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

Transcription

PNP-07897; No of Pages 9
Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2011) xxx–xxx
Contents lists available at ScienceDirect
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 xxxx
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: dcamfield@swin.edu.au, david.camfield@gmail.com (D.A. Camfield).
0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2011.02.011
Please cite this article as: Camfield DA, et al, Nutraceuticals in the treatment of Obsessive Compulsive Disorder (OCD): A review of
mechanistic and clinical evidence, Prog Neuro-Psychopharmacol Biol Psychiatry (2011), doi:10.1016/j.pnpbp.2011.02.011
2
D.A. Camfield et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2011) xxx–xxx
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
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
3
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
4
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
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
5
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
6
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.
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.
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