Nutraceuticals in the treatment of Obsessive Compulsive Disorder (OCD): A review of mechanistic and clinical evidence

Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 887–895

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Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p

Review article

Nutraceuticals in the treatment of Obsessive Compulsive Disorder (OCD): A review of mechanistic and clinical evidence David A. Camfield a,⁎, Jerome Sarris a,b, Michael Berk b,c,d,e a

National Institute of Complementary Medicine (NICM) Collaborative Centre for Neurocognition, Brain Sciences Institute, Swinburne University of Technology, Melbourne, Australia The University of Melbourne & The Melbourne Clinic Faculty of Medicine, Department of Psychiatry, Melbourne, Australia Deakin University, Geelong, Australia d The Mental Health Research Institute, Parkville, Australia e Orygen Youth Health Research Institute, Parkville Australia b c

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 7 January 2011 Received in revised form 10 February 2011 Accepted 16 February 2011 Available online 23 February 2011

Obsessive–Compulsive Disorder (OCD) is a debilitating mental illness which has a significant impact on quality of life. First-line SSRI treatments for OCD typically are of limited benefit to only 40–60% of patients, and are associated with a range of adverse side effects. Current preclinical research investigating nutraceuticals (natural products) for OCD, reveals encouraging novel activity in modulating key pathways suggested to be involved in the pathogenesis of OCD (glutamatergic and serotonergic pathway dysregulation). Emerging clinical evidence also appears to tentatively support certain nutrients and plant-based interventions with known active constituents which modulate these pathways: N-acetlycysteine, myo-inositol, glycine, and milk thistle (Silybum marianum). The serotonin precursor tryptophan is unlikely to be of use in treating OCD while 5-HTP may possibly be a more effective precursor strategy. However, there is currently no clinical evidence to test the efficacy of either of these substances. Currently the balance of clinical evidence does not support the use of St. John's wort (Hypericum perforatum) in OCD. While clinical research in this area is in its infancy, further research into nutraceuticals is warranted in light of the promising preclinical data regarding their mechanisms of action and their favourable side effect profiles in comparison to current SSRI treatments. It is recommended that future clinical trials of nutraceutical treatments for OCD utilize randomized placebocontrolled study designs and considerably larger sample sizes in order to properly test for efficacy. © 2011 Elsevier Inc. All rights reserved.

Keywords: Obsessive Compulsive Disorder Treatment Nutraceuticals Serotonin Glutamate

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . The neurobiology of OCD . . . . . . . Current pharmacotherapy for OCD . . Nutraceuticals in the treatment of OCD 4.1. N-acetylcysteine . . . . . . . . 4.2. Glycine . . . . . . . . . . . . 4.3. Myo-inositol . . . . . . . . . 4.4. Tryptophan and 5-HTP. . . . . 4.5. Plant-based compounds . . . . 5. Discussion . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . References . . . . . . . . . . . . . . . .

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Abbreviations: 5-HT, Serotonin; 5-HTP, 5-hydroxytryptophan; CSTC, Cortico-Striatal-Thalamo-Cortical; CSF, Cerebrospinal Fluid; DAG, Diacylglycerol; ERP, Exposure and Response Prevention therapy; GABA, Gamma Amino Butyric Acid; Glx, A composite measure of glutamate, glutamine, homocaronsine and GABA; GSH, Glutathione; LNAA, Large Netural Amino Acid; MAO, Monoamine Oxidase; MDD, Major Depressive Disorder; mGlu, Metabotropic glutamate receptor; MI, Myo-Inositol; MRS, Magnetic Resonance Spectroscopy; NAC, N-Acetylcysteine; NMDA, N-Methyl-D-Aspartate; PIP2, Phosphatidyl-inositol-(4–5) bisphosphate; PIP3, Inositol 1,4,5-trisphosphate; PKC, Protein Kinase C; PI cycle, Phosphoinositide secondary messenger cycle; SJW, St. John's Wort – Hypericum perforatum; SNRI, Serotonin and Norepinephrine Reuptake Inhibitor; SSRI, Selective Serotonin Reuptake Inhibitor; Y-BOCS, Yale-Brown Obsessive Compulsive Scale. ⁎ Corresponding author at: PO Box 218 Hawthorn, Vic, 3122 Australia. Tel.: +61 0392148259, +61 412 008 578; fax +61 3 9214 5230. E-mail addresses: dcamfi[email protected], david.camfi[email protected] (D.A. Camfield). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.02.011

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1. Introduction Obsessive Compulsive Disorder (OCD) is a debilitating illness that if left untreated often follows a chronic course. The World Health Organization (WHO) has identified OCD as one of the top 10 disabling illnesses by lost income and decreased quality of life (Bobes et al., 2001). Obsessions are recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate and that cause marked anxiety or distress, while compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly (American Psychiatric Association, 2000). The prevalence of OCD in the USA has been estimated to be 2.3% for lifetime prevalence and 1.2% for 12-month prevalence according to DSM-IV criteria (Ruscio et al., 2010). A similar 12-month prevalence rate has been noted in Australia, with OCD prevalence estimated to be 1.9% (CI 1.5–2.3) according to ICD-10 criteria (Slade et al., 2009). A high degree of comorbidity of OCD with other psychiatric disorders (affective, anxiety, substance use or personality disorders) has also been reported in Australia (79%) (Crino et al., 2005). The burden of disease associated with OCD is high, with financial costs associated with health care in the USA estimated to be around $10.6 billion per annum (Eaton et al., 2008). 2. The neurobiology of OCD Neuroimaging and neuropsychological studies suggest that the etiology of OCD may be related to abnormalities in orbito-striatal circuitry (Menzies et al., 2008). In particular, the finding of increased radiotracer uptake in the head of the caudate nucleus suggests increased activity in this area for OCD patients in comparison to controls (Whiteside et al., 2004). In relating these brain abnormalities to OCD symptomology, Saxena et al. (2001, 1998) propose that an imbalance in activity between the direct (excitatory) and the indirect (inhibitory) pathways within fronto-striatal circuitry leads to the development of obsessive–compulsive behaviours and cognitions. The serotonin transmitter has also been implicated in the pathophysiology of OCD, largely due to the discovery that drugs that inhibit the reuptake of serotonin have antiobsessional properties (Goddard et al., 2008). This has led to the formulation of the serotonin hypothesis of OCD, which relates OCD symptomology to a dysregulation of serotoninergic brain function (Barr et al., 1993). In particular, dysfunction in the availability of the serotonin transporter (5-HTT) has been the focus of a large number of OCD studies. Brain imaging studies using medication-free OCD patients have reported that reductions in 5-HTT availability are present in several brain regions including the thalamus/hypothalamus, midbrain and brainstem (Hasselbalch et al., 2007; Hesse et al., 2005; Stengler-Wenzke et al., 2004). Additionally post-synaptic cortical 5-HT2a receptors have also been implicated in the pathophysiology of OCD, with research suggesting that pharmacological agents that act as antagonists at frontal 5-HT2a receptors also have antiobsessional properties (Goddard et al., 2008). In addition to the serotonin transporter system the role of the ubiquitous neurotransmitter glutamate has also more recently been implicated in the pathogenesis of OCD (Pittenger et al., 2006a,b). A number of Magnetic Resonance Spectroscopy (MRS) studies of OCD have revealed abnormal glutamate transmission in brain regions associated with Cortico-Striatal-Thalamo-Cortical (CSTC) neurocircuitry. Glx, a composite measure used in MRS that refers to glutamate, glutamine, homocaronsine and GABA, has been found to be elevated in the caudate in OCD patients and to normalize again following SSRI treatment (Bolton et al., 2001; Moore et al., 1998; Rosenberg et al., 2001a,b, 2000). This finding is consistent with the metabolic hyperactivity in CSTC circuits that is a known hallmark of OCD

(Saxena et al., 1998). In contrast, Glx levels have been found to be decreased in the anterior cingulate (Rosenberg et al., 2004), a finding that parallels the inverse relationship between anterior cingulate and basal ganglia volume in OCD patients (Pittenger et al., 2006b). Further evidence of elevated glutamate levels associated with OCD comes from a study by Chakrabarty et al. (2005), who reported increased levels of glutamate in the CSF of drug-naïve OCD patients. The growing understanding of the role of glutamate in OCD provides a new avenue for the investigation of potential OCD treatments. 3. Current pharmacotherapy for OCD The current first line treatments for OCD are behavioural therapy using Exposure and Response Prevention (ERP) and/or pharmacotherapy with the tricyclic antidepressant clomipramine, Selective Serotonin Re-uptake Inhibitors (SSRIs) such as fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram and escitalopram, or dual reuptake inhibitors such as venlafaxine or duloxetine (Dell'Osso et al., 2006; Denys et al., 2007; Fineberg and Gale, 2005; Jenike, 2004). It has been estimated that only 40–60% of patients respond to an adequate trial of SSRIs with or without behavioural therapy (Pallanti et al., 2002). In clinical studies response is typically defined as a reduction in symptoms of greater than 30–35%, as measured by the Yale–Brown Obsessive Compulsive Scale (Y-BOCS) (Goodman et al., 1989a,b). This is a modest cut-off derived from the modest efficacy of available treatments. In practice, this means that these patients are likely to continue to experience OCD symptoms that significantly impact on their quality of life. Tolin et al. (2005) have noted that while a YBOCS reduction criterion of 30% appears to be appropriate for determining clinical improvement, a 40% to 50% reduction criterion is required for predicting mild illness at posttreatment. SSRIs have also been found to be associated with a number of significant dose-related side-effects including anxiety, nausea, dizziness, sedation, diarrhea, headache, insomnia, decreased libido and sexual dysfunction (Jenike, 2004). The dosage of antidepressants that are required for a clinically significant amelioration of OCD symptoms is typically higher than is required to treat Major Depressive Disorder (MDD) (Jenike et al., 1998). In addition to this, a number of patients experience rapid relapse after discontinuation of SSRI treatment (Pato et al., 1988; Steiner, 1995), and for this reason must continue on a long term maintenance dose (Jenike, 2004). An additional disadvantage of current antidepressant treatments is that there is a lengthy period between commencement of treatment and the onset of noticeable symptom amelioration which may take weeks or even months (Jenike, 2001). This delay can potentially lead to heightened patient anxiety with no reduction in OCD symptom severity yet a number of unpleasant side effects. In consideration that a number of different antidepressants must often be ‘trialled’ before an effective treatment is found for an individual (Jenike et al., 1998), the process of discovering an effective SSRI treatment may lead to a prolonged period of significant distress and disruption to occupational and social functioning. In regards to cognitive-behavioural therapies for OCD there is now convincing evidence to suggest that these therapies are as effective, if not more effective, than existing pharmacological treatments (Abramowitz, 1997; Foa et al., 2005). However, a full discussion of behavioural therapies for OCD is beyond the scope of the current review. Suffice to say that for many patients a combination of both behavioural and pharmacological treatment is often the most effective course of action (Jenike, 2004). 4. Nutraceuticals in the treatment of OCD In consideration of the shortfalls of traditional antidepressant treatments for OCD and the adverse side-effects associated with their use, it is critically important that new treatment options be identified

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that may be efficacious in ameliorating OCD symptoms. In this capacity, nutraceuticals (natural products) have received comparatively little research focus when compared to pharmaceutical substances. A nutraceutical may be defined as any substance which is considered a food, a part of a food, a vitamin, a mineral, or a herb that provides health benefits (Kalra, 2003). This narrative review details research involving nutraceuticals in preclinical models and clinical trials in the treatment of OCD. This has the dual purpose of highlighting clinical utility, and clarifying underlying mechanistic effects of activity. This evidence is detailed under two key mechanisms underpinning the pathogenesis of OCD: glutamatergic and serotonergic neurobiological dysregulation. Results of clinical studies (case reports, open label, and controlled studies) using these nutriceuticals in OCD are highlighted.

4.1. N-acetylcysteine NAC is the N-acetyl derivative of cysteine, and is less reactive, less toxic and less susceptible to oxidation than cysteine, as well as being more soluble in water. For these reasons it is a better source of cysteine than the parenteral administration of cysteine itself (Bonanomi and Gazzaniga, 1980). While cysteine can be found in a number of high protein foods, NAC is not usually obtained from dietary sources and must be added as a supplement. NAC has been examined in a diversity of other neuropsychiatric disorders including schizophrenia and bipolar disorder, and appears to have evidence of both safety and tolerability (Berk et al., 2008a,b; Dean et al., 2010). NAC is generally well tolerated, with a low incidence of adverse events in the dose ranges typically required for clinical effects. In respect to safety and tolerability of oral doses of NAC, up to 8000 mg/day have not been known to cause clinically significant adverse reactions (De Rosa et al., 2000), and in a review of over 46 placebo controlled trials, with NAC administered orally to a total of 4000 people, no significant adverse effects from NAC treatment were observed (Atkuri et al., 2007). In respect to pharmacokinetics, NAC is rapidly absorbed, with time to peak plasma levels (tmax) being 1.4 ± 0.7 h following oral administration. The average elimination half-life (t1/2) has been reported to be 2.5 ± 0.6 h (Pendyala and Creaven, 1995). The bioavailability of NAC increases according to the dose, with the peak serum level being on average 16 μmol/l after 600 mg and 35 μmol/ l after 1200 mg (Allegra et al., 2002). When taken orally NAC is readily taken up in the stomach and intestines and sent to the liver where it is converted almost entirely to cysteine and used for glutathione (GSH) synthesis (Atkuri et al., 2007). Cysteine that is not converted to GSH is capable of crossing the blood-brain barrier by means of sodiumdependent transport systems (Smith, 2000). N-acetylcysteine (NAC) has been proposed as a novel treatment for OCD due to the effects of inhibiting synaptic glutamate release through glial cystine-glutamate exchange. Group II metabotropic glutamate receptors (mGluR2/3) are located presynaptically on neurons in a large number of brain regions including the cortex, amygdala, hippocampus and striatum (Wright et al., 2001) and play an important role in the regulation of the synaptic release of glutamate (Schoepp, 2001). Stimulation of mGluR2/3 receptors by extracellular glutamate has an inhibitory effect on the synaptic release of glutamate (Moran et al., 2005). Extracellular levels of glutamate are maintained primarily by means of the cystine-glutamate antiporter (Baker et al., 2002). This Na+-independent antiporter is bound to plasma membranes and is found ubiquitously throughout the body, while being located predominantly on glial cells in the human brain (Pow, 2001). Cystine is the disulfide derivative of cysteine, consisting of two oxidized cysteine residues. When extracellular levels of cystine are increased in the brain, the antiporters on glial cells exchange extracellular cystine for intracellular glutamate; this leads to stimulation of mGluR2/3 receptors and inhibition of synaptic glutamate release (Moran et al., 2003). For this reason, cysteine prodrugs such as NAC have the ability to reduce the

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synaptic release of glutamate, with important implications for the treatment of psychiatric disorders. OCD has been associated with increased levels of oxidative stress (Behl et al., 2010). There is evidence of increased lipid peroxidation in OCD (Ozdemir et al., 2009), and severity of illness appears to be associated with greater levels of lipid peroxidation (Chakraborty et al., 2009). There are additionally changes in antioxidative enzyme systems in OCD (Ersan et al., 2006). Equally, immune activation is noted in OCD, evidenced by elevated levels of pro-inflammatory cytokines (Konuk et al., 2007). In this context, NAC has robust effects of reducing oxidative stress and inflammation that may be germane to its effect in OCD (Berk et al., 2008c; Ng et al., 2008). In a case study of a 58-year old woman with SSRI-refractory OCD, Lafleur et al. (2006) reported that NAC augmentation of fluvoxamine for 13 weeks resulted in a significant improvement in OCD symptoms as measured using the Y-BOCS. The NAC dose used in this study was titrated up from 1200 mg PO daily to 3000 mg daily over a six week period, and then maintained at this dosage level for a further 7 weeks. It is interesting to note that a reduction of 8 points on the Y-BOCS scale was noticed after only 1 week of treatment, which is indicative of rapid onset of treatment effects in comparison to conventional SSRI treatments for OCD which may take several weeks for effects to become noticeable (Fineberg and Gale, 2005). Pittenger and colleagues are currently conducting a follow-up randomized controlled double-blind trial of NAC 3000 mg/daily versus placebo in 40 treatment-refractory OCD patients (www.clinicaltrials.gov). This study will provide important data as to the potential efficacy of NAC as an augmentation strategy for OCD. A disorder related to OCD, that is classified as part of the OCD spectrum disorders is Trichotillomania (TTM), characterized by repetitive hair pulling. Grant et al. (2009) conducted a double-blind randomized placebo-controlled trial to assess the efficacy of NAC (1200–2400 mg/day) in fifty participants with TTM over a 12 week period. Patients in the NAC treatment group were found to have a significantly greater reduction in hair-pulling symptoms in comparison to placebo, using the Massachusetts General Hospital Hair Pulling Scale (MGHHPS). Significant improvements were observed from 9 weeks of treatment onwards. Fifty-six percent of patients were found to be “much or very much improved” in the NAC treatment group in comparison to only 16% assigned to the placebo group. Another OCD Spectrum disorder that NAC use has been investigated as a potential treatment strategy is compulsive nail-biting. Berk et al. (2009) present three case studies where patients with a life-long history of compulsive nail-biting were found to benefit from NAC treatment. In the first case study, a 46-year old woman was reported to have stopped nail biting altogether over a 7-month period using a dosage of 1000 mg NAC BID. In the second case study, a 44-year old woman was reported to have stopped nail biting after 4-months of treatment with NAC 1000 mg BID, and to have not recommenced on a 2 month follow-up. In the third case study, a 46-year old patient was not reported to have desisted nail biting all together, but noticed a reduction in this behavior after 28 weeks of NAC treatment. These findings in relation to compulsive nail biting should be further investigated using a randomized controlled clinical study. In addition to Trichotillomania and nail-biting, preliminary evidence suggests that NAC may potentially be effective in the reduction of skin-picking behavior (Odlaug and Grant, 2007). 4.2. Glycine The amino acid glycine is another nutrient that impacts on cortical glutamatergic function and has been investigated in an OCD case study and a preliminary clinical OCD trial. The opening of an NMDA receptor (NMDAR) requires four agonist molecules to be bound to the receptor; two glutamate and two glycine (Clements and Westbrook, 1991). The activation of NMDA receptors has been found to have an

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anti-compulsive effect in animal models of OCD (Albelda et al., 2010). In this regard glycine as well as D-serine are agonists at NMDA receptors, having the potential to ameliorate OCD in humans (Oliet and Mothet, 2009; Singer et al., 2010). While glycine is found in a number of high protein food products such as meat, dairy, fish and beans (U.S. Department of Agriculture, 2010); previous schizophrenia studies have revealed that high-dose glycine supplementation in excess of normal dietary levels is necessary for clinically significant effects (Javitt, 2006; Javitt et al., 2004). In a double-blind randomized placebo-controlled study Greenberg et al. (2009) administered 60 g/day of glycine to 24 adult OCD outpatients as augmentation therapy. Patients receiving glycine had an average 0.82 point decrease in Y-BOCS scores for each week they remained in the study in comparison to placebo; an effect that was approaching significance (p = 0.053). The authors noted that unfortunately the trial was hampered by a large rate of non-compliance due to the taste and nausea associated with administering such a large daily dose of glycine. An intriguing case study that documented the long term use of glycine in the treatment of OCD was detailed by Cleveland et al. (2009). The patient presented with marked OCD in which they were housebound by age 19 and found to be non-responsive to SSRI treatments. The patient was administered glycine over a 5 year period, which led to a large reduction in OCD symptoms, and resumption of education and social life. While these preliminary findings in relation to glycine in the treatment of OCD are encouraging, further randomized placebocontrolled trials are required in order to properly investigate its efficacy. A problematic issue associated with glycine administration is the side effect of nausea associated with such a large daily dose, which was noted in the RCT by Greenberg et al. (2009). In comparison to the glutamatergic agent NAC, the side effect profile associated with glycine is not as favourable. Future trials of glycine in OCD should investigate more palatable modes of administration. It is noteworthy that the full NMDA agonist D-serine is also currently under an FDA Investigational New Drug Application in patients with OCD (Singer et al., 2010).

4.3. Myo-inositol The glucose isomer myo-inositol (MI) is a substance which has a long history of use in the treatment of psychiatric disorders (Sarris et al., 2010). MI is an endogenous isomer of glucose, a cyclic carbohydrate that exists in nine possible stereoisomers. In the human central nervous system (CNS) MI is the most abundant biologically active stereoisomer (Frey et al., 1998). Dietary constituents that have been found to be highest in MI content include fruits, beans, grains and nuts; with the MI intake that can be provided by these food types ranging from 225 to 1500 mg/day per 1800 kcal (Clements and Darnell, 1980). In the human brain there is a particularly high concentration of MI, where it is synthesized de novo from Glucose-6-phosphate (Kim et al., 2005). Dietary MI is incorporated into neuronal cell membranes as inositol phospholipids, the most important being phosphatidyl-inositol-(4–5) bisphosphate (PIP2). A sustained supply of MI is required for the synthesis of membrane phospholipids and is a key metabolic precursor in the Phosphoinositide (PI) intracellular secondary messenger cycle (Kim et al., 2005). The PI-cycle is activated following ligand binding with (Gq)-protein coupled receptors across a broad range of neurotransmitter systems including adrenergic (α1A and α1B), serotonergic (5-HT1C and 5-HT2), dopaminergic (D1), glutaminergic (mGlu1 and mGlu5) and cholinergic (M1 and M3) receptor types (Fisher et al., 1992). Receptor activation results in hydrolysis of PIP2, producing the second messengers inositol 1,4,5-trisphosphate (IP3) which mobilizes intracellular Ca2+, and diacylglycerol (DAG) which activates protein kinase C (PKC) (Harvey, 1997). Exogenous administration of MI has been found to elevate levels of MI in both cerebrospinal fluid and the brain (Einat and Belmaker, 2001), where it is stored predominantly in astrocytes (Frey et al., 1998).

The possibility exists that both MI and SSRIs converge on the same mechanism of action, in view of the fact that 5-HT2 receptors are linked to the PI-cycle signal transduction pathway and that clinical response to MI is generally seen in the same response window (N4 weeks) to that seen with the SSRIs (Levine et al., 1999). The clinical spectrum whereby MI has been found to be effective also parallels that of the SSRIs (Einat and Belmaker, 2001). Recent animal research has linked the antidepressant activity of MI specifically to the 5-HT2 receptor class, with the finding that the 5-HT2A/5-HT2C receptor antagonist ritanserin but not the 5-HT1A/5-HT1B antagonist pindolol abolishes MI antidepressant effects (Einat et al., 2001). Studies of major depressive disorder and suicide have found that clinical symptoms are associated with increased 5-HT2A receptor binding, both in human platelets as well as the frontal cortex (Hrdina et al., 1993; Meyer et al., 2003; Pandey et al., 1990; Yates et al., 1990). This imbalance has been found to be corrected with chronic antidepressant treatment (Meyer et al., 2001; Yatham et al., 1999), with a resultant downregulation of 5-HT2A binding sites in the brain as well as a significant decrease in 5-HT2A receptor-mediated PI-hydrolysis (Pandey et al., 1995). While the exact mechanism by which MI exerts its therapeutic effects still remains to be elucidated, current theories suggest that it is linked to a modulatory effect on 5-HT transporter activity. Research into the therapeutic effect of MI in OCD has also helped to elucidate possible mechanisms of action. Research by Marazziti et al. (2002, 2000) has associated OCD with increased PKC activity, a downstream component of the PI cycle, which causes a resultant decrease in 5HT reuptake. MI may potentially correct hyperactivity in the PI pathway by means of down-regulating its activity through altered gene expression (Harvey et al., 2002). There is also evidence to suggest that MI may cause a slight increase in 5-HT2 receptor density as well as increased D2 receptor density in the striatum (Harvey et al., 2001). In recent years, preliminary clinical evidence for the efficacy of high dose MI in the treatment of OCD has been provided in a small number of studies. Early research by Fux et al. (1996) using a sample of 13 patients with OCD, reported that 18 g/day of MI for 6 weeks resulted in a significant reduction in Y-BOCS scores in comparison to placebo. A more recent open-label study by Carey et al. (2004) using a sample of 14 treatment-free OCD patients, reported that 12 weeks treatment of 18 g/day MI also resulted in a significant reduction in Y-BOCS scores for the group as a whole. Interestingly, Carey et al. (2004) reported that reduced brain perfusion in the prefrontal cortex, temporal lobe and parietal cortex was correlated with clinical response to MI using single photon emission computed tomography. In contrast, when MI has been used as an augmentation therapy in addition to SSRIs, evidence of efficacy is lacking. A follow-up study by Fux et al. (1999) failed to find evidence of efficacy for MI as a treatment for OCD when used in addition to ongoing SRI treatment; using the same 18 g/day MI dose over 6 weeks in 10 patients. Similarly an open-label MI augmentation study by Seedat and Stein (1999) also failed to find evidence of efficacy in 10 OCD patients using 18 g/day over 6 weeks; although three of the patients did report a clinically significant response. However, it is important to note that the 10 patients enrolled in this study had failed to respond to current and previous trials of SRIs, and for this reason may represent a particularly difficult to treat patient group (Seedat and Stein, 1999). In relation to the OCD spectrum disorders of TTM and compulsive skin picking, Seedat et al. (2001) presented 3 cases studies that also provided preliminary evidence for the efficacy of MI ameliorating symptom severity. In this study 18 g/day MI was administered over a 12 week period. In summary, the existing clinical evidence suggests that MI at a dose of 18 g/day may potentially be effective as monotherapy for OCD, while there is currently no evidence to suggest that it adds additional benefit above and beyond ongoing SSRI treatment. Side effects associated with MI administration are generally mild (Levine, 1997), however mild gastrointestinal side effects in the first

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two weeks of treatment have been reported in some patients. These include diarrhoea, flatulence, bloating and nausea (Carey et al., 2004). In comparison to existing SSRIs the side effect profile of MI is more favourable. An intriguing aspect of all of the published MI studies that warrants further investigating is studies have all utilized an identical treatment dose of 18 g/day. Presumably this dose was originally arrived at through clinical experimentation, yet it remains to be properly established whether this dose is the most effective for all patients. In consideration of the fact that small sample sizes were involved in all of these studies, randomized placebo-controlled clinical trials using larger sample sizes are warranted in order to further investigate the potential efficacy for MI for the treatment of OCD. 4.4. Tryptophan and 5-HTP A potential strategy for enhancing serotonergic transmission in the CNS is through precursor loading with either the essential amino acid tryptophan or its hydroxylated form 5-hydroxytryptophan (5-HTP). Dietary sources that are particularly high in tryptophan include egg white, cheese, Atlantic cod, spirulina, soybeans and pumpkin seed (U.S. Department of Agriculture, 2010). 5-HTP is not typically received directly through the diet; tryptophan is converted to 5-HTP within the body. Unfortunately, the use of orally administered tryptophan to boost brain levels of 5-HT is not a particularly successful strategy. It has been estimated that only around 2% of ingested tryptophan is used for 5-HT synthesis in the brain, with the majority of intracellular tryptophan used for protein synthesis (Brown, 1994; Sirek and Sirek, 1970). Furthermore, the amount of tryptophan that enters the brain is dependent on its ratio to other large neutral amino acids (LNAA), which it must compete with for a common transporter across the blood brain barrier (Birdsall, 1998; Feldman et al., 1997). For this reason, an increase in the systemic concentration of tryptophan may not necessarily result in higher 5-HT synthesis in the brain (Feldman et al., 1997). Considering the evidence that drug-naïve OCD patients have both lower plasma levels of tryptophan and lower tryptophan/LNAA ratios (Bellodi et al., 1997), it could be argued that tryptophan supplementation may more successfully raise brain serotonin levels in OCD patients in comparison to the normal population. However, acute experimentally-induced tryptophan depletion has not been found to lead to increases in OCD symptom severity (Smeraldi et al., 1996); suggesting that tryptophan availability in itself is not directly related to obsessive–compulsive symptom severity. The possibility remains that with chronic tryptophan treatment brain 5-HT levels could be raised and this could lead to a number of downstream effects on 5-HT receptors similar to those observed through the use of SSRIs. Unfortunately, while the notion that dietary supplementation with tryptophan may be of use in treating OCD has been considered many years ago (Yaryura Tobias and Bhagavan, 1977), there is currently no clinical evidence in support of its efficacy. According to current knowledge it is unlikely that tryptophan represents an efficacious treatment strategy for OCD due to weak mechanistic evidence and no clinical data. It is also worth noting that preclinical research suggests that prolonged tryptophan supplementation may lead to elevated levels of brain oxidative stress (Coşkun et al., 2006), which is a pathophysiological process already evident in the disorder. In addition to the use of tryptophan to boost 5-HT levels in the brain, oral administration with 5-HTP has also been suggested as a precursor strategy. Due to the fact that 5-HTP easily crosses the bloodbrain barrier without requiring a transport molecule, it does not have to compete with other LNAAs for transport and for this reason is a more viable means of raising brain 5-HT levels; with clinical evidence suggesting that it may be a useful strategy in the treatment of depression (Meyers, 2000; Turner et al., 2006; Zmilacher et al., 1988). A recent study by Gendle and Golding (2010) in 46 healthy adults provided evidence to suggest that oral 5-HTP is psychoactive at a low

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100 mg oral dose and has significant effects on cognition. However, similar to tryptophan there have currently been no randomized placebo-controlled trials conducted to investigate 5-HTP as a chronic treatment for OCD. 4.5. Plant-based compounds Natural products derived from plants have been studied for a variety of anxiety disorders and have a range of emerging evidence (Sarris, 2007). Two plant medicines used in the treatment of OCD which have active ingredients that have been found to modulate serotonergic activity were located in our literature search; Hypericum perforatum (St John's wort: SJW) and Silybum marianum (milk thistle). SJW has been studied extensively for depression (Rahimi et al., 2009; Sarris and Kavanagh, 2009), and has revealed equivalent efficacy to conventional antidepressants due to a range of neurobiological effects including re-uptake inhibition of monoamines, increased sensitization and binding to receptors e.g. 5-HT, and neuroendocrine modulation. The antidepressant activity of SJW has been attributed to a number of bioactive consituents including hyperforin, hypericin and pseduohypericin. Mechanisms of action associated with these compounds include monoamine oxidase (MAO) inhibition and the inhibition of serotonin, norepinephrine and dopamine re-uptake (Butterweck and Schmidt, 2007; Nathan, 2001). These effects on monoamine transmission may have a potentially beneficial effect on OCD. Due to this, SJW was assessed in an open label pilot trial in 2000 for efficacy in OCD (Taylor and Kobak, 2000). Twelve subjects with chronic (N12 months) DSM-IV diagnosed OCD were treated for 12 weeks with 450 mg of standardized SJW (0.3% hypericin) twice daily. A significant change from baseline to the endpoint was found, with a mean reduction on Y-BOCS of 7.4 points (p = 0.001). This change occurred at 1 week and continued to week 12. At the endpoint, five (42%) of twelve were rated as being “much” or “very much improved” on the clinician-rated CGI, six (50%) were “minimally improved,” and one (8%) had “no change.” Open label results always need to be interpreted with considerable caution, and a later RCT by the research group using SJW (LI 160) was performed to confirm these results. Sixty participants with a primary diagnosis of OCD of at least 12 months duration were randomized to 12 weeks of treatment of SJW (flexible dosing 600 mg–1800 mg depending on response) or matching placebo (Kobak et al., 2005). Subjects with Hamilton Depression Rating Scale scores of over 16 were excluded. Results revealed that the mean reduction on Y-BOCS in the SJW group (−3.43) did not significantly differ from placebo (−3.60; p = 0.89). No significant differences were found on any of the Y-BOCS subscales. The percentage of participant's rated as “much” or “very much” improved at endpoint was not significantly different between the groups: SJW (17.9%), placebo (16.7%). Given the small effect sizes in many OCD trials, the sample size needed to draw definitive conclusions may need to be larger, although current evidence does not endorse use of SJW in OCD. Milk thistle, a traditional Mediterranean and Persian plant used for a range of psychiatric disorders has also been proposed as a potential treatment for OCD. The putative anti-OCD effects of milk thistle may be attributable to the flavanoid complex silymarin (silibinin a key constituent), which in preclinical studies has been found to increase serotonin levels in the cortex (Osuchowski et al., 2004), and ameliorate decreases in dopamine and serotonin in the prefrontal cortex and hippocampus associated with methamphetamine abuse (Lu et al., 2010). The increase in cortical serotonin levels, and resultant anti-obsessional effects, may be attributable to silibinin's inhibition of MAO activity as revealed by in vitro research (Mazzio et al., 1998). A recent RCT with milk thistle was conducted in Iran (Sayyah et al., 2010). Thirty five participants with a Y-BOCS score of N21 were randomly assigned to 200 mg of milk thistle leaf extract (standardization and chemical profile not disclosed) or 10 mg of fluoxetine three times daily

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for eight weeks. Results revealed no significant difference in treatment effects between milk thistle and fluoxetine from baseline to endpoint (− 11.00 ± 4.15 Milk Thistle versus − 12.50 ± 4.54 fluoxetine; p = 0.43). Both interventions provided a highly significant reduction on Y-BOCS (p = 0.0001). Methodologically, non-inferiority designs need to be powered with far larger sample sizes than placebo controlled designs, and as such, this small study is difficult to interpret. It should be noted that baseline Y-BOCS score was very high (41 points), thus in this non-controlled study some statistically significant reduction was probable to occur, and both groups still had Y-BOCS score at completion of 17 for fluoxetine and 20 for milk thistle (specific data not detailed). No serious side effects associated with milk thistle administration were observed (Sayyah et al., 2010). While milk thistle has a plausible mechanism of action attributable to MAO inhibition, and the preliminary RCT reported efficacy comparable to fluoxetine, further largerscaled RCTs are required in order to further investigate its potential efficacy. A summary of clinical studies investigating nutraceutical treatments for OCD and OCD spectrum disorders is presented in Table 1. 5. Discussion In light of the continuing challenges concerning the use of pharmacotherapies such as clomipramine, the SSRIs and SNRIs for the treatment of OCD, it is timely to consider the use of alternative nutraceutical and plant-based treatments used either as monotherapy or in augmentation strategies. The recent research focus on glutamatergic treatments for OCD is a treatment avenue which holds potential. N-acetylcysteine (NAC), through its effects on cystineglutamate exchange and antioxidant pathways, is worthy of further research into its efficacy as a treatment for OCD. While only case reports and a single randomized trial have been conducted in relation to NAC in OCD spectrum disorders, the preliminary research findings are encouraging. The side effect profile associated with NAC appears to be favourable in comparison to SSRIs. Larger randomized controlled trials using NAC in OCD-spectrum disorders are now needed in order to further test its clinical efficacy. RCTs using the glutamatergic agents glycine and D-serine are also warranted, although palatability issues regarding glycine administration may need to be resolved. In regards to serotonergic modulation, the use of myo-inositol (MI) in the treatment of OCD has been studied for over 20 years. Currently there is some preliminary evidence of efficacy when MI is used as monotherapy, but not when it is used in addition to ongoing SSRI treatment. Unfortunately many of the studies of MI in OCD have been under-powered, making it difficult to detect clinical effects. While a large scale trial of MI is unlikely to be funded due to its status as an orphan compound; there is enough preliminary evidence that

has been obtained from pilot studies to suggest that its efficacy in the treatment of OCD cannot be discounted. It would be timely for a randomized and placebo-controlled MI OCD trial with an appropriate sample size to be conducted so that an assessment of its efficacy can be properly considered. The side effect profile associated with MI appears to be favourable in comparison to SSRIs. In regards to precursor loading strategies for boosting serotonin transmission, it is unlikely that tryptophan is an efficacious treatment for OCD, while 5-HTP may conceivably be of use although there is currently no clinical human evidence in support of its efficacy in treating OCD. Similarly, while the results from the Silybum marianum (milk thistle) study are also encouraging, a large scale randomized placebocontrolled study is also warranted so as to properly investigate its efficacy in the treatment of OCD. It is also conceivable that other plant medicines currently not studied may also hold promise of providing beneficial effects in OCD. An important issue that needs to be addressed in future OCD research using new and emerging treatments is whether efficacy can be demonstrated as a stand-alone treatment. For practical reasons it is often difficult to recruit drug-naïve participants, however another acceptable alternative may be to enforce a 30 day drug wash out period before commencement of the clinical trial. A pertinent example is the research by Fux et al. (1999, 1996) whereby a significant reduction in Y-BOCS score was observed when MI was used as monotherapy, yet no significant improvements were observed when MI was added to existing SSRI treatment. A possible explanation for this discrepancy is that it is harder to demonstrate efficacy when symptom severity is already partially reduced due to existing treatments. The use of drug free participants may be more relevant for nutraceutical treatments that have serotonergic mechanisms of action that may overlap with the mechanism of action of SSRIs. In regards to nutraceuticals with glutamatergic mechanisms of action such as N-acetylcysteine it could be argued that augmentation to SSRI is more likely to elicit a treatment response due to different modes of action in the brain. A number of methodological limitations undoubtedly need to be addressed in future nutraceutical clinical trials for OCD. While case studies and open label designs can provide preliminary data as to the potential efficacy of a new treatment they are no substitute for randomized placebo-controlled trials (RCT). Furthermore, even when RCTs are used they must also be adequately powered in order to be able to detect at least a medium effect size. In order to have an 80% probability of detecting a significant interaction (α = 0.05) between treatment group and time that is of medium effect size (f = 0.25) using two treatment groups and two time points it is necessary to have a minimum total sample size of 34 participants (calculated using G*Power 3.1.2). In order to have an 80% probability of detecting a

Table 1 Clinical studies investigating nutraceuticals in the treatment of OCD and OCD spectrum disorders. Nutraceutical

Mechanism of action

Condition

N

Dosage (daily)

Duration

Design

Evidence of efficacy

Reference

N-Acetylcysteine

Glu

Glycine

Glu

Myo-inositol

5-HT

1 50 3 24 1 13 13 10 3

1200–3000 mg 1200–2400 mg 2000 mg 60 g 50–66 g 18 g 18 g 18 g 18 g

13 weeks 12 weeks 6 months 12 weeks 5 years 6 weeks 6 weeks 6 weeks 8–16 weeks

Case study augmentation RCT Case studies RCT augmentation Case study RCT RCT augmentation Open label augmentation Case studies

Yes Yes Yes No Yes Yes No No Yes

(Lafleur et al., 2006) (Grant et al., 2009) (Berk et al., 2009) (Greenberg et al., 2009) (Cleveland et al., 2009) (Fux et al., 1996) (Fux et al., 1999) (Seedat and Stein, 1999) (Seedat et al., 2001)

St. John's wort

5-HT

Milk thistle

5-HT

OCD TTM Nail biting OCD OCD OCD OCD OCD TTM/Skin picking OCD OCD OCD OCD

14 12 60 35

18 g 900 mg 600–1800 mg 600 mg

12 weeks 12 weeks 12 weeks 8 weeks

Open label Open label RCT RCT Fluoxetine comparator

Yes Yes No Yes

(Carey et al., 2004) (Taylor and Kobak, 2000) (Kobak et al., 2005) (Sayyah et al., 2010)

OCD; Obsessive Compulsive Disorder, TTM; Trichotillomania, Glu; Glutamatergic, 5-HT; Serotonergic, RCT; Randomized Controlled Trial.

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significant interaction (α = 0.05) of small effect size (f = 0.1) with this design it is necessary to have a minimum total sample size of 200 participants (calculated using G*Power 3.1.2). It can be seen from Table 1 that out of the six RCTs reviewed, the total sample sizes ranged from only 13 to 60 participants. For the two MI trials conducted using 13 participants (Fux et al., 1999, 1996) there was only a 38% chance of detecting a significant interaction between time and treatment group at the α = 0.05 level (calculated using G*Power 3.1.2). In future trials it is important that sample sizes be adopted that are adequately powered. Another important consideration for future clinical OCD research with nutracueticals is to compare the efficacy of these substances to cognitive behavioural therapies such as ERP in addition to comparisons made with pharmacological treatments. As a proven and highly efficacious treatment for OCD, cognitive-behavioural therapies would act as a rigorous comparator arm in a parallel groups design. Further, a proper investigation of the efficacy of nutraceutical treatments in combination with behavioural therapies could open new treatment avenues for clinicians. In summary, further research into alternative treatments for OCD and OCD spectrum disorders is warranted, considering the considerable adverse effects and therapeutic delay in symptom amelioration observed with conventional pharmotherapeutic treatments for OCD. Through modulation of either glutamatergic or serotonergic mechanisms, a number of nutraceutical and plant-based substances may potentially be effective monotherapies or augmentation therapies in the treatment of OCD, and be better tolerated with a more favourable side-effect profile. Much further research is currently needed which utilizes randomized placebo-controlled study designs and considerably larger sample sizes so as to properly test their efficacy in the treatment of OCD. Acknowledgements Dr. Jerome Sarris is funded by an Australian National Health & Medical Research Council fellowship (NHMRC funding ID 628875), in a strategic partnership with The University of Melbourne and the Brain Sciences Institute at Swinburne University of Technology. References Abramowitz JS. Effectiveness of psychological and pharmacological treatments for obsessive–compulsive disorder: a quantitative review. J Consult Clin Psychol 1997;65:44–52. Albelda N, Bar-On N, Joel D. The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder. Psychopharmacology 2010;210:13–24. Allegra L, Dal Sasso M, Bovio C, Massoni C, Fonti E, Braga PC. Human neutrophil oxidative bursts and their in vitro modulation by different N-Acetylcysteine concentrations. Arzneim-Forsch 2002;52:669–76. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. . Text Revision (DSM-IV-TR)Fourth Edition. Washington, DC: American Psychiatric Association; 2000. Atkuri KR, Mantovani JJ, Herzenberg LA. N-Acetylcysteine-a safe antidote for cysteine/ glutathione deficiency. Curr Opin Pharmacol 2007;7:355–9. Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 2002;22:9134–41. Barr LC, Goodman WK, Price LH. The serotonin hypothesis of obsessive compulsive disorder. Int Clin Psychopharmacol 1993;8:79–82. Behl A, Swami G, Sircar SS, Bhatia MS, Banerjee BD. Relationship of possible stressrelated biochemical markers to oxidative/antioxidative status in obsessive– compulsive disorder. Neuropsychobiology 2010;61:210–4. Bellodi L, Erzegovesi S, Bianchi L, Lucini V, Conca R, Lucca A. Plasma tryptophan levels and tryptophan/neutral amino acid ratios in obsessive–compulsive patients with and without depression. Psychiatry Res 1997;69:9-15. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia–a double-blind, randomized, placebocontrolled trial. Biol Psychiatry 2008a;64:361–8. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder–a double-blind randomized placebocontrolled trial. Biol Psychiatry 2008b;64:468–75. Berk M, Ng F, Dean O, Dodd S, Bush AI. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci 2008c;29:346–51.

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