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Improvement in Refractory Obsessive Compulsive Disorder With Dronabinol

May 2008
American Journal of Psychiatry 165(4):536-7

DOI:10.1176/appi.ajp.2007.07061016

Source
PubMed

Authors:

Frank Schindler

Charité Universitätsmedizin Berlin

Ion Anghelescu

Mental Health Institute Berlin

Scores of Agitated Patients After the First Intramuscular Injection With Olanzapine

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536 Am J Psychiatry 165:4, April 2008

LETTERS TO THE EDITOR

ajp.psychiatryonline.org

ment of acute agitation in schizophrenia. Arch Gen Psychiatry

2002; 59:441–448

5. Meehan K, Zhang F, David S, Tohen M, Janicak P, Small J, Koch

M, Rizk R, Walker D, Tran P, Breier A: A double-blind, random-

ized comparison of the efficacy and safety of intramuscular in-

jections of olanzapine, lorazepam, or placebo in treating

acutely agitated patients diagnosed with bipolar mania. J Clin

Psychopharmacol 2001; 21:389–397

6. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ,

Saunders JC, Krueger J, Bradley P, San L, Bernardo M, Reinstein

M, Breier A: Double-blind, placebo-controlled comparison of

intramuscular olanzapine and intramuscular haloperidol in

the treatment of acute agitation in schizophrenia. Am J Psychi-

atry 2001; 158:1149–1151

CRISTIAN DAMSA, M.D.

Geneva, Switzerland

ERIC ADAM, M.Sc.

Liège, Belgium

CORALIE LAZIGNAC, M.D.

ADRIANA MIHAI, M.D.

Geneva, Switzerland

FRANCOIS DE GREGORIO, M.D.

Liège, Belgium

Geneva, Switzerland

JOSEPH LEJEUNE, M.D.

Liège, Belgium

SUSANNE MARIS, M.Sc.

EMMANUEL CLIVAZ, M.D.

Geneva, Switzerland

MICHAEL H. ALLEN, M.D.

Denver, Colo.

The authors report no competing interests.

This letter (doi: 10.1176/appi.ajp.2007.07060946) was accepted

for publication in October 2007.

Improvement in Refractory Obsessive

Compulsive Disorder With Dronabinol

TO THE EDITOR: It has been reported that 40%–60% of pa-

tients with obsessive-compulsive disorder (OCD) do not re-

spond to first-line treatment. Treatment options for these pa-

tients include switching to another agent or augmentation

(1). We report on two patients with treatment-resistant OCD

and comorbid axis I disorders who responded to an augmen-

tation with the cannabinoid dronabinol.

“Mrs. L” was a 38-year-old woman who was admitted

with recurrent major depression and OCD (Yale-Brown Ob-

sessive Compulsive Scale score: 20) after outpatient treat-

ment with paroxetine (60 mg) for 8 months and cognitive

behavioral therapy (CBT) were not efficacious. Switching

to clomipramine (300 mg) resulted in partial response af-

ter 12 weeks of treatment. Based on the patient’s report

that smoking marijuana usually relieved her symptoms,

an augmentation with dronabinol (2.5%; 10 mg t.i.d.) was

started. The prior medication was continued. While un-

dergoing treatment with dronabinol (2.5%), the patient’s

OCD symptoms decreased significantly within 10 days

(Yale-Brown Obsessive Compulsive Scale score: 10).

“Mr. K” was a 36-year-old man with schizophrenia and

OCD who was admitted for deterioration of psychotic and

obsessive symptoms (Yale-Brown Obsessive Compulsive

Scale score: 23). During his course of illness, Mr. K had

been treated with antipsychotics (including haloperidol,

olanzapine, risperidone, quetiapine, and aripiprazole),

both in monotherapy and in combination with selective

serotonin reuptake inhibitors. His OCD symptoms in par-

ticular remained predominately treatment resistant.

Treatment with clozapine (400 mg), which he had already

received for more than 1 year (in combination with parox-

etine [60 mg] for 13 weeks) resulted only in partial re-

sponse of his psychotic and OCD symptoms. Switching par-

oxetine to clomipramine (for another 10 weeks), followed

by an additional course of 18 electroconvulsive therapy

treatments (right unilateral high dose), did not improve

the patient’s psychotic or OCD symptoms significantly. Af-

ter the addition of dronabinol to ongoing treatment with

clomipramine (150 mg) and clozapine (400 mg), a signifi-

cant reduction of OCD symptoms was observed within 2

weeks (Yale-Brown Obsessive Compulsive Scale score: 15).

In order to prevent psychotic deterioration, dronabinol

(2.5%) was carefully increased to 10 mg b.i.d.

Apart from anticholinergic symptoms that preceded the

addition of dronabinol (patient 1: dry mouth, constipa-

tion; patient 2: constipation, hypotension), both patients

reported no side effects. In particular, there was no dete-

rioration of psychotic or mood disorder symptoms.

Based on data from case reports and small clinical trials

suggesting that cannabinoids can reduce symptoms of tic dis-

order (2) and on findings from genetic studies linking tic dis-

order with OCD (3), we hypothesized that cannabinoids

FIGURE 1. Scores of Agitated Patients After the First Intramuscular Injection With Olanzapine

t=10.59, p<0.0001

t=12.00, p<0.0001

t=11.43, p<0.0001

Score on Agitated

Behavior Scale

Score on Clinical Global

Impression, Severity Rating

Score on Positive and

Negative Syndrome Scale,

Excited Component

Baseline DischargeAfter 2

Hours

Baseline DischargeAfter 2

Hours

Baseline DischargeAfter 2

Hours

Am J Psychiatry 165:4, April 2008 537

LETTERS TO THE EDITOR

ajp.psychiatryonline.org

might also reduce OCD symptoms. Moreover, there is evi-

dence suggesting that besides serotonergic and dopaminer-

gic systems, glutamatergic hyperactivity is involved in the

pathophysiology of OCD (4, 5). This view is supported by data

suggesting the efficacy of glutamate modulating drugs, such

as topiramate, memantine, riluzole, or N-acetylcysteine, in

the treatment of OCD (6). It has been reported that canna-

binoids inhibit glutamate release in the CNS (7, 8). Addition-

ally, cannabinoid type 1 (CB

) receptors are distributed abun-

dantly in the striatum (8), a brain region frequently associated

with OCD. Hence, it can be speculated that the anti-obsessive

effect observed in our patients may have been a consequence

of the glutamate modulation of the cannabinoid dronabinol.

Since it is well known that cannabinoids may trigger psy-

chotic symptoms in patients with schizophrenia (8), caution

is warranted when prescribing for patients with a history of

the disorder.

References

1. Kaplan A, Hollander E: A review of pharmacologic treatments

for obsessive-compulsive disorder. Psychiatr Serv 2003; 54:

1111–1118

2. Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H,

Daldrup T, Emrich HM: Delta-9-tetrahydrocannabinol (THC) is

effective in the treatment of tics in Tourette syndrome: a 6-

week randomized trial. J Clin Psychiatry 2003; 64:459–465

3. Shavitt RG, Hounie AG, Rosário Campos MC, Miguel EC:

Tourette’s syndrome. Psychiatr Clin North Am 2006; 29:471–

486

4. Arnold PD, Sicard T, Burroughs E, Richter MA, Kennedy JL:

Glutamate-transporter gene SLC1A1 associated with obsessive-

compulsive disorder. Arch Gen Psychiatry 2006; 63:769–776

5. Chakrabarty K, Bhattacharyya S, Christopher R, Khanna S:

Glutamatergic dysfunction in OCD. Neuropsychopharmacology

2005; 30:1735–1740

6. Pittenger C, Krystal JH, Coric V: Glutamate-modulating drugs as

novel pharmacotherapeutic agents in the treatment of obses-

sive-compulsive disorder. NeuroRx 2006; 3:69–81

7. Fujiwara M, Egashira N: New perspectives in the studies on en-

docannabinoid and cannabis: abnormal behaviors associate

with CB1-receptor and development of therapeutic applica-

tion. J Pharmacol Sci 2004; 96:363–366

8. Pacher P, Bátkai S, Kunos G: The endocannabinoid system as

an emerging target of pharmacotherapy. Pharmacol Rev 2006;

58:389–462

FRANK SCHINDLER, M.D.

ION ANGHELESCU, M.D., P

H.D.

FRANCESCA REGEN, M.D.

MARIA JOCKERS-SCHERUBL, M.D., P

H.D.

Berlin, Germany

The authors report no competing interests.

This letter (doi: 10.1176/appi.ajp.2007.07061016) was accepted

for publication in September 2007.

Maintenance Treatment With Transcranial

Magnetic Stimulation in a Patient With Late-

Onset Schizophrenia

TO THE EDITOR: A recent meta-analysis (1) concluded that re-

petitive transcranial magnetic stimulation (rTMS) efficiently

reduces resistant auditory hallucinations in patients with

schizophrenia (effect size=0.76). Nevertheless, treatment is

presently only provided over short periods of time, and little is

known about longer-term impact. Maintenance treatment

protocols have been developed, and we previously described

a case report involving a maintenance protocol with a weekly,

once-a-day stimulation (2); however, we failed to demon-

strate long-term benefits. To our knowledge, the case pre-

sented below is the first report of a twice-daily transcranial

magnetic stimulation as efficacious for auditory hallucina-

tions, both in acute and maintenance treatment.

“Ms. A,” a 55-year-old right-handed, postmenopausal

woman who had DSM-IV late-onset schizophrenia with an

illness duration of 2 years, was referred for transcranial

magnetic stimulation treatment. She was noted to have

benzodiazepine addiction involving the use of lorazepam

(9 mg/day). She had been suffering from resistant audi-

tory hallucinations for 2 years (very frequent and loud,

with >5 critical and command voices). She was unrespon-

sive to four antipsychotic medication trials lasting > 4

months each, including haloperidol (5 mg/day), amisul-

pride (1200 mg/day), olanzapine (15 mg/day), and risperi-

done (8 mg/day). A detailed assessment did not reveal

any other pathology or transcranial magnetic stimulation

contraindications. Auditory hallucinations were assessed

using the Auditory Hallucination Rating Scale (3), and pos-

itive symptoms were assessed using the Scale for the As-

sessment of Positive Symptoms (SAPS). Lorazepam with-

drawal was completed without exacerbation of the

psychotic symptoms (Auditory Hallucination Rating Scale

score: 34). Four months after her initial presentation, the

patient gave informed consent and was included in a

transcranial magnetic stimulation protocol. Twice-a-day,

1000 low-frequency repetitive stimulations (1 Hz) were

administered to the temporoparietal cortex at 100% of

motor threshold over a 5-day period. The patient’s cur-

rent dose of risperidone was maintained during treat-

ment with transcranial magnetic stimulation. After the

first course, auditory hallucinations were moderately im-

proved, with a 35% reduction in her Auditory Hallucina-

tion Rating Scale score, which did not change over the

next several months, as observed in a follow-up assess-

ment. However, the patient’s general SAPS score im-

proved, with a 30% reduction in severity.

Six months after the first course of transcranial mag-

netic stimulation therapy, the patient presented with a

relapse of hallucinations. A new transcranial magnetic

stimulation course, with the same parameters, was con-

ducted. This second course was followed by a once-per-

month, twice-daily maintenance protocol (one session in

the morning, the other in the afternoon on the same day).

The patient’s auditory hallucinations were greatly im-

proved, by 80%, and her SAPS score decreased from 38 to

16. This maintenance course was associated with a remis-

sion of auditory hallucination symptoms, with a stabiliza-

tion of SAPS scores at 10 over the next 6 months. Pres-

ently, more than 1 year later, Ms. A is not receiving any

antipsychotic medication, and her Auditory Hallucination

Rating Scale and SAPS scores remain at 0.

Our case raises the question as to whether twice-daily

transcranial magnetic stimulation may be useful in some pa-

tients as a possible maintenance intervention. Certainly, fur-

ther research will help us to understand whether the benefits

observed in this single case might also be evident in larger

studies.

Cannabis Improves Obsessive-Compulsive Disorder—Case Report and Review of the Literature

Article

Full-text available

Jul 2020

Although several lines of evidence support the hypothesis of a dysregulation of serotoninergic neurotransmission in the pathophysiology of obsessive-compulsive disorder (OCD), there is also evidence for an involvement of other pathways such as the GABAergic, glutamatergic, and dopaminergic systems. Only recently, data obtained from a small number of animal studies alternatively suggested an involvement of the endocannabinoid system in the pathophysiology of OCD reporting beneficial effects in OCD-like behavior after use of substances that stimulate the endocannabinoid system. In humans, until today, only two case reports are available reporting successful treatment with dronabinol (tetrahydrocannabinol, THC), an agonist at central cannabinoid CB1 receptors, in patients with otherwise treatment refractory OCD. In addition, data obtained from a small open uncontrolled trial using the THC analogue nabilone suggest that the combination of nabilone plus exposure-based psychotherapy is more effective than each treatment alone. These reports are in line with data from a limited number of case studies and small controlled trials in patients with Tourette syndrome (TS), a chronic motor and vocal tic disorder often associated with comorbid obsessive compulsive behavior (OCB), reporting not only an improvement of tics, but also of comorbid OCB after use of different kinds of cannabis-based medicines including THC, cannabis extracts, and flowers. Here we present the case of a 22-year-old male patient, who suffered from severe OCD since childhood and significantly improved after treatment with medicinal cannabis with markedly reduced OCD and depression resulting in a considerable improvement of quality of life. In addition, we give a review of current literature on the effects of cannabinoids in animal models and patients with OCD and suggest a cannabinoid hypothesis of OCD.

Acute Effects of Cannabis on Symptoms of Obsessive-Compulsive Disorder

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Oct 2020

Background Little is known about the the acute effects of cannabis on symptoms of OCD in humans. Therefore, this study sought to: 1) examine whether symptoms of OCD are significantly reduced after inhaling cannabis, 2) examine predictors (gender, dose, cannabis constituents, time) of these symptom changes and 3) explore potential long-term consequences of repeatedly using cannabis to self-medicate for OCD symptoms, including changes in dose and baseline symptom severity over time. Method Data were analyzed from the app Strainprint® which provides medical cannabis patients a means of tracking changes in symptoms as a function of different doses and strains of cannabis across time. Specifically, data were analyzed from 87 individuals self-identifying with OCD who tracked the severity of their intrusions, compulsions, and/or anxiety immediately before and after 1,810 cannabis use sessions spanning a period of 31 months. Results Patients reported a 60% reduction in compulsions, a 49% reduction in intrusions, and a 52% reduction in anxiety from before to after inhaling cannabis. Higher concentrations of CBD and higher doses predicted larger reductions in compulsions. The number of cannabis use sessions across time predicted changes in intrusions, such that later cannabis use sessions were associated with smaller reductions in intrusions. Baseline symptom severity and dose remained fairly constant over time. Limitations The sample was self-selected, self-identified as having OCD, and there was no placebo control group. Conclusions Inhaled cannabis appears to have short-term beneficial effects on symptoms of OCD. However, tolerance to the effects on intrusions may develop over time.

Chronic ∆-9-tetrahydrocannabinol administration delays acquisition of schedule-induced drinking in rats and retains long-lasting effects

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Rationale Schedule-induced drinking (SID) is a behavioural phenomenon characterized by an excessive and repetitive drinking pattern with a distinctive temporal distribution that has been proposed as a robust and replicable animal model of compulsivity. Despite cannabis currently being the most widely consumed illicit drug, with growing interest in its clinical applications, little is known about the effects of ∆-9-tetrahydrocannabinol (THC) on SID. Objectives The effects of chronic and acute THC administration on SID acquisition, maintenance and extinction were studied, as were the effects of such administrations on the distinctive temporal distribution pattern of SID. Methods THC (5 mg/kg i.p.), or the corresponding vehicle, was administered to adult Wistar rats for 14 days in a row. Subsequently, THC effects on SID acquisition were tested during 21 sessions using a 1-h fixed-time 60-s food delivery schedule. Acute effects of THC were also evaluated after SID development. Finally, two extinction sessions were conducted to assess behavioural persistence. Results The results showed that previous chronic THC treatment delayed SID acquisition and altered the distinctive behavioural temporal distribution pattern during sessions. Moreover, acute THC administration after SID development decreased SID performance in animals chronically pre-treated with the drug. No great persistence effects were observed during extinction in animals pre-treated with THC. Conclusions These results suggest that chronic THC affects SID development, confirming that it can disrupt learning, possibly causing alterations in time estimation, and also leads to animals being sensitized when they are re-exposed to the drug after long periods without drug exposure.

Patterns of Cannabis Use Among Individuals with Obsessive-Compulsive Disorder: Results from an Internet Survey

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Background Americans increasingly use cannabis, including those with psychiatric disorders. Yet little is known about cannabis use among individuals with obsessive-compulsive disorder (OCD). Thus, we conducted the first survey of cannabis users with OCD. Methods Adults with OCD (i.e., prior professional diagnosis and/or score above the cutoff on a validated scale) who reported using cannabis were recruited from internet sources to complete a survey querying demographic information, medical/psychiatric history, cannabis use patterns, and perceived cannabis effects. Results Of 1096 survey completers, 601 met inclusion criteria. Inhalation/cannabis flower were the most common method/formulation participants endorsed; most identified using high-potency cannabis products; 42% met criteria for cannabis use disorder. Nearly 90% self-reported using cannabis medicinally, 33.8% had a physician's recommendation, and 29% used specifically to manage OCD symptoms. Most participants reported cannabis improved obsessions/compulsions; those with increased obsession severity perceived less benefit. Finally, most participants were not receiving evidence-based OCD treatment, and the odds of receiving treatment decreased with increased cannabis use. Conclusions In this survey, participants with OCD reported both subjective benefits and harms from cannabis use. Future research should clarify the risks and benefits of cannabis use to those with OCD and develop treatment models to better support this population.

Obsessive-Compulsive Disorder: Definition, Contexts, Neural Correlates and Clinical Strategies

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Starting from the categorical definitions of "obsessive-compulsive disorder", we proceeded to list the individual forms provided by the DSM-V, with a particular focus on historical, clinical, neurobiological and therapeutic profiles, concluding the analysis of the possible strategies to be used to finalize the resolutions to problems arising from the disorder in question

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Marijuana (Cannabis sativa) is an important annual medicinal plant that belongs to the Cannabaceae family. It contains 421 substances of 18 chemical types-the most significant compound is δ-9-tetrahydrocannabinol, which causes several effects, both in the Central Nervous System and in several peripheral locations in the organism. The objectives of this scientific review are to mention the anatomical distribution, chemical characteristics and biosynthesis of cannabinoids, as well as its actions mechanisms. The endogenous cannabinoid system, the therapeutic properties of C. sativa and its action on the nociceptive control are described. Finally, the modulators of the cannabinoid system in clinical use are indicated, together with marijuana legalization benefits.

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Serotonin reuptake inhibitor (SRI) medications are well established as first-line pharmacotherapeutic treatment for Obsessive-Compulsive Disorder (OCD). However, despite the excellent safety profile and demonstrated efficacy of these medications, a substantial proportion of individuals with OCD fail to attain sufficient benefit from SRIs. In this narrative review, we discuss clinical features of OCD that have been associated with poorer response to SRIs, and we present pharmacotherapeutic interventions that have been explored as augmenting or alternative treatments for treatment-resistant OCD. We additionally highlight non-SRI interventions for OCD that are currently under investigation. Pharmacotherapeutic interventions were identified via expert consensus. To assess the evidence base for individual pharmacotherapies, targeted searches for relevant English-language publications were performed on standard biomedical research databases, including MEDLINE. Information relevant to ongoing registered clinical trials in OCD was obtained by search of ClinicalTrials.gov. Pharmacotherapies are grouped for review in accordance with the general principles of Neuroscience-based Nomenclature (NbN). Clinical features of OCD that may suggest poorer response to SRI treatment include early age of onset, severity of illness, duration of untreated illness, and the presence of symmetry/ordering or hoarding-related symptoms. Based on evolving pathophysiologic models of OCD, diverse agents engaging serotonin, dopamine, norepinephrine, glutamate, and anti-inflammatory pathways have been explored as alternative or adjunctive therapies for treatment-resistant OCD and have at least preliminary evidence of efficacy. Medications with dopamine antagonist activity remain the most robustly evidence-based of augmenting interventions, yet dopamine antagonists benefit only a minority of those who try them and carry elevated risks of adverse effects. Interventions targeting glutamatergic and anti-inflammatory pathways are less well evidenced, but may offer more favorable benefit to risk profiles. Ongoing research should explore whether specific interventions may benefit individuals with particular features of treatment-resistant OCD.

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Objective: Limited studies have investigated cannabis use in patients with obsessive-compulsive disorder (OCD), despite its widespread use by patients with psychiatric illnesses. The aim of this study was to assess the frequency, correlates, and clinical impact of cannabis use in an Italian sample of patients with OCD. Methods: Seventy consecutive outpatients with OCD were recruited from a tertiary specialized clinic. To assess cannabis-related variables, patients completed a questionnaire developed for the purpose of this study, investigating cannabis use-related habits and the influence of cannabis use on OCD symptoms and treatments. A set of clinician and self-reported questionnaires was administered to measure disease severity. The sample was then divided into three subgroups according to the pattern of cannabis use: "current users" (CUs), "past-users" (PUs), and "non-users" (NUs). Results: Approximately 42.8% of patients reported lifetime cannabis use and 14.3% reported current use. Approximately 10% of cannabis users reported an improvement in OCD symptoms secondary to cannabis use, while 23.3% reported an exacerbation of anxiety symptoms. CUs showed specific unfavorable clinical variables compared to PUs and NUs: a significant higher rate of lifetime use of tobacco, alcohol, and other substances, and a higher rate of pre-OCD onset comorbidities. Conversely, the three subgroups showed a similar severity of illness. Conclusion: A considerable subgroup of patients with OCD showed a predisposition towards cannabis use and was associated with some specific clinical characteristics, suggesting the need for targeted consideration and interventions in this population.

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A Review of Pharmacologic Treatments for Obsessive-Compulsive Disorder

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Full-text available

Sep 2003

Obsessive-compulsive disorder is a chronic and often disabling disorder that affects 2 to 3 percent of the U.S. population. Optimal treatment involves a combination of pharmacologic and cognitive-behavioral therapies. Advances in psychopharmacology have led to safe and effective treatments for obsessive-compulsive disorder that provide clinically significant improvement in symptoms. In this article the authors review studies of pharmacologic treatments. A MEDLINE search was conducted to identify relevant articles from 1991 to 2002. Double-blind, placebo-controlled studies as well as open-label studies and case reports were included. The serotonin reuptake inhibitors (SRIs), including clomipramine, fluvoxamine, fluoxetine, sertraline, and paroxetine, have been approved by the U.S. Food and Drug Administration for the treatment of adults with obsessive-compulsive disorder; three of these (clomipramine, fluvoxamine, and sertraline) have been approved for treatment of children and adolescents. Clomipramine and the selective serotonin reuptake inhibitors (SSRIs) are first-line agents. However, 40 to 60 percent of patients with obsessive-compulsive disorder do not respond to adequate treatment trials with SRIs, and agents that alter serotonin receptors and other neurotransmitter systems, such as dopamine, norepinephrine, and second-messenger systems, may play a role in treatment. Treatment options for patients who do not respond to SRIs include switching, augmentation, or novel-agent strategies. Up to two-thirds of patients with obsessive-compulsive disorder have comorbid psychiatric disorders, which may present a challenge in pharmacologic treatment. Major depressive disorder is the most common comorbid condition. Nonpharmacologic invasive techniques may play a role in refractory cases of obsessive-compulsive disorder, but further research is warranted.

New Perspectives in the Studies on Endocannabinoid and Cannabis: Abnormal Behaviors Associate With CB1 Cannabinoid Receptor and Development of Therapeutic Application

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Full-text available

Jan 2005

Delta9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component of marijuana, induces catalepsy-like immobilization and impairment of spatial memory in rats. Delta9-THC also induces aggressive behavior in isolated housing stress. These abnormal behaviors could be counteracted by SR141716A, a CB1 cannabinoid receptor antagonist. Also Delta9-THC inhibited release of glutamate in the dorsal hippocampus, but this inhibition could be antagonized by SR141716A in an in vivo microdialysis study. Moreover, NMDA and AMPA-type glutamate receptor enhancers improved the Delta9-THC-induced impairment of spatial memory. On the other hand, Delta9-THC markedly inhibited the neurodegeneration in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis and reduced the elevated glutamate level of cerebrospinal fluid induced by EAE. These therapeutic effects on EAE were reversed by SR141716A. Taken together, our results demonstrate that the inhibition of glutamate release via activation of the CB1-cannabinoid receptor is one mechanism involved in Delta9-THC-induced impairment of spatial memory, and the therapeutic effect of Delta9-THC on EAE, and a Delta9-THC analog might provide an effective treatment for psychosis and neurodegenerative diseases.

Glutamatergic Dysfunction in OCD

Article

Full-text available

Oct 2005

The role of glutamatergic dysfunction in the pathophysiology of OCD has hardly been explored despite recent reports implicating glutamatergic dysfunction in OCD. We decided to investigate CSF glutamate levels in adult OCD probands compared to psychiatrically normal controls. In total, 21 consenting psychotropic drug-naïve adult OCD patients, diagnosed using SCID-IV-CV, and 18 consenting psychiatrically normal controls with age within 10 years of age of the patients, who did not have any history of head injury or neurological illness, were included into the study. Aseptically collected and stored CSF samples obtained from the patients and control subjects were used for glutamate estimation, which was carried out by a modification of the procedure described by Lund (1986). CSF glutamate (micromol/l) level was found to be significantly higher [F(1,31)=6.846, p=0.014] in OCD patients (47.12+/-4.25) compared to control subjects (41.36+/-3.63) on analysis of covariance. There was no effect of gender, age, duration of illness, Y-BOCS score, or CGI-S score on CSF glutamate levels. Our study provides preliminary evidence implicating glutamatergic excess in the pathophysiology of OCD, which needs to be further explored by studies from other centers involving larger sample sets from different age groups.

Delta(9)-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: A 6-week randomized trial

Article

Apr 2003

Background: Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. Method: In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette- Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Results: Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p < .05) or a trend toward a significant difference (p < .05) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p < .05) between both groups. ANOVA as well demonstrated a significant difference (p = .037). No serious adverse effects occurred. Conclusion: Our results provide more evidence that THC is effective and safe in the treatment of tics. It, therefore, can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology.

Delta 9-Tetrahydrocannabinol (THC) is Effective in the Treatment of Tics in Tourette Syndrome

Article

Apr 2003

Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette-Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p <.05) or a trend toward a significant difference (p <.10) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p <.05) between both groups. ANOVA as well demonstrated a significant difference (p =.037). No serious adverse effects occurred. Our results provide more evidence that THC is effective and safe in the treatment of tics. It, therefore, can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology.

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Article

Feb 2006

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD. These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.

Tourette's Syndrome

Article

Jul 2006
PSYCHIAT CLIN N AM

This article has focused on TS, and the relationship between TS and OCD has been addressed from different perspectives. In patients who have OCD, the presence of TS seems to have some impact in the clinical manifestation of OCD symptoms. One of the main features of tic-related OCD is the frequent presence of sensory phenomena preceding the compulsions, in the absence of obsessions. Genetic epidemiologic studies provide consistent evidence for the association between TS and OCD. Although no major loci have been identified so far, family and segregation analysis studies support the assumption that genes play a major role in the etiology of TS and related disorders. Genes interact with environmental factors,which can modulate the expression of TS or OCD and determine the onset of these disorders. Neuroimaging studies suggest that the pathophysiology of TS encompasses projections of primary, secondary, and somato sensory cortex to the putamen, dorsolateral caudate nucleus, and globus pallidus,whereas the pathophysiology of OCD involves more ventral structures,such as orbitofrontal-caudate-thalamic-cortical areas. Current treatment strategies for TS include education, behavioral therapy, pharmacotherapy,and support from patients associations. Alfa-adrenergic agents such as guanfacine and clonidine are first-choice treatments for TS; typical antipsychotics are more effective but are troublesome because of their long-term side-effect profiles. For comorbid TS plus OCD, each condition should be treated with its respective first-line option. Nonetheless, for patients who have tic-related OCD who are unresponsive to monotherapy with serotonin reuptake inhibitors, augmentation of serotonin reuptake inhibitors with atypical antipsychotics may be of benefit. Despite important advances, re-search is needed to clarify further the biologic and behavioral aspects of TS and its relationship with the frequently associated conditions, with particular attention to their management and prognosis.

Glutamate Transporter Gene SLC1A1 Associated With Obsessive-compulsive Disorder

Article

Aug 2006
ARCH GEN PSYCHIAT

There is strong evidence from family and twin studies that genetic determinants play an important role in the etiology of obsessive-compulsive disorder (OCD). In the only genome scan of OCD to date that we are aware of, suggestive linkage was reported to the chromosomal region 9p24, a finding that was subsequently replicated. This region contains the gene encoding the neuronal glutamate transporter, SLC1A1. SLC1A1 represents an excellent candidate gene for OCD based on evidence from neuroimaging and animal studies that altered glutamatergic neurotransmission is implicated in the pathogenesis of this disorder. To determine whether sequence variants in SLC1A1 are associated with transmission of the OCD trait. A family-based candidate gene association study. A specialized anxiety disorders outpatient clinic. One hundred fifty-seven white probands with DSM-IV OCD recruited from consecutive referrals and their first-degree relatives (476 individuals in total). Nine single nucleotide polymorphisms spanning SLC1A1 were genotyped. Single-locus and haplotype analyses were performed using the Family-Based Association Test and the Transmission Disequilibrium Test. Traits examined included DSM-IV OCD diagnosis and highest lifetime symptom severity as measured using the Yale-Brown Obsessive-Compulsive Scale. Correction for multiple comparisons was performed using permutation tests. After correction for multiple comparisons, 2 variants, rs301434 (chi 2 = 12.04; P = .006) and rs301435 (chi 2 = 9.24; P = .03), located within a single haplotype block were found to be associated with transmission of OCD. Furthermore, a specific 2-marker haplotype within this block was significantly associated with OCD (chi 2 = 12.60; P = .005). This haplotype association was statistically significant in transmissions to male but not female offspring. Although requiring replication in larger samples, these findings provide preliminary evidence that sequence variation in SLC1A1 is associated with susceptibility to OCD, particularly in males. Furthermore, these results provide support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

The endocannabinoid system as an emerging target of pharmacotherapy

Jan 2006
389-462

P Pacher
S Bátkai
G Kunos
M D Frank Schindler
M D Ion Anghelescu
Ph D Francesca Regen

Pacher P, Bátkai S, Kunos G: The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58:389–462 FRANK SCHINDLER, M.D. ION ANGHELESCU, M.D., PH.D. FRANCESCA REGEN, M.D.