exclusion criteria. A total of 11 children were eligible and agreed to participate in the study. The investigational pharmacist randomized 5 children to NAC treatment and 6 to placebo.
Speculation by children and investigators about randomization suggested that blinding was successful (2 of 3 children receiving NAC and 3 of 6 children receiving placebo guessed treatment assignment correctly at week 12). In the NAC group, two participants did not complete the trial.
One child did not complete any follow-up assessments, decided to discontinue after taking one to two tablets (but reported no side effects), and contributed no follow-up data and one child took the medication inconsistently in the setting of family turmoil (impending divorce of parents) and was dropped from the trial after week 4 (Fig. 1).
FIG. 1. CONSORT diagram. NAC, N-acetylcysteine.
International OCD Foundation | New Horizons in OCD Research and the Potential Importance of Glutamate. Can We Develop Treatments That Work Better and Faster?
By Michael H. Bloch, MD; Vladimir Coric, MD; & Christopher Pittenger, MD, PhD
This article was initially published in the Spring 2009 edition of the OCD Newsletter.
First-line treatments for obsessive compulsive disorder (OCD) – cognitive behavior therapy drug therapy with selective serotonin re-uptake inhibitors (SSRIs) or both – are quite effective for many patients.
However, approximately one third of patients do not experience a significant reduction in symptoms from these treatments or from established second-line interventions.
Even in patients who do respond, symptom reduction usually occurs only over the course of two to three months, and response is often not complete. The development of treatments that work better and faster is a major goal of ongoing research.
Glutamate in OCD
Existing medications for OCD target two neurotransmitters (brain chemicals): serotonin and dopamine. However, there has been substantial interest over the last eight years in the potential involvement of another neurotransmitter, glutamate, in OCD.
Glutamate is the most abundant excitatory neurotransmitter in the brain; it is critical to the communication of nerve cells with one another in practically every circuit in the nervous system.
An abnormally high level of glutamate can lead to neuron damage, and glutamate-modulating therapies (medications aimed at affecting or normalizing the actions of glutamate in the brain) have been explored in medical conditions, such as “Lou Gehrig’s Disease” (ALS) and in stroke.
Evidence from several sources suggests that abnormal levels of glutamate may contribute to OCD. Investigators at the Ruhr University in Germany examined the cerebrospinal fluid (CSF) of patients with OCD who were not on any medication.
They found that individuals with OCD had higher levels of glutamate in the CSF than psychiatrically healthy controls. Since the CSF bathes the brain, this suggests that the brain is exposed to high levels of glutamate in patients with OCD. A similar increase of glutamate in the brain has been seen using another technique, magnetic resonance spectroscopy (MRS) by investigators at Wayne State University and elsewhere.
The presence of abnormally high levels of glutamate in the brains of individuals with OCD does not prove that it contributes to the disease – problems with glutamate could be a consequence of the illness rather than a cause.
However, recent genetic findings lend support to the idea that glutamate imbalance may be an important causal factor in at least some cases of OCD.
Two independent groups from the University of Toronto and the University of Chicago published evidence in 2006 that a protein that carries glutamate in the brain is linked to OCD in some cases; more recent studies from groups at the Massachusetts General Hospital and Johns Hopkins University have found the same thing.
Although it is not yet clear whether these genetic linkages correspond to a functional problem with this protein, problems with these glutamate transporters can increase the amount of glutamate found outside neurons, which might explain the increased glutamate seen in the brain, and possibly lead to OCD symptoms.
Recent findings in mice further support the idea that changes in glutamate in the brain can produce behaviors that resemble OCD. Researchers at Duke University have described a mouse that is anxious and grooms itself compulsively They genetically altered the mouse so that it is missing the SAPAP3 gene.
The SAPAP3 gene is a critical piece in structure of the glutamate receptor. The anxiety and compulsive grooming behavior of these mice decreased when they were given an OCD medication – a selective serotonin re-uptake inhibitor (SSRI).
A few doses of an SSRI did not decrease compulsive symptoms; the medication has to be given over a long period of time to have an affect – the same pattern seen with patients taking SSRIs to treat their OCD.
Although it remains unclear whether this gene (SAPAP3) is involved in OCD, the one genetic study performed to date in humans with OCD from researchers at Duke and Johns Hopkins, showed preliminary evidence of a relationship to grooming disorders, such as Trichotillomania, but no links to OCD. Regardless, further work in this and related animal models will increase our understanding of how changes in the brain, glutamate, and how neurons respond to it, can lead to compulsive behavior patterns.
Is it possible then that medications that affect glutamate in the brain will benefit patients whose OCD does not respond to existing therapies? This hope has guided research in our clinic over the past several years, and early results from our group and elsewhere are promising – although the evidence for such drugs is not yet conclusive.
Fortunately a number of medications that affect glutamate levels are already FDA approved for other medical conditions and are therefore readily available for research and clinical use .
One such medication is riluzole (Rilutek®), which has been marketed since 1996 for Lou Gehrig’s disease (ALS). Riluzole affects glutamate levels in several ways.
In an initial open-label study in 2005, and a case series in 2008, we found that approximately half of the severely ill treatment refractory patients who have not responded to other treatments improved significantly when riluzole was added to their SSRI.
Researchers at the National Institute of Mental Health have found similar results using riluzole in children with OCD. Controlled double-blind studies (the best way to test the effectiveness of a medication) for riluzole in adult and pediatric OCD have already begun.
A second drug that is already available and affects how neurons respond to glutamate is memantine (Namenda®).
Several case reports and two recent open-label case series suggest that the addition of memantine to standard medication therapy can benefit both children and adults with OCD.
As in the case of riluzole these studies are uncontrolled and need to be replicated in larger placebo-controlled studies.
There is also some limited evidence suggesting that a third medication – N-acetylcysteine or NAC – also has benefit in the treatment of OCD. NAC is available without a prescription. It is an antioxidant and is used in cases of acetaminophen (Tylenol®) overdose to protect the liver from damage.
However, animal studies by researchers at the Medical University of South Carolina have found that NAC can affect levels of brain glutamate as well. We worked with a patient with OCD who improved significantly after we added NAC to her existing medications.
Unpublished clinical experience, from our group and elsewhere, further suggests that the agent may be of benefit in at least some patients with OCD. Well controlled studies have shown benefit from NAC in a variety of other disorders of compulsive and impulsive behaviors, including pathological gambling, Trichotillomania, and drug craving.
Because it is inexpensive, has no significant side effects, and is available over-the-counter, this drug is a potentially attractive therapeutic option, though the evidence for benefit in OCD remains extremely thin.
Glutamate in Depression and the Possibility of a Rapidly-acting Anti-obsessional Drug
Abnormal glutamate levels may also play an important role in major depressive disorder.
All of the medications discussed above (riluzole, memantine, and N-acetylcysteine) have been investigated in depression by researchers at Yale, the National Institutes of Health, and elsewhere.
Indeed an important question for future research is how the glutamate problems in these two disorders which often occur together, differ from one another.
Glutamate is a neurotransmitter – a chemical that communicates from one nerve cell to another.
A neuron can respond to glutamate when it binds to a specific kind of protein, a receptor (a receiver of a brain chemical message your cell phone receiving a phone call).
So, alterations in glutamate affect nerve cells by changing the activation of these receptors, and targeting the receptors with medications can change how the neurons respond to glutamate.
There are several receptors for glutamate; a particularly important one is called the NMDA receptor. Drugs that affect these NMDA receptors have recently been found to produce a remarkably rapid antidepressant response. This contrasts starkly with the delayed response typically seen with SSRIs in both depression and OCD.
This observation was first made by researchers at Yale who reported in 1998 that depressed patients receiving a single dose of the NMDA-targeting drug, ketamine, became rapidly better and stayed better for up to a week. Ketamine can produce a short “high,” lasting 1 or 2 hours.
However, the improvements of mood were greatest at 24 hours and lasted in some subjects for as long as seven days, making it clear that they were not just a result of this high. This striking and unexpected effect was reproduced in a double-blind study at the National Institutes of Health in 2006. Memantine also affects NMDA receptors, but its effect is much weaker than that of ketamine.
Unfortunately, a controlled study of memantine in depression from the National Institute of Mental Health did not show benefit. Newer medications that act on this NMDA receptor are under development.
Ketamine is by no means the answer for major depression. The antidepressant effects of ketamine usually wear off by a week or two. Furthermore, ketamine’s addictive and abuse potential, and the fact that it needs to be administered intravenously, limit its long-term use.
Potentially unpleasant psychological symptoms, such as anxiety, sadness, disorientation, flashbacks, and hallucinations can sometimes emerge during ketamine administration, and also limit its potential for widespread use.
However, a limited trial of ketamine may be useful to help a patient break a particularly severe or treatment-refractory depression. In addition, the rapid antidepressant effect of ketamine opens a window into an entirely new way of thinking about how to treat depression.
A better understanding of how this drug works in the brain could lead to the development of new drugs that do not have ketamine’s drawbacks, but do have its advantages – in particular a more rapid effect than any standard antidepressants.
These observations raise exciting new possibilities for the field of OCD research.
If glutamate contributes to both depression and OCD, and if ketamine can produce a rapid antidepressant effect, would this medication, or similar drugs that affect glutamate or the NMDA glutamate receptor, also be effective treatments for OCD? Depression frequently occurs along with OCD – could drugs that affect the NMDA receptor ketamine be of benefit to both? Most excitingly, the antidepressant effects of ketamine are remarkably rapid – much more so than traditional medication or psychotherapy. It has long been possible to rapidly treat severe depression using ECT; but ECT is not effective in the treatment of OCD, and no rapid treatments have been available. Perhaps this unfortunate limitation will change.
In sum, increasing evidence indicates that abnormal levels of the neurotransmitter glutamate contribute to OCD and may be a fruitful target for new therapies.
Ketamine’s unexpected rapid antidepressant effect suggests that similar anti-obsessional effects are a real possibility, since the disorders frequently occur together and problems with glutamate appear to be associated with both.
No investigations of ketamine in OCD have been published to date, but developing new clinical treatments this, our advancing understanding of OCD at the molecular, cellular, and systems level, has the potential to usher in a new era of therapeutics that work better and faster than those we have today.
Michael Bloch, MD is a Fellow in the Solnit Integrated Program in Child and Adult Psychiatry at Yale University and the Assistant Director of the Yale OCD Research Clinic.
Vladimir Coric, MD is a Senior Research Scientist and Past Director of the Yale OCD Research Clinic. He is also an Associate Clinical Professor of Psychiatry at Yale University and a member of the OCF Scientific Advisory Board.
Christopher Pittenger, MD, PhD is an Assistant Professor of Psychiatry and Director of the Yale OCD Research Clinic. He is also an Attending Psychiatrist at the Connecticut Mental Health Center and an Associate at Yale-New Haven Hospital.