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Drug Discovery Today  Volume 13, Numbers 7/8  April 2008 REVIEWS

Serotoninergic mechanisms in the POST SCREEN treatment of obsessive–compulsive 

disorder Reviews

Andrew W. Goddard1, Anantha Shekhar2, Aaron F. Whiteman3 and Christopher J. McDougle4

1 Department of , Indiana University School of Medicine, University Hospital, UH3124, 550 North University Boulevard, Indianapolis, IN 46202, United States 2 Department of Psychiatry, Indiana University School of Medicine, 1111 West 10th Street, Suite 313, Indianapolis, IN 46202, United States 3 Fairbanks Hospital, Clearvista Recovery Associates, 8102 Clearvista Parkway, Indianapolis, IN 46256, United States 4 Department of Psychiatry, Indiana University School of Medicine, 1111 West 10th Street, PB A305, Indianapolis, IN 46202-4800, United States

Obsessive–compulsive disorder (OCD) is a disabling psychiatric condition affecting 1–2% of the community. Although modern drug, behavioral and psychosurgical therapies have improved the prognosis of OCD considerably, approximately 30% of patients remain treatment-refractory. Currently, selective (5-HT) reuptake inhibitors (SSRIs) are the drug treatments of choice for OCD. Accordingly, this review evaluates the evidence for a role of the serotonin (5-HT) neurochemical system in the treatment and pathophysiology of OCD. However, drug treatment approaches that modify function of interrelated neurochemical systems, such as the and glutamate systems, are also briefly discussed as they promise to complement and enhance SSRI treatment effects.

Obsessive–compulsive disorder (OCD) is a familial disorder account for the clinical heterogeneity seen in OCD. OCD tends to affecting 1–2% of the general community [1]. Once thought to be manifest in the teen and early adult years with more than half of all quite rare, it is now known to be the fourth most common mental cases having illness onset before 25 years of age. It usually runs a illness, after depression, and social . chronic course without treatment. Also, it is complicated by a high OCD is a disorder in which the patient’s mental state and daily rate of psychiatric with up to 70% of cases eventually activities are dominated by morbid obsessions or compulsions, or, having an additional psychiatric diagnosis, most oftendepression or more typically, a combination of both these. Obsessions are persis- another anxiety disorder [4]. In addition, there is a well-described tent, intrusive and inappropriate thoughts (such as intense con- clinical association between OCD and other psychiatric syndromes tamination fears), impulses or images that are distressing for the such as Tourette’s syndrome, motor disorders and autistic dis- patient. Compulsions are repetitive behaviors or mental acts that a orders, which have been conceptualized by some experts as OCD person feels driven to perform (e.g. handwashing or checking), that spectrum disorders [5]. The pathophysiologic basis of OCD symp- are generally aimed at reducing the distress caused by the obses- toms has not yet been clearly delineated. However, neurochemical sions. Recent advances in diagnosis have resulted in the proposal of dysfunction (with putative abnormalities in serotonin, dopamine a dimensional typology comprising several subtypes: obsessions/ (DA) and transmitter systems) in cortico-thalamo- checking, hoarding, contamination/cleaning and symmetry/order- striatal-cortical circuits has been implicated in its pathogen- ing [2,3]. These dimensions are hypothesized to have distinct esis [6,7]. genetic, neurobiological and treatment correlates, and may better Advances in antiobsessional therapy over the past two decades have improved the prognosis of this condition considerably. Modern treatment options, including behavioral therapies, drug Corresponding author: Goddard, W. Andrew ([email protected]), Shekhar, Anantha therapies (selective serotonin reuptake inhibitor (SSRI) with or ([email protected]), Whiteman, F. Aaron ([email protected]), McDougle, J. Christopher ([email protected]) without an atypical neuroleptic) [8] and psychosurgical interven-

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tions (cingulotomy, deep brain stimulation) [9,10], offer partial (Fig. 1). Chronic administration of these agents, via a sequence of symptom relief for many. However, despite these therapeutic neuroadaptive changes, has a net facilitatory effect on 5-HT neu- advances, 30% of patients remain treatment-refractory [11,12]. rotransmission [13]. Unlike patients with major depression, in With respect to dimensions of OCD psychopathology, the hoard- whom maintenance of SSRI treatment effects require continued ing dimension has been associated with particularly high rates of availability of presynaptic 5-HT [14], OCD patients do not experi- comorbidity and treatment-refractoriness [2]. ence disruption of SSRI therapeutic effects under conditions of In this review, we will outline the evidence suggesting a role for /5-HT depletion [15,16], implicating long-term post- the serotonin (5-HT) system in the treatment of synaptic 5-HT receptor changes in therapeutic mechanisms in Reviews OCD. We will also briefly mention the therapeutic potential of OCD. Some of these changes, mentioned in more detail later, newer treatment strategies beyond the 5-HT system acting via may account for the later onset of therapeutic action of SSRIs in 

OTSCREEN POST and glutamatergic mechanisms. Effective treat- OCD (up to 12 weeks) compared to major depression (4–6 weeks). ments strategies are likely to modulate the cortico-thalamic-stria- Owing to the selective effectiveness of SRI agents, there has been tal-cortical circuitry mentioned earlier at different levels thereby a focused search for an association between OCD, and the genes re-regulating functioning within multiple neurotransmitter sys- coding for the 5-HTT protein and its expression. A 44 bp insertion/ tems (5-HT, DA, glutamate, g-aminobutyric acid [GABA]). deletion polymorphism (5-HTTLPR) has been identified in the promoter region of the 5-HTT gene that regulates 5-HTT protein Drugs targeting the 5-HT transporter expression. Efforts to associate allelic variation in the 5-HTTLPR A key piece of evidence implicating the brain 5-HT system in the region with OCD have thus far been mixed with some studies treatment and possibly the pathophysiology of OCD has been the [17,18] suggesting increased expression of two copies of the long discovery of the antiobsessional properties of the SSRIs and the allele form (l/l) (linked to maximum transcriptional efficiency) of serotonin reuptake inhibitor (SRI), (see Table 1 for the gene in OCD, and others failing to find this association [19– details). By contrast, many other classes of psychotropic medica- 23]. One group has identified a trend toward increased frequency tions used for mood and anxiety disorders (e.g. other of the 5-HTTLPR short allele (s) in female OCD patients [24]. Given , MAO inhibitors, benzodiazepines, mood stabili- the clinical heterogeneity of OCD spectrum disorder, further zers, 5-HT1A partial agonists) do not substantially affect the core investigation of illness subgroups (e.g. early onset OCD, family symptoms of OCD. The SSRIs potently block the action of the 5-HT history positive patients, dimensional subtypes) and 5-HTT alleles transporter (5-HTT) protein, which is responsible for the uptake of may yet prove rewarding. Preliminary work investigating the intrasynaptic 5-HT released following an action potential, thereby interaction of 5-HTTLPR genotype and SSRI treatment response promoting an acute increase in intrasynaptic 5-HT concentrations in OCD did not find differing response status among the three

TABLE 1 Antiobsessional agents targeting the 5-HTT protein

Agent Status as T1/2 Usual dose Relative Relative Drug–drug Clinical issues an OCD (hours) range potency of potency of interaction treatment for OCD 5-HT reuptake DA reuptake potential (mg/day) inhibition [80] inhibition Established 24–72 40–80 + +++ Anecdotal data on high-dose admin. (Prozac) (168–216a) >100 mg/day Established 24–26 100–200 ++ ++ + Potentially more rapid improvement (Zoloft) versus fluoxetine [81]. High dose admin. (250–400 mg/day) can improve refractory OCD [82] Established 21–24 40–60 ++++ + ++ Discontinuation symptoms can be a (Paxil) problem clinically Established. Most 15–26 100–300 ++ +++ Potent CYP-3A4 P450 isoenzyme (Luvox) studied for OCD inhibitor Established 33–35 40–60 +++ Minimal IV administration possible [83] (Celexa) 30–33 10–30 ++++ Minimal More potent enantiomer of citalopram (Lexapro) Clomipramine Established. 17–28 150–250 + + SEs: , sedation; concern (Anafranil) First FDA- about >250 mg/day. ? Bigger approved effect size versus SSRIs. Cardiotoxicity medicine for in O/D. IV studies – may be a way to OCD hasten treatment in resistant patients [84]. Active desmethyl metabolite is primarily a NE reuptake blocker

a Active nor-fluoxetine metabolite.

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FIGURE 1 A model serotonin synapse, identifying some of the key receptors and other synaptic components that may mediate SSRI therapeutic effects in OCD. Serotonin (5-hydroxytryptamine or 5-HT) is shown from synthesis to synaptic release and then binding to presynaptic and postsynaptic receptors. Tryptophan hydroxylase (TrpH) catalyzes the rate-limiting step in the synthesis of 5-HT from tryptophan (Trp). The vesicular type-2 (VMAT2) transports 5-HT into presynaptic vesicles. These vesicles then release 5-HT, where 5-HT interacts with postsynaptic receptors including 5-HT1A, 5-HT1B/D, 5-HT2A, 5-HT2C and 5-HT3. 5-HT also binds to somatodendritic (5-HT1A) and terminal (5-HT1B/D) autoreceptors. The (5-HTT) transports 5-HT from the synaptic space back into the presynaptic . Monoamine oxidase-A (MAO-A) breaks down 5-HT. The SSRIs blocks the 5-HTT, and ultimately increase CREB and BDNF expression in frontal, striatal and limbic brain areas. different genotypes, when considering total clinical improvement. speculated that lessened transcriptional efficiency of the 5-HTTPR However, improvement in compulsive behaviors rather than total in OCD patients could account for the striking delay in onset of OCD psychopathology may vary with genotype, with l/s genotype SSRI therapeutic effects compared to other conditions such as associated with a better response [22]. Another group has also depression and panic disorder [27]. Other possible explanations linked l/s genotype to SSRI/SNRI responder status [25]. These for the discrepant findings between OCD and MDD SSRI response results are divergent from the treatment findings in patients with status and 5-HTT genotype are differences in the underlying major depression where the l/l genotype confers SSRI responder neurobiology of the syndromes as well as their treatment mechan- status [26], and the s/s genotype, nonresponder status. Some have isms. For example, frontal cortical 5-HT mechanisms may be more

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involved in OCD treatment responses [28], while hippocampal vation of other 5-HT receptor subtypes (e.g. 5-HT1A, 5-HT2C). and hypothalamic 5-HT mechanism may be of greater significance Therapeutic effects of SSRIs in OCD are probably mediated by 5-HT for MDD. The recent discovery of the functional equivalence of the effects at a number of different postsynaptic receptors, and simul- LG allele with the S allele [29,30] is also likely to add refinement to taneous 5-HT2A antagonism may enhance these effects. The emer- the prediction of SSRI treatment responses and adverse event ging clinical evidence that atypical drugs, many of burden [31] in OCD spectrum disorders, and may lead to reinter- which are potent 5-HT2A antagonists, are useful augmenting pretation of the published literature on this topic. Though pro- agents for treatment-resistant OCD, fits to some degree with this mising as a clinical tool, additional work is needed to ascertain theory (Table 2). Based on this treatment literature, it appears that Reviews whether pretreatment 5-HTT genotyping could routinely inform the therapeutic effect of 5-HT2A antagonist/ treatment selection and planning in OCD. coadministration takes four to six weeks to become established, 

OTSCREEN POST Complementary to the genetic data reviewed, a number of and is maximally effective with low-dose regimens [28]. The latter studies have now been conducted attempting to observation may be because of 5-HT2A antagonism of receptors in map out the density of the 5-HTT protein in brain regions impli- the medial frontal cortex. Higher-dose atypical therapy results in cated in OCD, as well as determine brain physiological responses 5-HT2A receptor antagonism in other cortical structures impli- to effective SSRI therapy. There is evidence of abnormal reductions cated in OCD treatment responses, especially the orbito-frontal in 5-HTT availability in the /hypothalamus, cortex, which may actually be countertherapeutic [41]. However, and of medication-free OCD patients based on single it should be noted that these agents (the atypical ) photon emission computed tomography (SPECT) 123-iodine- have a complex pharmacological profile that also includes 5-HT2C labeled 2-b-carbomethoxy-3-b-(4-iodophenyl)-tropane (123I b- and D2 receptor antagonism, characteristics that could also relate CIT) imaging assessments [20,32,33]. Other groups have observed to treatment response. Furthermore, some of the agents men- findings in the opposite direction in a midbrain–pons region of tioned above, such as and to a lesser extent, mirtaza- interest (ROI) utilizing a similar imaging method [34] or no sig- pine, can block a subpopulation of a-2 adrenoreceptors which are nificant change in these ROIs versus control subjects [35], the last presynaptic heteroreceptors on 5-HT , and which regulate group employing a positron emission tomography technique. In a release of 5-HT (Fig. 1). In theory this action would also further study of OCD patients treated with the SSRI citalopram, there was a enhance other SSRI therapeutic effects such as desensitization of 37% reduction in 5-HTT density in the midbrain/pons area follow- the 5-HT1D terminal autoreceptor [28]. ing short-term therapy [36], presumably reflecting treatment- Other investigations have begun to examine the role of the 5- related increases in synaptic 5-HT concentrations. A concomitant HT2C receptor in OCD. For example, 5-HT2C knock-out mice have increase (40%) in dopamine transporter (DAT) availability was also been reported to exhibit (repetitive chewing noted in this study, suggesting the potential contribution of of non-nutritive substances) [42]. In another animal model of functional 5-HT/DA interactions in the mechanisms of antiobses- OCD (persistence of rewarded alternation behavior), 5-HT2C sional therapy. SPECT b-CIT imaging performed on patients after receptor agonism, because of either chronic meta-chlorophenyl- one year of effective citalopram treatment, indicated normaliza- (m-CPP) or chronic fluoxetine administration, was tion of 5-HTT availability in the thalamus, midbrain and brain- implicated in the observed reductions in compulsive behaviors stem. Patients with higher initial levels of thalamic 5-HTT [43]. In addition, the hallucinogen, , a mixed 5-HT2C/ occupancy by the SSRI citalopram tended to have better 12-month 2A/1A receptor agonist, has been reported to produce acute reduc- treatment outcomes [37]. Although the imaging studies above tions in symptomatology in with OCD [44]. There is have been conducted with small samples, overall they support preclinical data that, following eight weeks of SSRI administration, an instrumental role of the 5-HTT in the effective SSRI treatment of postsynaptic 5-HT2A/C receptors in orbito-frontal cortex projec- OCD. Additionally, these neurochemical findings further empha- tion areas (a brain region implicated in OCD), remain size the need for neurocircuitry models to better conceptualize the normosensitive [45]. These intact receptors may be crucial to the pathophysiology of OCD, and gain a more complete mechanistic mediation of antiobsessional effects of a variety of drugs including understanding of treatment effects. Research strategies that com- SSRIs and hallucinogens [46]. bine 5-HTT genotyping, neuroimaging approaches and treatment Thus, there is accumulating evidence that agents that are 5- protocols may be especially informative. HT2A antagonists (given in low doses) or agents that are 5-HT2C receptor agonists may be useful augmentation therapies for OCD. Drugs targeting 5-HT receptor subtypes Drug development efforts aiming to produce agents with both SSRI 5-HT2 receptors properties, and these additional 5-HT2 receptor effects, could be The potential involvement of postsynaptic 5-HT2 receptors (Fig. 1) particularly beneficial for OCD patients. in therapeutic mechanisms in OCD is suggested by clinical obser- vations that psychotropic agents with potent 5-HT2 antagonist The 5-HT1D receptor properties, such as risperidone [38] and [39], have Several lines of evidence have implicated the 5-HT1D receptor in antiobsessional properties. In addition, some investigators have the pathogenesis of OCD and compulsive behaviors, thereby sti- hypothesized that synergistic treatment effects may occur across a mulating interest in this molecular target as an opportunity for broad range of mood and anxiety syndromes, including OCD, with novel therapies. 5-HT1D and possibly 5-HT1B receptors regulate 5-HT2A antagonist/SSRI combination treatment [40]. This view is release of 5-HT from the presynaptic terminal, thereby reducing 5- partly based on laboratory observations that 5-HT2A receptor HT neurotransmission (Fig. 1). Therefore, activation of the 5-HT1D stimulation may antagonize behavioral effects produced by acti- receptor by an agonist compound would be expected to worsen

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TABLE 2 antagonists for OCD Drug Status as an Dose range Relative Relative Other properties Clinical issues OCD treatment for OCD potency potency of (mg/day) of D2 receptor 5-HT2A antagonism receptor antagonism SSRI augmenting 1–3 ++++ – – Four-week trial, in which agent for refractory OCD patients (n = 34) OCD. Positive RCT data on combination (FVX + haloperidol) had a superior response versus FVX + PLAC

(39% versus 0% responders) POST SCREEN  [85]. OCD patients with responded especially well

Risperidone SSRI augmentation 0.5–3 +++ ++ 5-HT2C antag. ++ Six-week, RCT 50% of Reviews in refractory OCD completers were responders (n = 36) [38]. Second RCT (n = 16) – 40% became responders. Patients respond independent of tic status [86] Negative, open-label 50–200 + ++++ H1 antag. ++++; Ten-week trial monotherapy trial in 5-HT2C antag ++; (n = 10) [87]

refractory OCD a1 antag. ++++; 5-HT1A antag. + Two positive open-label 2.5–10 ++ ++ H1 antag. ++++ n = 10 patients in SSRI augmentation open-label study – 16% trials in refractory patients reduction in Y-BOCS scores [88]. n = 26 patients – 68% responders after 12 weeks. Maintained improvement at 12 months [89] Negative RCT RCT Â six weeks, n = 44 resistant or partially resistant patients following eight weeks of fluoxetine. No btw group differences [90] One positive, single-blind, 25–300 + ++ 5-HT2C antag. ++ 64% response rate in SSRI augmentation RCT refractory patients on SSRI + quetiapine regimen (n = 27) [91] One positive, open-label, 31% were responders augmentation trial at one of the two treatment sites involved (n = 30) [92] Positive monotherapy 10–30 +++ +++ Partial D2 agonist; 43% of patients open trial 5-HT1A partial classified as responders ag. +++ n = 8; eight-week trial [93]

OCD symptoms, because OCD is a disorder with presumptive three of four studies [55–58]. Furthermore, a recent study replicated chronic deficits in 5-HT functioning [47]. Pharmacologic challenge and extended this result in a group of female studies with m-CPP, a nonspecific 5-HT agonist (5-HT1D, 5-HT2C, patients, some of whom met criteria for OCD [59]. Thus, one 5-HT1A), have reported symptom exacerbation in OCD patients pathophysiological hypothesis of OCD is that 5-HT1D receptors [48–50], consistent with the above notion. Not all studies, however, are supersensitive in this condition, resulting in chronic reductions have been positive [51]. Furthermore, challenge with oral sumi- in synaptic levels of 5-HT. SSRI treatment, then, may work partly , a selective 5-HT1D agonist, provoked OCD symptoms in via terminal 5-HT1D receptor desensitization, a physiological the hands of one group [52], but not others [53]. Another challen- event which coincides with the delayed onset (8–12 weeks) of ging study was conducted with a more potent agent, , therapeutic effects seen in OCD patients [60]. 5-HT1D, and possibly in this class because sumitriptan has poor CNS penetrance. How- 5-HT1B antagonist compounds (in development) might be ever, this too was negative [54]. A silent polymorphism of the 5- expected to hasten the onset of therapeutic action of SSRIs in HT1D gene, G861C, has been associated with OCD diagnosis in OCD by rapidly producing a state of 5-HT1D receptor insensitivity.

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Other 5-HT receptor subtypes OCD patients [68]. Also, in pediatric OCD, there are magnetic Other 5-HT receptor subtypes may also be of therapeutic signifi- resonance spectroscopic data documenting abnormally elevated cance for OCD. In the depression treatment literature, consider- caudate glutamate/glutamine levels in unmedicated patients, able has been given to augmentation strategies that which normalize with SSRI/paroxetine treatment [69]. Lack of could hasten effects. In theory, 5-HT1A antago- serotoninergic inhibition of orbito-frontal cortical, thalamic and nists, such as the b blocker, , have the capacity to hasten striatal areas may permit glutamatergic hyperactivity in these areas the antidepressant effect of SSRIs by interrupting 5-HT1A soma- in OCD [6,70]. By contrast, other brain regions, such as the todendritic autoreceptor inhibition of cell firing that occurs early anterior , exhibit reductions in glutamatergic Reviews in treatment. Although this approach has been disappointing in activity in both OCD and depression [71]. Alternatively, allelic depression, there is some promising controlled data in OCD [61]. variation within glutamate transporter genes could account for 

OTSCREEN POST Furthermore, the anxiolytic potential of 5-HT3 receptor antagon- perturbations in glutamatergic neurotransmission, and is now ism has been demonstrated in a number of animal models of considered a risk factor for OCD [72]. Also, knock-out of a cytos- anxiety. Although this strategy has met with limited success in keletal protein, SAPAP3, found in the postsynaptic region of clinical trials of some anxiety disorders (GAD, panic), there is glutamatergic cortico-striatal projection neurons, produces exces- modest evidence that , a clinically available 5-HT3 sive grooming behaviors in mice reminiscent of OCD, which are antagonist, could be a monotherapy for some OCD patients [62]. reversed by both fluoxetine administration and restoration of the Finally, the biological role of some of the more recently identified synaptic protein [73]. Accordingly, psychoactive agents that inhi- 5-HT receptors, such as the 5-HT6 receptor, have not been fully bit/modify glutamatergic function have become important novel elucidated (Fig. 1). However, there is preliminary data that 5-HT6 treatment options for this condition. , an antiglutamater- receptor agonists may reduce compulsive drinking behaviors in gic drug originally marketed for ALS, has been evaluated in an one model of OCD [63], possibly via frontal cortical modulation of open-label manner as an augmentation therapy for SSRI-resistant GABA and glutamate neurons, and thus 5-HT6 antagonists may OCD, with improvements observed not only in core OC symptoms have an antiobsessional spectrum of action. but also in associated anxiety and depressive symptoms [74]. Furthermore, case reports suggest that the noncompetitive Dopamine receptor antagonists/antipsychotics NMDA/glutamate receptor antagonist, , could also Although much of the emphasis of pathophysiologic theories of have antiobsessional properties [75,76]. Also, the glutamatergic OCD has been on 5-HT, a growing body of evidence supports a role antagonist/anticonvulsant, topiramate, has been reported in an for increased midbrain/ dopaminergic (DA) neuro- open-case series to be somewhat therapeutic as an adjunct to transmission in this disorder [64,65]. Behavioral models ongoing SSRI therapy in patients with refractory OCD [77]. Finally, of OCD/compulsive behaviors would seem to be a compatible lamotrigine, an inhibitor of glutamate release, has been tested in hyperdopaminergic hypothesis. Psychostimulant administration an open-label manner in bipolar patients with OCD spectrum in animals is known to induce stereotypic behaviors, while in symptoms, with equivocal results till date [78,79]. Thus, glutama- humans psychostimulants and other DA agonists (e.g. apomor- tergic hyperactivity, which may be a pathophysiological substrate phine) can provoke OCD symptoms. Also, SPECT b-CIT imaging of OCD, can be ameliorated by a number of currently available work has identified an abnormally increased left caudate/ drugs. In particular resistant cases of OCD, triple therapy with an region density of DAT in OCD, compatible with dysfunction in the SSRI/D2 antagonist/and glutamate antagonist may be required to DA system in this condition [66]. Finally, an impressive amount of address the simultaneous occurrence of neurochemical dysfunc- clinical treatment data is now available on the utility of classical tions in multiple brain regions. and atypical antipsychotic (D2 receptor antagonists) as adjunctive treatments for OCD (see Table 2 for a comprehensive summary). As Conclusions mentioned earlier, the atypical antipsychotics have a complex There has been substantial progress in the psychiatric manage- receptor affinity profile. However, the combination of D2 receptor ment of OCD in recent years together with a richer appreciation of blockade and 5-HT2A antagonism is thought to be central to their its significance as a public health problem, as well as its clinical and therapeutic mechanism in psychotic illnesses, as well as their pathophysiological complexity. SSRI drugs that facilitate 5-HT improved motor side-effect profile over the classical agents. An neurotransmission have been the medical treatments of choice important clinical observation is that antipsychotic monotherapy for OCD over the past two to three decades. There is a central role is not especially effective in OCD. Rather it is the synergism for the 5-HT system in treatment mechanisms in OCD, via its between the SSRIs and the antipsychotics (especially low-dose diverse receptors: the 5-HTT protein, 5-HT1A/1D/1B presynaptic administration) that produces optimal therapeutic effects. Case and 5-HT2A//3 postsynaptic receptor subtypes. SSRI therapeu- reports suggest that the new generation antipsychotic, perospir- tic mechanisms in OCD appear to be somewhat distinct from those one, with a mixture of 5-HT2A antagonism, D2 antagonism and 5- at work in major depression in that they are not dependent on the HT1A agonist properties, may be clinically useful for the comorbid short-term availability of 5-HT and its precursors. In the future, MDD/OCD patient [67]. novel treatments are likely to be developed that will selectively target some of these elements of the 5-HT system, in addition to Glutamatergic treatment approaches the 5-HTT, to either hasten onset of therapeutic effects, and/or More recently a role for glutamatergic hyperactivity in the patho- promote a more complete treatment response. In addition, other physiology of OCD has been hypothesized. For example, CSF neurochemical systems interacting with 5-HT, such as the DA and levels of glutamate are abnormally elevated in unmedicated glutamatergic systems, have now been implicated in the patho-

330 www.drugdiscoverytoday.com Drug Discovery Today  Volume 13, Numbers 7/8  April 2008 REVIEWS physiology and treatment of OCD, and antagonist drugs that spectrum disorders in which multiple medical, behavioral and modify DA and glutamatergic functioning are now becoming surgical treatment options targeting these interrelated systems, an accepted part of the therapeutic armamentarium. We are on are likely to advance care with a similar magnitude to the intro- the threshold of a new era of psychiatric therapeutics for OCD duction of the SSRIs several decades ago.

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