CNS Spectrums (2014), 19, 50–61. & Cambridge University Press 2013 doi:10.1017/S1092852913000618

SCHOLARLY CASE-BASED REVIEW

Pharmacological, experimental therapeutic, and transcranial magnetic stimulation treatments for compulsivity and impulsivity Stefano Pallanti,1,2,3* and Eric Hollander3 1

University of Florence, School of Medicine, Florence, Italy Ichan School of Medicine at Mount Sinai, New York, New York, USA 3 Albert Einstein College of Medicine and Montefiore Medical Center, New York, New York, USA 2

Obsessive-compulsive disorder (OCD) has been recently drawn apart from anxiety disorder by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and clustered together with related disorders (eg, hoarding, hair pulling disorder, skin picking), which with it seems to share clinical and neurophysiological similarities. Recent literature has mainly explored brain circuitries (eg, orbitofrontal cortex, striatum), molecular pathways, and genes (eg, Hoxb8, Slitrk5, Sapap3) that represent the new target of the treatments; they also lead the development of new probes and compounds. In the therapeutic field, monotherapy with cognitive behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs) is recommendable, but combination or augmentation with a dopaminergic or glutamatergic agent is often adopted. A promising therapy for OCD is represented by repetitive transcranial magnetic stimulation (rTMS), which is suitable to treat compulsivity and impulsivity depending on the protocol of stimulation and the brain circuitries targeted. Received 3 July 2013; Accepted 13 August 2013; First published online 1 November 2013 Keywords: Compulsivity, impulsivity, obsessive compulsive, OCD, pharmacotherapy, TMS, transcranial magnetic stimulation, treatment.

Introduction

Clinical Implications ’

Harm Avoidance was the basic concept of the previous classification of obsessive-compulsive disorder (OCD), whereas the actual classification allude to the animal model of Dysfunctional Grooming.

’

The importance of glutamatergic and dopaminergic circuitries as pathways beyond the serotoninergic mechanisms has been shown. These are now identified as targets in OCD treatments.

’

The dorsal striatum and the accumbens connection with orbito-frontal cortex (OFC) that correlated to a failure in the rewarding signals is in the pathophysiology in OCD patients.

’

Given these findings, non-invasive neuromodulations such as transcranial magnetic stimulation (TMS) are now purposed in OCD, with different targets and paradigms.

During the past several years, research on obsessivecompulsive disorder (OCD) has embraced a multidimensional approach, evaluating neurobiological, genetic, and molecular mechanisms involved in the pathophysiology of the disorder. Given the aim to complement contributions from clinical observations and neuroscientific findings with the purpose of finding new therapeutic compounds, a review of recent findings concerning targets for therapeutics and pharmacological treatment is presented. Particular attention is given to transcranial magnetic stimulation (TMS) as an encouraging treatment for compulsivity and impulsivity typical of OCD and related disorders.

Brief Review of Targets for Therapeutics *Address for correspondence: Stefano Pallanti, University of Florence, School of Medicine, 50134, Florence (I); Ichan School of Medicine at Mount Sinai, NY 10029 (US); Albert Einstein College of Medicine and Montefiore Medical Center, NY 10461 (US). (Email: [email protected]) The authors thank Anna Marras, PhD, for her collaboration in editing this paper.

Neurotransmitter systems, molecular pathways, and brain circuitry The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) has been recently published with much fanfare, although some of the

CNS SPECTRUMS

early promise from the research planning agenda1 on the use of endophenotypes or ‘‘external validators’’ of syndromal descriptions were ultimately not included in this edition. The research domain criteria (RDoC) classification has been presented as a complementary and noncompeting framework for this goal. Nevertheless, DSM-5 does reflect an advancement in the scientific assessment of clinical manifestations of brain disease, the clustering of related categories of illnesses, and the introduction of dimensional measures. OCD is now considered separate from the anxiety disorders, and obsessive-compulsive (OC) and related disorders include body dysmorphic disorder (BDD), hoarding, trichotillomania, skin picking, OCD due to or induced by substances, and other specified OC related disorders such as body-focused repetitive behavior disorder and obsessional jealousy. This clustering is based on both clinical similarities and presumed underlying frontostriatal circuitry dysfunction, and is consistent with genetic research, which was ultimately not included as a DSM-5 diagnostic validator.

Genetic and molecular targets The most convincing evidence of a familial risk for OCD came from a recently published study that showed that the risk for first-degree relatives was significantly higher than that for second- and third-degree and nonbiological relatives, and the second-degree relatives had higher risk for OCD than third-degree relatives despite different degrees of shared environment. Separate twin modeling analyses confirmed that familial risk for OCD was largely attributable to additive genetic factors, with no significant effect of shared environment.2 OCD subjects are apparently inclined to assortative mating, since nonbiological relatives (spouses or partners who have at least 1 child together) also had a higher risk for OCD.3 OCD is associated with multiple genes, most of which have a modest association with OCD. A genetic multimodal liability has been demonstrated in a recent genome-wide association study (GWAS),4 which has led to a greater understanding of pathophysiology in many disorders. Although no single nucleotide polymorphisms (SNPs) were identified to be associated with OCD at a genome-wide significant level in a combined trio–case–control sample, a highly significant enrichment of methylation in the frontal lobe was reported within the top-ranked SNPs (P , 0.01). This involvement of frontal lobe genetics has been interpreted as having a broad role in gene expression in the brain, and it is consistent with the general hypotheses and therefore in the etiology of OCD. OCD has been inconsistently associated with serotoninrelated polymorphisms (5-HTTLPR and HTR2A) and, in males only, with polymorphisms involved in catecholamine

51

modulation (COMT and MAOA). Nonsignificant trends were also reported for 2 dopamine-related polymorphisms (DAT1 and DRD3) and a glutamate-related polymorphism (rs3087879). The neuronal glutamate transporter gene SLC1A1 is a candidate gene for OCD based on linkage studies and convergent evidence implicating glutamate in the etiology of the disease, and it is the only genomic region with a consistently demonstrated OCD association, in particular when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs.5 Future studies with sufficient power to detect small effects are needed to investigate the genetic basis of OCD subtypes, such as early vs late onset OCD. The OC and Related Disorders section in DSM 5 alludes to ‘‘dysfunctional grooming’’ as a prototype of OCD to a greater degree than harm avoidance, which was referred to when OCD was included in the anxiety section of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Thus, translational approaches to the investigation of molecular pathways adopted from animal models to translate data from neurofunctional and genetic studies is extremely informative in addressing specific candidate genes to probe in human subjects. These studies have 2 major tautological limitations. First, in mouse models, we are limited to grooming and other repetitive behaviors, while it is impossible to determine the subjective experience (core in OCD in humans) of the animal motivating the behavior.6 However, the validity of OCD animal models is more convincing when the evidence for concurrent anxiety (increased face validity) or biological evidence of cortico-striatal dysfunction (construct validity) is included. Second, ‘‘knock out’’ approaches are limited, since single-gene variation may not grab more subtle changes in gene expression that are implicated in complex traits. In addressing these limitations, there has been a consistent proliferation of findings that may improve the understanding of the role of glutamate dysfunction in leading to obsessivecompulsive symptoms.

Hox gene

It was has been shown Hox genes are involved in organizing body plans by providing positional values along the major axes of the embryo,7 but it was quite unexpected that disruption of a Hox gene leads to pathological grooming.8 Hox genes also have direct roles in the formation of the hematopoietic system, and, with respect to Hoxb8, they are involved in maintenance and differentiation of myeloid progenitor cells, as well as one of the two known sources of microglia.9,10 Hoxb8 is

52 S. PALLANTI AND E. HOLLANDER

functionally related to a neural circuit that serves as a behavioral regulator of the grooming in the adult brain, thus bridging OCD phenomena. SAPAP3 and SAPAP4 and the response to SSRIs

In mice, genetic deletion of SAPAP3, a synapseassociated protein 90/postsynaptic density protein 95-associated protein 3 that is an excitatory postsynaptic protein, correlates to OCD-like behaviors that are rescued by striatal expression of SAPAP3, which demonstrates the importance of striatal neurotransmission for OCD-like behaviors. SAPAP3 is a well-known scaffolding protein that is highly expressed in striatal excitatory synapses, which normally inhibit the mGluR5-driven endocytosis of AMPA-type glutamate receptors AMPARs.11 Of interest is the response to fluoxetine, as reduction of OC features has been reported in this model.12 Of even greater interest in the striatum, there are two main excitatory synaptic circuits: corticostriatal and thalamostriatal. Either or both of these circuits could potentially contribute to the OCD-like behaviors of SAPAP3 knockout (KO) mice. In a recent study,13 it has been reported that SAPAP3 deletion reduces corticostriatal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptor-mediated synaptic transmission, while corticostriatal synapses and thalamostriatal synaptic activity is unaffected by SAPAP3 deletion. At the molecular level, another SAPAP family member, SAPAP4, is present at thalamostriatal, but not corticostriatal, synapses, which is consistent with a molecular rationale for the functional divergence we observe between thalamic and cortical striatal circuits in SAPAP3 KO mice, and provides evidence that SAPAP isoforms may be localized to synapses according to circuit-selective principles. SLITRK5

The loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (SLITRK5), leads to a different OCD-like model in mice, where increased anxiety-like behaviors are presented, and which are alleviated by the SSRI fluoxetine. SLITRK5(–/–) mice show selective over-activation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology, and alterations in glutamate receptor composition, which contributes to deficient corticostriatal neurotransmission.14 D1CT-7 and the dopaminergic system

Campbell et al.15 described D1CT-7 transgenic mice as the first genetic mouse model for OCD, and tics expressed it with an intracellular form of cholera toxin (CT) under the control of the D1 promoter. The CT

toxin is a neuropotentiating agent that chronically activates stimulatory G-protein (Gs) signal transduction and cyclic adenosine monophosphate (cAMP) synthesis. The use of a D1 promoter restricts CT expression to D1 dopamine receptor subtype positive (D11) neurons. D1CT-7 mice led to a wide range of compulsive behaviors and repetitive behaviors, including nonaggressive biting of siblings and repetitive leaping.15 Furthermore, D1CT-7 mice also display tic-like movements with a juvenile age of onset more prevalent in males. These features make the D1CT-7 mouse a suitable model for Tourette syndrome (TS), a disorder that frequently co-occurs with OCD in humans.16 Since the expression of CT in the brain of these mice overlaps with regions implicated with OCD, the authors suggest that chronic potentiation of D11 neurons leads to over-activation of glutamatergic output to the striatum. Adding a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist to indirectly stimulate cortical-limbic glutamate output has also been shown to increase compulsive-like behavior in the D1CT-7 model.16,17 A DRD4 VNTR polymorphism is associated with OCD, and the presence of the 2R allele was significantly associated with the symmetry dimension, which might represent a more homogeneous subtype of OCD with a genetic etiology.18 In summary, Hoxb8, SAPAP3, and SLITRK5 lead to pathological behaviors, including adult-onset excessive grooming with mild-tosevere hair loss and self-injury. In 2 of the models, the SAPAP3-deficient and the SLITRK5-deficient mice, the abnormal grooming behaviors are associated with enhanced anxiety, and these pathological behaviors can be curtailed with subchronic administration of a SSRI, suggesting the predictive validity of such models.

Brain areas and circuitries involved in OCD The possible role of amygdala in OCD

Amygdala activation does not play a central role in the pathophysiology of OCD, as is seen in other anxiety disorders.19 Even though there is some evidence to associate OCD with enhanced amygdala activation, but not just in response to aversive stimuli,20–22 the amygdala plays a central role in the identification of threat and stress,23 and in the development of fear and arousal.24 The hyper-activation of the amygdala in response to threat of punishment has been hypothesized to contribute to the exaggerated emotional response to negative stimuli exhibited by OCD patients,20 which could mediate their tendency to over-estimate threat signals and possibilities.25 The crucial role of the striatum in OCD

While amygdala importance appears to be reduced, most neurobiological theories of OCD attribute a crucial

CNS SPECTRUMS

53

FIGURE 1. Brain circuitries and pathways involved in OCD. In OCD, the direct pathway is strongly activated in relation to the indirect pathway resulting in OFC-subcortical hyperactivity. Large arrows represent inputs that are strengthened in patients with OCD. GPi 5 globus pallidus internal segment; SNr 5 substantia nigra reticulata. Reproduced with permission from Stein (2006).26

role to the striatum, especially to its dorsal part in the pathophysiology.27,28 The ventral striatal nucleus accumbens is regarded as a core feature of the neural reward system,29–31 and thus the current example of its poor response to rewarding outcome in OCD patients may reflect a failure in the rewarding signals in OCD patients.32 Imbalance in responsiveness to threat vs reward in OCD has been recently addressed as the core dysfunction. A recent behavioral study found that OCD patients respond faster than controls in avoiding negative stimuli and slower in approaching positive stimuli, which can be interpreted as representing a motivational bias toward potential negative vs positive stimuli in OCD.33 Abnormal neural responsivity in OCD patients to threat and reward was also exemplified here at the circuit level via reduced limbic–frontal functional and structural connectivity, and has been correlated with symptom severity. Reduction in either functional or structural connectivity is regarded as an indication of disruptions in information processing between distant brain regions.30,34,35 Another core feature in models of OCD is related to disrupted neural circuitry and thus reduced information processing between limbic and frontal regions. This model implies that deficiencies in connectivity may lead to imbalanced limbic responsivity and reduced integrity of amygdala–prefrontal fiber tracts associated with impaired down-regulation of anxiety36,37 and top-down regulation failure of limbic activity by frontal brain areas correlated with pathological emotional responses.38 All these effects happen according to the most commonly reported brain abnormality in OCD, ie, hyper-activation of the neural feedback circuit that includes frontal, limbic, and striatal structures (see Figure 1), as a result of a compensatory, even if insufficient, attempt of the

frontal cortical regions to regulate the unbalanced limbic responsivity. The negative correlation found between limbic–frontal connectivity strength, both structural and functional, to symptom severity adds further support to this hypothesis, as indeed the dysfunctional hyper-activation in OCD seems to normalize with successful treatment with either CBT39 or a pharmacological agent.27,40–43 The specific relationship of the amygdala to the dorsal anterior cingulate cortex (dACC) and of the nucleus accumbens (nACC) to the OFC is still to be clarified. The repeated demonstration of anterior cingulate cortex (ACC) hyperactivation in OCD patients was interpreted as underlying their ongoing subjective constant sense that something is not right or is wrong even when there is not.44–46 The relation of the OFC to the nACC may be mediated through their shared involvement in reward processing as well,47 as both regions displayed reduced activation in response to reward in OCD,48–50 forming a unified dysfunctional circuit to mediate the ‘‘destructive risk aversion.’’ With consequent inadequate response to threatening and rewarding cues in the environment, 2 of the main components contribute to elevated risk aversion, greatly impairing daily function in OCD patients. Accurate identification of the dysfunctional neural indices that underlie such abnormal behavior allow for a more specific and possibly more effective approach in future therapy, either by identifying neural predictors of treatment response51,52 or individually localizing neural targets to optimize neuromodulatory invasive or non-invasive, circuit-based neuromodulatory interventions. The increased regional metabolic activity in the orbitofrontal cortex and caudate in OCD patients versus controls, in both resting and symptomatic states, has

54

S. PALLANTI AND E. HOLLANDER

been one of the most replicated findings in psychiatric imaging since the publication of Insel’s commentary ‘‘Towards a Neuroanatomy of Obsessive-Compulsive Disorder‘‘ 20 years ago.53

Orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment

A recent experiment was conducted in mice that have chronically received the SRI clomipramine or the noradrenaline reuptake inhibitor (NRI) desipramine. The mice were examined for 5-HT1BR-induced OCDlike behavior, or 5-HT1BR binding and G-proteincoupling in the caudate-putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior with a weekly followup for 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5HT1BR agonist infusion or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment. Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time course that parallels the delayed therapeutic onset in OCD patients and down-regulated 5-HT1BR expression in the orbitofrontal cortex. The intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and the intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment. These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice, and that SSRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs, which is consistent with an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.54 The fronto-striatal model of obsessive-compulsive disorder (FSMOCD) has been investigated in human trough event-related potential (ERP) studies, which have provided further insight about the involvment of the ACC, basal ganglia (BG), and OFC and their related cognitive functions, such as monitoring and inhibition.55 The ERPs study included the error-related negativity (ERN), N200, and P600, where both N2 responses during conflict tasks and enhanced P600 during working memory (WM) tasks have been documented. There is converging evidence from the ERP study (especially regarding ERN and N200 amplitude enhancement), with neuroimaging and neuropsychological findings suggesting abnormal activity in the OFC, ACC, and BG in OCD patients; for a review see Melloni et al.55 Other areas, such as the dorsolateral prefrontal and parietal cortex, might be involved in executive function (EF) deficits, suggesting the existence of a self-monitoring imbalance involving inhibitory deficits and executive dysfunctions. OCD patients present an impaired ability to monitor, control, and inhibit intrusive thoughts, urges,

feelings, and behaviors. By summarizing all these findings in a model, we may figure out all the OCD dysfunctions as a chain of events that is triggered by an excitatory role of the BG (associated with cognitive or motor actions without volitional control) and inadequate inhibitory activity of the OFC, as well as excessive monitoring of the ACC to block excitatory impulses, and that interacts with the reduced activation of the parietal-dorsolateral prefrontal cortex (parietal-DLPC) network, leading to executive dysfunction. Based on this growing background of research, several treatment options are now available for OC and related disorders.

Therapeutics of OCD Meta-analyses of CBT with ERP and drug trials of SSRI and clomipramine have reported effect-sizes demonstrating equivalent efficacy for these treatments in OCD. CBT or SSRI pharmacotherapy usually constitute the first-line recommended treatments without predictors to a preferential response. Individual preference or therapist availability lead the choice of modality for adult first-line treatment, while for children and adolescents, due to concerns about the potential adverse effects associated with SSRIs, the recommendation is that CBT should be used as first-line treatment in children with OCD. However, compared to SSRIs, CBT is less costeffective, according to health-economic analysis, which is an especial consideration in this age of economic crisis. A secondary analysis of a large, randomized, placebocontrolled treatment trial reported that hoarding and symmetry symptoms predicted a poorer overall outcome with SSRIs, and hoarding responds poorly to CBT.

Monotherapy or combination treatment? According to current guidelines, the evidence supporting the additional benefit of combining CBT with medication is not sufficiently strong; therefore based on a cost-effectiveness assessment, CBT or pharmacotherapy should initially be provided as a monotherapy. As OCD typically responds slowly to treatment, at least 12 weeks of medication at optimized dosage and 16 hours of CBT with ERP are required to test efficacy. Combination strategies (eg, CBT 1 SSRI) are recommended only in severe illness or in cases that fail to respond to monotherapy (see Table 1).

Resistant OCD Definition of resistance in OCD

The definition of treatment resistance, representing an inadequate response following an adequate trial of treatment with good adherence, should usually be made

CNS SPECTRUMS

55

TABLE 1. Evidence-based treatment algorithm for translational OCD studies > Stage 1: SSRI (fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram, and escitalopram) at optimal dose (12 wks), OR CBT (16 individual sessions), incorporating exposure

and response prevention (ERP)* > Stage 2: SSRI 1 CBT (12 wks) > Stage 3: SSRI 1 antipsychotic (risperidone (0.5–2 mg), quetiapine (, 5 300 mg), olanzapine (, 5 15 mg), aripiprazole (, 5 20 mg), amisulpride (200–400 mg),

haloperidol (0.5–2 mg), listed in decreasing preference; reserved for patients with documented failure to respond to a therapeutic trial of at least one SSRI and at least moderate impairment (12 wks), OR high-dose SSRI (12 wks) > Stage 4: As per Stage 3, or clinician’s choice (including clomipramine, novel compounds) Response Criteria > Full response: . 35% improvement in baseline Y-BOCS scores > Partial response: $ 25% improvement in baseline Y-BOCS scores > Nonresponse:,25% improvement in baseline Y-BOCS scores In case of full response: The patient maintains the SSRI or SSRI 1 antipsychotic at the effective dose for at least 1 year, or CBT follow-up for 1 year. In case of partial or nonresponse: The patient moves to the next treatment stage.

*For adolescents, CBT is usually used first line. (from ‘Evidence-based treatment-pathways for translational studies in Obsessive-Compulsive Disorders,’’ Fineberg NA, Pallanti S, Reghunandanan S.56) SSRI 5 selective serotonin reuptake inhibitors; CBT 5 cognitive behavioral therapy; ERP 5 exposure and response prevention; Y-BOCS 5 Yale-Brown Obsessive Compulsive Scale.

in relation to a specific treatment or series of treatments. Pallanti et al.57 proposed the introduction of operational criteria for assessment of stages of response and suggested that it should be seen as a continuum from remission to refractoriness. Treatment resistance may be defined as less than 25% improvement in baseline Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Though the terms ‘‘resistance’’ and ‘‘refractory’’ are sometimes used interchangeably, treatment resistance may be defined as nonresponse following an adequate trial of one SSRI, while treatment refractoriness refers to a lack of response to several trials of evidence based treatment; according to Pallanti et al.,57 these should include 3 SSRI agents, augmentation trials with 2 antipsychotics, and at least 20–30 hours of CBT.

Increasing dose for resistant OCD cases?

SSRIs show evidence of efficacy compared to placebo across the full range of approved doses. Only a limited number of fixed-dose studies has suggested that higher doses of some SSRIs (escitalopram, fluoxetine, paroxetine) are more efficacious than lower doses. Yet higher doses are associated with a greater adverse effect burden, and it would be helpful to know in advance whether or not dose escalation is required for an individual patient. There have been no dose-finding studies of clomipramine. Daily doses ranging from 75 mg to 300 mg of clomipramine have been found to be effective, though doses exceeding 250 mg should only be used with caution. Some research suggests that intravenous administration of drugs may have a better effect than oral administration in OCD patients. Intravenous (iv) citalopram58 and iv pulse loading with citalopram59 and clomipramine60 have been reported

only in limited samples. Also, some advantage in terms of relapse prevention in the maintenance phase has been reported.61 Targeting other 5HT receptors

Ondansetron is a 5-HT3 receptor antagonist that has been shown to reduce the reinforcing effects of a variety of abused drugs, including alcohol and amphetamines. In a study that examined the influence of ondansetron monotherapy in 8 OCD patients, 3 of the 6 patients who completed the study achieved a clinically significant response. Pallanti et al.62 conducted a single-blind trial in 14 patients with OCD who were treatment resistant and were receiving treatment with SSRIs and antipsychotic augmentation. Nine (64.3%) of the patients showed treatment response, and none of the patients experienced symptom exacerbation or significant adverse effects. Granisetron, another 5-HT(3) receptor antagonist, has been adjunct to SSRI in patients with severe OCD in a double-blind, placebo-controlled trial in a short-term treatment and has been reported as effective, but this compound deserves further investigation.63 Dopaminergic augmentation (SSRI)

Involvement of the dopamine system in OCD symptoms has been consistently reported, and modest usefulness of atypical antipsychotics to augment the response to SSRIs has been shown by 3 meta-analyses.64 Adding antipsychotics to SSRIs might be an effective strategy to augment the response in treatment-resistant OCD patients, especially for those with comorbid tic disorder who respond better to antipsychotic augmentation. Evidence that the population of patients who has OCD plus tic disorder is unique and responds differently to

56 S. PALLANTI AND E. HOLLANDER

standard treatment is also found among pediatric patients. Basal ganglia have a significant patho-physiological impact at least on specific subgroups of patients. Not only are movement disorders more common in OCD and schizophrenia, but they have prognostic implications (ie, only OCD patients with movement disorder respond to typical neuroleptic augmentation strategies).65 In conclusion, augmentation of ongoing serotonergic treatment with an antipsychotic for treatment-resistant OCD patients is one of the most studied and well documented strategies. However, it is important to note that the effects are modest and might be driven by a specific subtype (eg, tic-related disorders), and that there are long-term consequences to the use of atypical antipsychotics; these may include a significantly higher rate of increased body mass index, elevated fasting blood glucose, elevated triglycerides, and total cholesterol levels. These data emphasize the importance of the assessment of the metabolic and nutritional aspects in the management of treatment-resistant OCD patients who receive augmentation treatment with an atypical antipsychotic. On the other hand, 2 small, double-blind, placebocontrolled, single-dose, crossover studies found dextroamphetamine (d-amphetamine) 30 mg to be clearly superior to placebo in relieving symptoms of OCD, and a 5-week, double-blind, caffeine-controlled study to test the hypothesis that d-amphetamine, added after an adequate SSRI or serotonin-norepinephrine reuptake inhibitor (SNRI) trial, is more effective than caffeine in reducing residual OCD symptoms of moderate or greater severity. At week 5, the responders’ mean Y-BOCS score decreases were 48% (range 20–80%) for the d-amphetamine group (last observation carried forward) and 55% (range, 27–89%) for the caffeine group.66 Augmentation with dopaminergic agents might be an option in OCD patient partial- or nonresponders to SSRIs or SNRIs.

were 7.2 among the cases and 4.6 among the control patients receiving standard treatment.71 Another study72 compared the efficacy of memantine in OCD and generalized anxiety disorder. Ten OCD subjects and 7 generalized anxiety disorder subjects received 12 weeks of open-label memantine, as either monotherapy or augmentation of their existing medication. Among the OCD group, the average improvement in the Y-BOCS score was 4.75 (40.6%). Consistent with the hypothesis of a glutamatergic involvement in OCD, a small recent study demonstrated some improvement in OCD severity with intravenous ketamine. Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive OC thoughts. This first randomized, controlled trial represents ‘‘a proof of concept ‘‘that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI.73

Glutamatergic augmentation

When and how to augment or switch

Glutamate-modulating drugs have been investigated in open-label augmentation studies, the rationale being that an SSRI in OCD reduces the glutaminergic tone in the cortical striatal network. In these pilot studies, topiramate (a glutamate agonist)67 and riluzole (a glutamate antagonist)68 have been reported to be effective in some resistant OCD patients or, in the case of topiramate, at least on the compulsive features.69 A noncompetitive glutamate antagonist, memantine, has also been examined as augmentation in treatmentresistant OCD patients receiving SSRIs. In a small, open-label trial, almost half of the patients had a meaningful improvement in symptoms.70 In a singleblinded, case-control study of memantine augmentation among severe OCD patients, Y-BOCS score decreases

If a patient has been treated for several months and has not yet responded to treatment with several SSRIs, the physician should perform a careful reassessment of resistant and/or residual clinical symptoms and any comorbid conditions to determine which next-step treatment would be the most appropriate.75 At this point, there is not a universally prescribed ‘‘next step.’’

CBT augmentation

One of the recent promising fields of investigation, even though currently there is less enthusiasm about it, is cycloserine. Cycloserine is an NMDA partial agonist. NMDA (glutamate) receptor stimulation has been linked with amygdala neural plasticity and fear extinction effects. Since cycloserine has been used for years in humans to treat tuberculosis and is not associated with significant adverse effects, at weight-dependent dose, there was no obstacle for carrying out clinical research with this compound, even in children and adolescents, who are difficult to treat.74 Cycloserine has been administered before an exposure task in various anxiety disorders in the hope that stimulation of the NMDA receptor might extinguish fear. The preliminary results were mixed, and so further research, especially in the early phases of treatment, is needed.

Obsessive Compulsive Spectrum Disorders: The Compulsive Side of the Coin Hoarding Compulsive hoarding, which is characterized by the acquisition of and failure to discard a large number of

CNS SPECTRUMS

possessions, is increasingly recognized as a significant public health burden. Thus, evidence that hoarding lead to its own diagnosis is introduced in DSM-5.0. The dimension as a common affective-motivational underpinning bridging OCD to hoarding has been addressed in the incompleteness/‘‘not just right experiences’’ (NJREs). While the belief that hoarding does not respond to SSRIs has been contradicted,76 a novel treatment approach for obsessive compulsive personality disorder (OCPD) that focuses on habituation to NJREs may be useful.77

Body dysmorphic disorder A Cochrane Review on body dysmorphic disprder (BDD) and a treatment practice guideline on OCD and BDD from the United Kingdom’s National Institute for Health and Clinical Excellence (National Health Service) recommend CBT, which might be adapted to specifically target BDD symptoms (and SSRIs as first-line treatments for BDD. Most published studies of CBT for BDD have included cognitive restructuring, exposure (eg, to avoided social situations) and response (ritual) prevention (eg, not seeking reassurance) that are tailored specifically to BDD symptoms. Additional strategies (used in combination with the above approaches) include perceptual retraining with mirrors, habit reversal for BDD-related skin picking or hair plucking, cognitive approaches that target core beliefs, incorporation of behavioral experiments into exposure exercises, motivational interviewing tailored to BDD, and these approaches. This hypothesis is supported by clinical observations and neurocognitive (eg, fMRI) research findings that indicate that persons with BDD excessively focus on detail rather than on larger configural elements of visual stimuli. Patients with delusional BDD beliefs are as likely to respond to SSRI monotherapy, because they are patients with nondelusional beliefs. In adults, relatively high SSRI doses are often needed, and a 12–16 week trial is recommended to determine efficacy.

57

are common to some people with HPD. These authors suggest that an addiction model may be appropriate for conceptualizing HPD among these patients. For example, Schlosser et al.81 found that the first-degree relatives of patients with HPD were more likely to present with substance-related disorders than healthy controls. More recently, hair pulling disorder and skin picking have been categorized with OC-related disorders in the DSM-582 and are considered to be an expression of dysfunctional grooming. A recent cluster analysis also revealed that HPD falls within a nosology referred to as disorders of reward deficiency (eg, Tourette’s disorder, pathological gambling, hypersexual disorder),83 which implies dysfunction of the dopamine (DA) reward system in the brain.84 Genes related to the DA pathway (ie, DRD1-5, DAT1, DBH, COMT) have been strongly linked to impulsivity, novelty seeking, and reward deficiency.85–90 In addition, naltrexone, a pharmacological agent that is often used for the treatment of opioid dependence, may be efficacious for the treatment of HPD,91 which implies dysregulation of the mesolimbic DA circuitry.79 A recent systematic review concluded that clomipramine was the most efficacious pharmacological intervention for HPD.92 Evidence suggests that the 2 disorders, HPD and SPD, co-occur more often than can be expected by chance, have substantial similarities in a variety of clinical characteristics (eg, symptom presentation and course of illness), and may have some distal risk factors in common (eg, genetic vulnerabilities). Implications for classification in the DSM-5, clinical management, and research on etiology were discussed recently.93 Results show that behavior therapy (habit reversal) has consistently been shown to be effective. SSRIs seem not to work, but preliminary data suggest that other drugs (eg, N-acetylcysteine) may benefit some patients.93

Treatment of Comorbidity Comorbidity is common in OCD, and the nonresponse related to the presence of comorbid conditions requires adjustment of the treatment.94

Hair pulling disorder (HPD) and skin-picking disorder (SPD) Hair pulling disorder (HPD; also known as trichotillomania) has been classified as an impulse control disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR),78 but only recently has it included in the OC-related disorders. A narrower, though still somewhat broadly defined, phenotype of HPD (ie, focused pulling) is characterized by a dysfunctional pleasure-seeking behavior (eg, pulling in an effort to obtain pleasure/gratification). Grant et al.79 have proposed that pleasure- or novelty-seeking, which has been associated with increased substance use,80

Bipolar spectrum, attention deficit disorder, addiction, etc There are high rates of comorbidity in OCD with both depressive disorders (DD; 50%) and bipolar disorder (BPD; 10%).95 Assessment in these cases requires special considerations. Treatment of the affective instability has to be treated first, then the OC symptoms. Moreover, Centorrino et al.96 suggest that comorbid BPD-OCD patients may be clinically more similar to BPD than OCD patients, and that BPD-OCD comorbidity may not negatively impact the long-term clinical outcome.

58 S. PALLANTI AND E. HOLLANDER

Venlafaxine should not be considered as a first-line medication treatment for patients with OCD. However, in specific clinical situations (eg, co-morbid OCD with attention-deficit hyperactivity disorder [ADHD]), venlafaxine might be considered, alongside other components such as amphetamine or methylphenidate that can serve both as augmentation for OCD and for treating ADHD. As a first-choice mood stabilizer to target both impulsivity and affective instability, lithium might be a good option, since it is the only drug reported to be effective both in impulse control disorders, specifically pathological gambling,97 and in adult ADHD.98

OCD, addiction to substances, and not-substances As compulsive behavior is common both in OCD and in addiction, it has been hypothesized that the opioid antagonist naltrexone may be effective in OCD. In a double-blind treatment trial with once a week oral morphine,99 a significant reduction of OCD symptoms in some treatment-resistant OCD patients was reported. Although the mechanism of action is unknown; the involvement of m-agonists and glutamate antagonists has been hypothesized but deserves clarification. In another small, placebo-controlled investigation, the effect of naltrexone augmentation to SSRI treatment was compared with placebo. Naltrexone was associated with an increase in depression and anxiety among OCD patients, without any significant effect on Y-BOCS scores in this small study.100

TMS for Compulsivity and Impulsivity Previous studies Over the last decade, a wealth of studies on TMS treatment in OCD has accumulated. Most have investigated the left dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), and the orbitofrontal cortex (OFC) as target areas in the treatment of OCD. Though a complete review has been presented by Jaafari et al.,101 we briefly summarize the most important findings of the studies. The most consistent number of studies investigated the DLPFC as the target area, either bilaterally102,103 or on a specific side (RDLPFC).103–107 The findings mainly suggest moderate effects of stimulation on obsessions and compulsions103 or no improvement of OCD symptomatology.104,107,108 SMA trials were all conducted with low-frequency repetitive transcranial magnetic stimulation (rTMS). Most studies come from the work of Mantovani et al.,109–112 whose main results appear to be significant reductions of Y-BOCS scores and modest reductions of OCD symptoms.

Regarding OFC trials, since obsessions and compulsions seem to be mediated by hyperactivity in the orbitofrontal-subcortical circuits and increased functional activity in the OFC,113–116 the trials were conducted using low-frequency (1 Hz) rTMS on this area. The main result was a global reduction of Y-BOCS scores in the active group compared to the sham group. In conclusion, the results do not yet supporting the inclusion of TMS in the toolbox for OCD, but they do appear to be promising. Different modalities of stimulation might be more suitable for specific subtypes or dimensions of OCD, such as the SMA for more impulsive (including Tourette syndrome), or DLPF and OFC for more anxiety or obsessive features. Also, new generation devices and coils would help to reach new targets such as the ACC or the insula.

Conclusion While waiting for new compounds, research has focused on identifying the new targets of the cures for OCD, either CBT or drugs, in terms of circuitries and neurotransmitters. The road toward these new treatments has been already drawn, and the DSM-5 new classification is oriented in this direction, while RDoC criteria encourage translational effort from behavioral dimensions toward definition of the circuitries involved.

Disclosures Stefano Pallanti does not have anything to disclose. Dr. Hollander has the following disclosures: Research Grants: Transcept, Roche, Brainsway, Forest. Consulting: Transcept, Roche.

REFERENCES: 1. Kupfer DJ, First MB, Regier DA. A Research Agenda for DSM-V. Arlington, VA: American Psychiatric Publishing; 2008. 2. Mataix-Cols D, Boman M, Monzani B, et al. Population-based, multigenerational family clustering study of obsessive-compulsive disorder. JAMA Psychiatry. 2013; 70(7): 709–717. 3. van Grootheest DS, van den Berg SM, Cath DC, Willemsen G, Boomsma DI. Marital resemblance for obsessive-compulsive, anxious and depressive symptoms in a population-based sample. Psychol Med. 2008; 38(12): 1731–1740. 4. Stewart SE, Yu D, Scharf JM, et al. D. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry. 2012; 18(7): 788–798. 5. Stewart SE, Mayerfeld C, Arnold PD. Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1. Am J Med Genet B Neuropsychiatr Genet. 2013; 162(4): 367–379. 6. Abramowitz JS, Deacon B, Olatunji B, et al. Assessment of obsessive-compulsive symptom dimensions: development and evaluation of the Dimensional Obsessive-Compulsive Scale. Psychol Assess. 2010; 22: 180–198.

CNS SPECTRUMS

7. Capecchi MR. Hox genes and mammalian development. Cold Spring Harb Symp Quant Biol. 1997; 62: 273–281. 8. Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in the mouse. Neuron. 2002; 33: 23–34. 9. Chen SK, Tvrdik P, Peden E, et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010; 141(5): 775–785. 10. Antony JM. Grooming and growing with microglia. Sci Signal. 2010; 3(147): jc8. 11. Wan Y, Feng G, Calakos N. Sapap3 deletion causes mGluR5dependent silencing of AMPAR synapses. J Neurosci. 2011; 31(46): 16685–16691. 12. Welch JM, Lu J, Rodriguiz RM, et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature. 2007; 448: 894–900. 13. Wan Y, Ade KK, Caffall Z, et al. Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessivecompulsive disorder. Biol Psychiatry. In press. DOI: 10.1016/ j.biopsych.2013.01.008. 14. Shmelkov SV, Hormigo A, Jing D, et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med. 2010; 16(5): 598–602. 15. Campbell KM, de Lecea L, Severynse DM, et al. OCD-like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D11 neurons. J Neurosci. 1999; 19: 5044–5053. 16. Nordstrom EJ, Burton FH. A transgenic model of comorbid Tourette’s syndrome and obsessive-compulsive disorder circuitry. Mol Psychiatry. 2002; 7: 617–625, 524. 17. McGrath MJ, Campbell KM, Parks CR, Burton FH. Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette’s syndrome and obsessive-compulsive disorder. Brain Res. 2000; 877: 23–30. 18. Taj M J RJ, Viswanath B, Purushottam M, et al. DRD4 gene and obsessive compulsive disorder: do symptom dimensions have specific genetic correlates? Prog Neuropsychopharmacol Biol Psychiatry. 2013; 41: 18–23. 19. Cannistraro PA, Rauch SL. Neural circuitry of anxiety: evidence from structural and functional neuroimaging studies. Psychopharmacol Bull. 2003; 37: 8–25. 20. Mataix-Cols D, Cullen S, Lange K, et al. Neural correlates of anxiety associated with obsessive-compulsive symptom dimensions in normal volunteers. Biol Psychiatry. 2003; 53: 482–493. 21. Van den Heuvel OA, Veltman DJ, Groenewegen HJ, et al. Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography. Psychiatry Res. 2004; 132: 225–237. 22. Simon D, Kaufmann C, Musch K, et al. Fronto-striato-limbic hyperactivation in obsessive-compulsive disorder during individually tailored symptoms provocation. Psychophysiology. 2010; 47: 728–738. 23. LeDoux JE. Synaptic Self: How Our Brains Become Who We Are. New York: Viking Penguin; 2002. 24. Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992; 15(1): 353–375. 25. Sookman D, Pinard G. Overestimation of threat and intolerance of uncertainty in obsessive compulsive disorder. In: Frost RO, Steketee G, eds. Cognitive Approaches to Obsessions and Compulsions: Theory, Assessment and Treatment. Oxford, UK: Elsevier; 2002: 63–89. 26. Stein DJ. Advances in understanding the anxiety disorders: the cognitive-affective neuroscience of ‘‘false alarms’’. Ann Clin Psychiatry 2006; 18: 173–182. 27. Saxena S, Brody AL, Schwartz JM, et al. Neuroimaging and frontalsubcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry. 1998; 173(35): 26–37.

59

28. Menzies L, Chamberlain SR, Laird AR, et al. Integrating evidence from neuroimaging and neuropsychological studies of obsessive–compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev. 2008; 32(3): 525–549. 29. Depue R, Collins P. Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion. Behav Brain Sci. 1999; 22(3): 491–517. 30. Harrison BJ, Soriano-Mas C, Pujol J, et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch Gen Psychiatry. 2009; 66(11): 1189–1200. 31. Haber SN, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010; 35(1): 4–26. 32. Szechtman H, Woody E. Obsessive–compulsive disorder as a disturbance of security motivation. Psychol Rev. 2004; 111(1): 111–127. 33. Endrass T, Kloft L, Kaufmann C, et al. Approach and avoidance learning in obsessive–compulsive disorder. Depress Anxiety. 2011; 28(2): 166–172. 34. Beaulieu C. The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed. 2002; 15(7–8): 435–455. 35. Sporns O. Brain networks and embodiment. In: Mesquita B, Feldman B, eds. Mind in Context. New York: Guilford Press; 2010: 42–64. 36. Banks SJ, Eddy KT, Angstadt M, et al. Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci. 2007; 2(4): 303–312. 37. Kim MJ, Whalen PJ. The structural integrity of an amygdalaprefrontal pathway predicts trait anxiety. J Neurosci. 2009; 29(37): 11614–11618. 38. Phillips ML, Drevets WC, Rauch SL, et al. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry. 2003; 54(5): 515–528. 39. Brody AL, Saxena S, Schwartz JM, et al. FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder. Psychiatry Res. 1998; 84(1): 1–6. 40. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive–compulsive disorder. Psychiatr Clin North Am. 2000; 23(3): 563–586. 41. Menzies L, Williams GB, Chamberlain SR, et al. White matter abnormalities in patients with obsessive–compulsive disorder and their first-degree relatives. Am J Psychiatry. 2008; 165(10): 1308–1315. 42. Del Casale A, Kotzalidis GD, Rapinesi C, et al. Functional neuroimaging in obsessive–compulsive disorder. Neuropsychobiology. 2011; 64(2): 61–85. 43. Milad MR, Rauch SL. Obsessive–compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci. 2012; 16(1): 43–51. 44. Aouizerate B, Guehl D, Cuny E, et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol. 2004; 72(3): 195–221. 45. Maltby N, Tolin DF, Worhunsky P, et al. Dysfunctional action monitoring hyperactivates frontal-striatal circuits in obsessivecompulsive disorder: an event-related fMRI study. Neuroimage. 2005; 24(2): 495–503. 46. Fitzgerald KD, Welsh RC, Gehring WJ, et al. Error-related hyperactivity of the anterior cingulate cortex in obsessivecompulsive disorder. Biol Psychiatry. 2005; 57(3): 287–294. 47. Kringelbach ML. The human orbitofrontal cortex: linking reward to hedonic experience. Nat Rev Neurosci. 2005; 6(9): 691–702. 48. Remijnse PL, Nielen MM, van Balkom AJ, et al. Reduced orbitofrontal-striatal activity on a reversal learning task in

60 S. PALLANTI AND E. HOLLANDER

49.

50.

51.

52.

53. 54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

obsessive-compulsive disorder. Arch Gen Psychiatry. 2006; 63(11): 1225–1236. Chamberlain SR, Menzies L, Hampshire A, et al. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science. 2008; 321(5887): 421–422. Figee M, Vink M, de Geus F, et al. Dysfunctional reward circuitry in obsessive-compulsive disorder. Biol Psychiatry. 2011; 69(9): 867–874. Rauch SL, Dougherty DD, Cosgrove GR, et al. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder. Biol Psychiatry. 2001; 50(9): 659–667. Hendler T, Goshen E, Tzila Zwas S, et al. Brain reactivity to specific symptom provocation indicates prospective therapeutic outcome in OCD. Psychiatry Research: Neuroimaging. 2003; 124(2): 87–103. Insel TR. Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 1992; 49(9): 739. Shanahan NA, Velez LP, Masten VL. Essential Role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice. Biol Psychiatry. 2011; 70(11): 1039–1048. ˜o L, et al. The extended frontoMelloni M, Urbistondo C, Seden striatal model of obsessive compulsive disorder: convergence from event-related potentials, neuropsychology and neuroimaging. Front Hum Neurosci. 2012; 6: 259. Fineberg NA, Pallanti S, Reghunandanan S, Baldwin DS, Leonard BE (eds). Anxiety Disorders. Mod Trends Pharmacopsychiatry. Basel, Karger, 2003: 29: 164–177. Pallanti S, Hollander E, Bienstock C, et al. Treatment nonresponse in OCD: methodological issues and operational definitions. Int J Neuropsychopharmacol. 2002; 5(2): 181–191. Pallanti S, Quercioli L, Koran LM. Citalopram intravenous infusion in resistant obsessive-compulsive disorder: an open trial. J Clin Psychiatry. 2002; 63(9): 796. Pallanti S, Grassi G. Citalopram pulse loading for severe treatment-resistant OCD: a case series of acute response, one year follow-up and tolerability. J Depress Anxiety. In press. DOI: 10.4172/2167-1044.S10-002. Koran LM, Aboujaoude E, Ward H, et al. Pulse-loaded intravenous clomipramine in treatment-resistant obsessive-compulsive disorder. J Clin Psychopharmacol. 2003; 26(1): 79–83. Ross S, Fallon BA, Petkova E, Feinstein S, Liebowitz MR. Long-term follow-up study of patients with refractory obsessivecompulsive disorder. J Neuropsychiatry Clin Neurosci. 2008; 20(4): 450–457. Pallanti S, Bernardi S, Antonini S, Singh N, Hollander E. Ondasetron augmentation in treatment-resistant obsessivecompulsive disorder. CNS Drugs. 2009; 23(12): 1047–1055. Askari N, Moin M, Sanati M, et al. Granisetron adjunct to fluvoxamine for moderate to severe obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. CNS Drugs. 2012; 26(10): 883–892. Hollander E, Pallanti S. Current and Experimental Therapeutics of Obsessive Compulsive Disorders, pp 1647–1664, Neuro psychopharmacology: The Fifth Generation of Progress, An Official Publication of the American College of Neuropsychopharmacology, Edited by KL Davis, D. Charney, JT Coyle and C. Nemeroff, Lippincott/Williams and Wilkins, 2002. Kaplan A, Hollander E. A review of pharmacologic treatments for obsessive-compulsive disorder. Psychiatr Serv. 2003; 54(8): 1111–1118. Koran LM, Aboujaoude E, Gamel NN. Double-blind study of dextroamphetamine versus caffeine augmentation for treatment-

67.

68.

69.

70

71.

72.

73.

74.

75.

76. 77.

78.

79.

80.

81.

82.

83.

84.

resistant obsessive-compulsive disorder. J Clin Psychiatry. 2009; 70(11): 1530–1535. Mowla A, Khajeian AM, Sahraian A, Chohedri AH, Kashkoli F. Topiramate augmentation in resistant OCD: a double-blind placebo-controlled clinical trial. CNS Spectr. 2010; 15(11): 613–617. Grant P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of riluzole, a glutamate antagonist, in children with treatmentresistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2007; 17(6): 761–767. Berlin HA, Koran LM, Jenike MA, et al. Double-blind, placebocontrolled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2011; 72(5): 716–721. Aboujaoude E, Barry JJ, Gamel N. Memantine augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. J Clin Psychopharmacol. 2009; 29(1): 51–55. Abudy A, Juven-Wetzler A, Zohar J. Pharmacological management of treatment-resistant obsessive-compulsive disorder. CNS Drugs. 2011; 25(7): 585–596. Feusner JD, Kerwin L, Saxena S & Bystritsky A. Differential efficacy of memantine for obsessive-compulsive disorder vs. generalized anxiety disorder: an open-label trial. Psychopharmacology bulletin. 2009; 42(1): 81. Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. In press. DOI: 10.1038/npp.2013. Farrell LJ, Waters AM, Boschen MJ, et al. Difficult-to-treat pediatric obsessive-compulsive disorder: feasibility and preliminary results of a randomized pilot trial of d-cycloserine augmented behavior therapy. Depress Anxiety. 2013; 30(8): 723–731. Pallanti S, Hollander E, Goodman WK. A qualitative analysis of nonresponse: management of treatment-refractory obsessivecompulsive disorder. J Clin Psychiatry. 2004; 65(14): 6–10. Saxena S. Pharmacotherapy of compulsive hoarding. J Clin Psychol. 2011; 67(5): 477–484. ¨nner S. Incompleteness as a link between Ecker W, Kupfer J, Go obsessive-compulsive personality traits and specific symptom dimensions of obsessive-compulsive disorder. Clin Psychol Psychother. In press. DOI: 10.1002/cpp.1842. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text rev. Arlington, VA: American Psychiatric Association; 2000. Grant JE, Odlaug BL, Potenza MN. Addicted to hair pulling? How an alternate model of trichotillomania may improve treatment outcome. Harv Rev Psychiatry. 2007; 15(2): 80–85. Lange LA, Kampov-Polevoy AB, Garbutt JC. Sweet liking and high novelty seeking: independent phenotypes associated with alcohol-related problems. Alcohol Alcohol. 2010; 45(5): 431–436. Schlosser S, Black DW, Blum N, Goldstein RB. The demography, phenomenology and family history of 22 persons with compulsive hair pulling. Ann Clin Psychiatry. 1994; 6(3): 147–152. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association. Lochner C, Hemmings SM, Kinnear CJ, et al. Cluster analysis of obsessive-compulsive symptomatology: identifying obsessivecompulsive disorder subtypes. Isr J Psychiatry Relat Sci. 2008; 45(3): 164–176. Blum K, Braverman ER, Holder JM, et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of

CNS SPECTRUMS

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs. 2000; 32(Suppl: i–iv): 1–112. Laine TP, Ahonen A, Rasanen P, et al. The A1 allele of the D2 dopamine receptor gene is associated with high dopamine transporter density in detoxified alcoholics. Alcohol Alcohol. 2001; 36(3): 262–265. Laine TP, Ahonen A, Rasanen P, et al. Dopamine transporter density and novelty seeking among alcoholics. J Addict Dis. 2001; 20(4): 91–96. Retz W, Rosler M, Supprian T, et al. Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology. J Neural Transm. 2003; 110(5): 561–572. Ray LA, Bryan A, Mackillop J, et al. The dopamine D Receptor (DRD4) gene exon III polymorphism, problematic alcohol use and novelty seeking: direct and mediated genetic effects. Addict Biol. 2009; 14(2): 238–244. Demetrovics Z, Varga G, Szekely A, et al. Association between novelty seeking of opiate-dependent patients and the catechol-Omethyl transferase Val(158)Met polymorphism. Compr Psychiatry. 2010; 51(5): 510–515. Loos M, Pattij T, Janssen MC, et al. Dopaminereceptor D1/D5 gene expression in the medial prefrontal cortex predicts impulsive choice in rats. Cereb Cortex. 2010; 20(5): 1064–1070. O’Sullivan RL, Philips KA, Keuthen NJ. Near fatal skin picking from delusional body dysmorphic disorder responsive to fluvoxamine. Psychosomatics. 1999; 40(1): 79–81. Bloch MH, Landeros-Weisenberger A, Dombrowski P, et al. Systematic review: pharmacological and behavioral treatment for trichotillomania. Biol Psychiatry. 2007; 62(8): 839–846. Snorrason I, Belleau EL, Woods DW. How related are hair pulling disorder (trichotillomania) and skin picking disorder? A review of evidence for comorbidity, similarities and shared etiology. Clin Psychol Rev. 2012; 32(7): 618–629. Pallanti S, Grassi G, Sarrecchia ED, Cantisani A, Pellegrini M. Obsessive-compulsive disorder comorbidity: clinical assessment and therapeutic implications. Front Psychiatry. 2011; 2: 70. Timpano KR, Rubenstein LM, Murphy DL. Phenomenological features and clinical impact of affective disorders in OCD: a focus on the bipolar disorder and OCD connection. Depress Anxiety. 2012; 29(3): 226–233. Centorrino F, Hennen J, Mallya G, et al. Clinical outcome in patients with bipolar I disorder, obsessive compulsive disorder or both. Hum Psychopharmacol. 2006; 21(3): 189–193. Hollander E, Buchsbaum MS, Haznedar MM, et al. FDG-PET study in pathological gamblers. 1. Lithium increases orbitofrontal, dorsolateral and cingulate metabolism. Neuropsychobiology. 2008; 58(1): 37–47. Dorrego MF, Canevaro L, Kuzis G, Sabe L, Starkstein SE. A randomized, double-blind, crossover study of methylphenidate and lithium in adults with attention-deficit/hyperactivity disorder preliminary findings. J Neuropsychiatry Clin Neurosci. 2002; 14(3): 289–295. Koran LM, Aboujaoude E, Bullock KD, et al. Double-blind treatment with oral morphine in treatment-resistant obsessivecompulsive disorder. J Clin Psychiatry. 2005; 66(3): 353–359. Amiaz R, Fostick L, Gershon A, Zohar J. Naltrexone augmentation in OCD: a double-blind placebo-controlled cross-over study. Eur Neuropsychopharmacol. 2008; 18(6): 455–461. Jaafari N, Rachid F, Rotge JY, et al. Safety and efficacy of repetitive transcranial magnetic stimulation in the treatment of

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

61

obsessive-compulsive disorder: a review. World J Biol Psychiatry. 2012; 13(3): 164–177. Greenberg BD, George MS, Martin JD, et al. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessivecompulsive disorder: a preliminary study. Am J Psychiatry. 1997; 154(6): 867–869. Sachdev PS, McBride R, Loo CK, et al. Right versus left prefrontal transcranial magnetic stimulation for obsessive-compulsive disorder: a preliminary investigation. J Clin Psychiatry. 2001; 62(12): 981–984. Alonso P, Pujol J, Cardoner N, et al. Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Am J Psychiatry. 2001; 158(7): 1143–1145. Kang JI, Kim CH, Namkoong K, et al. A randomized controlled study of sequentially applied repetitive transcranial magnetic stimulation in obsessive-compulsive disorder. J Clin Psychiatry. 2009; 70(12): 1645–1651. Sarkhel S, Sinha VK, Praharaj SK. Adjunctive high-frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) was not effective in obsessive-compulsive disorder but improved secondary depression. J Anxiety Disord. 2010; 24(5): 535–539. Prasko J, Paskova´ B, Za´lesky´ R, et al. The effect of repetitive transcranial magnetic stimulation (rTMS) on symptoms in obsessive compulsive disorder: a randomized, double blind, sham controlled study. Neuro Endocrinol Lett. 2006; 27(3): 327–332. Sachdev PS, Loo CK, Mitchell PB, et al. Repetitive transcranial magnetic stimulation for the treatment of obsessive compulsive disorder: a double-blind controlled investigation. Psychol Med. 2007; 37(11): 1645–1649. Mantovani A, Lisanby SH, Pieraccini F, et al. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette’s syndrome (TS). Int J Neuropsychopharmacol. 2006; 9(1): 95–100. Mantovani A, Leckman JF, Grantz H, et al. Repetitive transcranial stimulation of the supplementary motor area in the treatment of Tourette syndrome: report of two cases. Clin Neurophysiol. 2007; 118(10): 2314–2315. Mantovani A, Simpson HB, Fallon BA, et al. Randomized shamcontrolled trial of repetitive transcranial magnetic stimulation in treatment-resistant obsessive-compulsive disorder. Int J Neuropsychopharmacol. 2010; 13(2): 217–227. Mantovani A, Westin G, Hirsch J. Functional magnetic resonance imaging guided transcranial magnetic stimulation in obsessivecompulsive disorder. Biol Psychiatry. 2010; 67(7): e39–e40. Alptekin K, Degermenci B, Kivircik B, et al. Tc-99 m HMPAO brain perfusion SPECT in drug-free obsessive-compulsive patients without depression. Psychiatry Res. 2001; 107(1): 51–56. Baxter LR, Schwartz JM, Mazziotta JC, et al. Cerebral glucose metabolic rates in non-depressed patients with obsessivecompulsive disorder. Am J Psychiatry. 1988; 145(12): 1560–1563. Swedo SE, Schapiro MB, Grady CL, et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry. 1989; 46(6): 518–523. Ruffini C, Locatelli M, Lucca A, et al. Augmentation effect of repetitive transcranial magnetic stimulation over the orbitofrontal cortex in drug-resistant obsessive-compulsive disorder patients: a controlled investigation. Prim Care Companion J Clin Psychiatry. 2009; 11(5): 226–230.