Switching from serotonin reuptake inhibitors to agomelatine in patients with refractory obsessive-compulsive disorder: a 3 month follow-up case series
© Fornaro; licensee BioMed Central Ltd. 2011
Received: 2 November 2010
Accepted: 28 February 2011
Published: 28 February 2011
Serotonin reuptake inhibitors (SRIs) currently represent the cornerstone of obsessive-compulsive disorder (OCD) pharmacotherapy. However, OCD is characterized by high rates of partial and/or absent response to standard, recommended treatments, often prompting pharmacological and non-pharmacological augmentation or switching of strategies. Agomelatine, a novel melatonin agonist and selective serotonin antagonist (MASSA) antidepressant approved for major depressive disorder (MDD) has recently been additionally proposed as a treatment for anxiety disorders such as social anxiety disorder (SAD) and panic disorder (PD), but not yet OCD. Nonetheless, agomelatine may have a role in the management of OCD, essentially due to its anxiolytic 5-hydroxytryptamine (HT)2C blockade action, while melatonin (MT)1 and MT2 modulation might contribute to circadian rhythm restoration if impaired.
This case series reports the outcome of six patients with or without comorbid mood and/or other anxiety disorders who were treated with SRIs at adequate doses for at least 8 weeks, showing partial or no response. Patients were then switched to agomelatine 50 mg/day, and followed up for 12 weeks.
Three out of six patients, in particular those with relevant circadian rhythm subjective impairment, showed a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score reduction of ≥35%. No relevant side effects were observed, but initial, transient, self-remitting dizziness in one patient and weight gain in another were seen.
Although clinical confounding factors (subthreshold bipolarity and eventually the presence of impaired circadian rhythms) and methodological boundaries (lack of control and neurophysiological recording, tiny sample size and short follow-up) limit the validity of this preliminary observation, it does indicate agomelatine may have a role in some SRI-refractory OCD cases, thus prompting the validity of investigation by further controlled studies, even for drug-naïve OCD patients.
Obsessive-compulsive disorder (OCD) is a common condition that affects individuals of all ages. This disorder has been listed as one of the 10 most disabling illnesses by the World Health Organization , while the National Comorbidity Survey Replication indicated that OCD is the anxiety disorder with the highest percentage (50.6%) of serious cases . Approximately 2% to 3% of the world's population will suffer from OCD at some point in their lives , and it has been estimated that most individuals with OCD spend an average of 17 years before receiving an appropriate diagnosis and treatment for their illness . Additionally, OCD usually exhibits a waxing and waning course, frequently increasing in severity when left untreated, which causes unnecessary pain to those afflicted and to their families. Hence, the need for appropriate management is imperative.
Although serotonin reuptake inhibitors (SRIs), including the widely prescribed selective SRIs (SSRIs), are considered the cornerstone of pharmacological treatment of OCD , at least 40% of cases do not respond satisfactorily to these medications . Augmentation strategies with antipsychotic medications, psychotherapies such as cognitive behavioral therapy (CBT) and others , as well as switching to newer classes of drugs such as the selective serotonin norepinephrine reuptake inhibitors (SNRIs)  have all been considered. Indeed, OCD management remains a debated issue essentially due to a still not fully understood etiopathology and to a number of eventually concomitant clinical features, mainly referable to bipolarity , which may account for some of the treatment-refractory cases.
Within the past few years, greater attention has been paid toward the neurobiological factors underpinning OCD, including the investigation of circadian rhythms  and neurosteroid  imbalance. Among other factors, a delayed slow wave sleep (SWS) phase  as well increased nocturnal secretion of adrenocorticotropic hormone (ACTH) and cortisol, a melatonin-related  'stress hormone' , have been documented in the course of some OCD cases, although the investigation of the circadian pattern by proxy measurement (axillary temperature) essentially showed the absence of a relationship between OCD and melatonin , so it remains unclear if and how circadian rhythm impairment might subjectively or objectively impact on OCD burden and its perception.
Recently, the availability of agomelatine, a novel antidepressant acting as a melatonin agonist and selective serotonin antagonist (MASSA; acting against melatonin 1 (MT1) and MT2, and 5-hydroxytryptamine (HT)2C, respectively)  led to the exploration of its potential role even for anxiety disorders [16, 17], suggesting its possible use for OCD.
This paper reports a case series of six patients with SRI-refractory OCD diagnosed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) Axis-I (SCID-I)  who were switched from SRIs to agomelatine and followed-up for at least 3 months. This is the first report of its kind in the literature to date.
Examples of clinical factors potentially linked to obsessive-compulsive disorder (OCD) treatment-refractory responses
Eventual OCD clinical features contributing to OCD refractory response toward SRI antidepressants
Sample references by first author and year
Poor-insight feature, global severity of OCD
Age at onset, familial history, duration of untreated illness and other sociodemographic features
Clinical interview/SCID-I demographics
Axis-I comorbidities (for example, MDD/other anxiety disorders)
Medical comorbidities, including those affecting the cognitive status
Clinical interview/specific assessment
Fornaro 2009 
Impaired circadian rhythms?
Giglio 2009a 
At the end of the study, three out of six patients, in particular those reporting higher subjective sleep disturbances at baseline but not at the end point, showed a clinically significant OC improvement (Y-BOCS reduce by ≥35%). Interestingly, patients largely unchanged within the 3 month trial with 50 mg/day agomelatine (n = 3) did not report any relevant circadian rhythm impairment at baseline or end point, but were more suggestive for 'soft bipolar' features according to the TEMPS-A evaluation (two out of three had a cyclothymic temperament) and/or had poor insight features.
Concerning the side-effect profile, agomelatine 50 mg/day was a generally well tolerated therapy, although one patient exhibited weigh gain and another experienced, transient (spontaneously remitting) dizziness despite a prudent downtitration from the previous SRI medication.
Clinical and demographic characteristics of SRI-refractory OCD patients treated with agomelatine 50 mg/day for a minimum of 3 months
Age at onset
DSM-IV Axis-I comorbidities
Resistant MDD, social anxiety disorder
Impulse-control disorder, substance abuse disorder
Bulimia nervosa, panic disorder
First-degree relatives family history
Bipolar disorder II (brother)
Weight gain (BMI 32 to 34 within 3 months)
Dizziness (initial, spontaneously remitting)
Last failed SRI trial
Fluoxetine 60 mg/day
Sertraline 200 mg/day
Fluoxetine 60 mg/day
Amitriptyline 300 mg/day
Fluvoxamine 250 mg/day
Duloxetine 120 mg/day + CBT
Main clinical features/OC symptoms
Hoarding/insertion of thought and intrusive images with sexual contents/checking
Fear of losing control toward food (in absence of BED)
Y-BOCS total score (baseline to week 12)
Remission: 21 to 9
Remission: 32 to 11
Remission: 22 to 8
Actual, subjective circadian rhythms impairment (BRIAN)
Any relevant disruptions
Reported stable insomnia
Any relevant disruptions
Any relevant disruptions
Reported daily hypersomnia and nocturnal awakening
Any relevant disruptions
Lifetime bipolar spectrum signs (TEMPS-A at week 12)
Any specific (but presence of PD)
Poor insight feature (BABS, baseline-week 12)
The second patient was a 44-year-old trader who received his first diagnoses of OCD, impulse control and substance abuse disorders at the age of 36. His OC symptoms were essentially represented by repetitive belching compulsions and fear about losing self-control in the presence of other people, especially his customers, with consequent impact on his ability to work. The typical OCD egodystonic characteristic was almost lost over the years, leading to trials of multiple SRI prescriptions (including clomipramine 300 mg/day and other tricyclic antidepressants (TCAs)) augmented with the typical antipsychotic pimozide (4 mg/day) for the 'poor insight' feature (confirmed by a baseline BABS total score of 28 with 'conviction' item score = 4, the maximum possible score, inversely related to insight of illness). His last SRI prescription was sertraline 200 mg/day corresponding to a Y-BOCS score of 21 (HAM-D21 = 15; HAM-A = 16; BRIAN 'seldom' = acceptable in most of the domains but with severe, stable subjective initial insomnia already unresponsive to benzodiazepines (BDZs) and antihistamine drugs) prior to a 2 week wash-out period and subsequent therapy with agomelatine 50 mg/day. Monthly scheduled Y-BOCS score measurements indicated a progressive and fast, substantial reduction (Y-BOCS at week 4 = 16; week 8 = 11; week 12 = 9; week 12 BABS of 10 and subjective improvement sleep quality according to the BRIAN) without relevant side effects. Actual pharmacological regimen, including 4 mg/day pimozide and the anticholinergic drug biperidone 4 mg/day augmentation (added to prevent extrapyramidal symptoms), was confirmed in the presence of a TEMPS-A-demonstrated anxious temperament.
The third patient was a married, 66-year-old retired woman whose OC symptoms consisted of religious obsessions, continuous rituals regarding touching holy pictures of saints in her pocket and continuative fear of cursing against God. Both cognitive status and insight of illness (as measured by a BABS total score of 11) were maintained without any significant personal or familial medical or psychiatric anamnesis. The patient showed her first symptoms at the age of 57 when she experienced the loss of her only daughter, a nun. When the patient retired from her occupation (teacher) at the age of 60 she progressively experienced a worsening of her symptomatology, which became more time consuming until she finally sought medical care. She underwent different 'adequate' SRI trials (both with TCAs and SSRIs) prior to being treated with fluoxetine 60 mg/day. Before being switched to agomelatine 50 mg/day (after the 3 week wash-out period for fluoxetine), her symptomatology was quantified as Y-BOCS = 22, HAM-D21 = 23 and HAM-A = 25, while the BRIAN scale showed a predominant 'activity' pattern impairment ('sometimes') but not a remarkable impairment of sleep pattern. None of the subsequent observations showed modification in the reference scores apart from HAM-A, which was reduced by 2 points (HAM-A = 23) after the 12 week follow-up assessment; her week 12 BABS score was 10 and Y-BOCS = 22 at baseline. Analogously, administration of TEMPS-A did not show any relevant temperamental feature.
The fourth patient was a 53-year-old painter who developed her first OC symptoms at the age of 20. The patient also reported a history of bulimia nervosa (BN) diagnosed at the age of 24 (apparently spontaneously recovered after 8 years) and a lifetime history of panic disorder (PD) diagnosed by the age of 21. Her OC symptoms, mainly consisting of hoarding, insertion of thought (sexual images when painting fruits or other objects which shape could resemble her the male genitals) and checking rituals were very disabling and she said they might have eventually lead her to 'commit suicide to stop her sufferance. The patient had a firm insight of illness (baseline BABS total score = 9). The patient was treated with CBT from the age of 29, leading to repetitive failure and a final cessation of any psychotherapeutic support. She started her pharmacotherapy with amitriptyline 300 mg/day at the age of 44 exhibiting a transient response. Although reporting an episodic course of anxious illness (instead of a chronic waxing course) and BN and PD predictive factors, she had no personal or familial history for bipolar disorders (BD) but had a TEMPS-A result suggestive for cyclothymic temperament, despite absence of manic switch history even at considerable TCA doses without mood stabilizers. Before being switched to agomelatine 50 mg/day (after 2 week wash-out period for amitriptyline), her symptomatology was quantified by Y-BOCS = 27, HAM-D21 = 23 and HAM-A = 17 scores, while the BRIAN scale result showed a predominant 'social' pattern impairment ('often' = most of the time) but not sleep core disruptions. Over the whole 3 month follow-up, agomelatine was not associated with any side effects, including (hypo)mania, but was not related to any clinical improvement either (at week 12, Y-BOCS = 26 and BABS = 9).
The patient decided to return to her psychotherapist, disregarding the advice of waiting longer for a potential onset of action of the pharmacological treatment, switching to an atypical antipsychotic, or the suggestion of a combined approach.
The fifth patient was a 25-year-old student who experienced his first OC symptoms at the age of 15, predominantly consisting in checking behavior (door locks, gas knobs on the cooker and so on) and repeating, schizotypal-like (baseline BABS = 13) rituals (for example, mentally counting pairs of numbers in a 10 min period every 3 h). Considering the age of the subject and the early onset of the symptoms, OCD appeared severe, as confirmed by a Y-BOCS total score of 32 even after an 8 month trial with fluvoxamine 250 mg/day, with relevant social withdrawal and (law) college course abandonment associated with daily hypersomnia and nocturnal awakening. No familial or personal comorbidities were shown. At that point, his HAM-D21 total score was 25, HAM-A = 39 and BRIAN results showed almost constant 'chronotype' and 'sleep' disruptions. After a 2 week SSRI wash-out period, the patient started a 50 mg/day agomelatine trial, showing a progressive, considerable remission (Y-BOCS at week 4 = 19, Y-BOCS at week 8 = 13, Y-BOCS at week 12 = 11 and week 12 BABS = 8). Almost all the OC symptoms appeared to be in remission and his circadian rhythms recovered, suggesting continuation of the same therapy in the absence of any relevant TEMPS-A temperamental cluster. Finally, no side effects were reported during the treatment.
The sixth and final patient was 33-year-old waitress who developed her first OC symptoms at the age of 24. Her obsessions were mainly related to fear of lack of control toward food. Curiously, she had no personal or familial history for any eating disorder (ED), including binge eating disorder (BED) or night eating, or any dysmorphophobic bodily perceptions, but had a personal history of PD with episodic attacks since the age of 18. She had a history of repetitive failure on antidepressant trials, with the last one being the SNRI duloxetine 120 mg/day and the BDZ clonazepam 4 mg/day for 3 months plus CBT for 6 months. At baseline, her Y-BOCS total score was 22 and BABS = 9 with HAM-D21 = 22 and HAM-A = 35. BRIAN administration did not show any relevant impairment. After a 2 week SNRI and BDZ wash-out period, the patient started a 50 mg/day agomelatine trial, showing a progressive, consistent remission (Y-BOCS at week 4 = 19; Y-BOCS at week 8 = 14; Y-BOCS at week 12 = 8 and week 12 BABS = 8). TEMPS-A temperamental evaluation did not show any relevant cluster. Finally, the patient accepted continuing the therapy; no side effects were reported during the treatment but modest, transient, self-remitting dizziness despite a progressive downtitration of venlafaxine prior to the agomelatine switch. She experienced no panic attacks during the whole period she was taking agomelatine.
In the present case series the efficacy of a 12 week trial of agomelatine (50 mg/day) has been assessed in six patients refractory to previous treatments with SRIs, with and without other psychiatric comorbidities. At the end of the treatment, three out of six patients showed a clinical improvement with a symptom reduction ≥35% over the pretreatment Y-BOCS scores, which is considered a significant treatment response in current clinical trials .
Although recently introduced, agomelatine appears to be an effective MDD treatment , but to date there has been no investigation with regard to its potential role in the management of OCD.
However, the 5-HT2C modulation and subsequent norepinephrine and dopamine firing disinhibition (NDDI action) at the prefrontal cortex, with reduction of stress-induced increase of glutamate via synergy with melatonergic and 5-HT2C receptor-dependent pathways , as well as the influence of MT1 and MT2 agonism (which in case of agomelatine is a mechanism predominant toward the 5-HT2C blockade) on circadian rhythms (impaired in some OCD cases), might suggest a potential role of agomelatine in the management of anxiety disorders, including OCD, as already analogously proposed for SAD  and PD .
Additionally, the efficacy of SRIs, including the widely prescribed SSRIs, for mood and anxiety disorders has been questioned , prompting the exploration of other classes of drugs including NDDIs with proof of direct 5-HT2A stimulating action, such as trazodone, mirtazapine and agomelatine.
With regard to the dose of agomelatine for OCD, there is no actual evidence to suggest starting at 50 mg/day or its initial introduction at 25 mg/day, although agomelatine has been reported to be a generally well tolerated treatment without the need for a specific uptitration . Additionally, OCD is a generally harder to treat condition compared to MDD as is shown by the fact that acceptable response rates (Y-BOCS ≤35%) are lower than the corresponding ones adopted for MDD remission (HAM-D17 ≤50%), and that the clinical practice often suggests the use of higher doses of (serotonergic) drugs for OCD in comparison to MDD (the approved range for agomelatine is 25-50 mg/day).
While the determination of appropriate dosage of agomelatine in course of SRI-refractory OCD is beyond the scope and possibilities of this report, it is likely that a 'dose bias' might further influence the validity of these very preliminary results, already conditioned by methodological issues, a tiny, heterogeneous sample size and short follow-up. Additionally, a number of issues, including OCD subtype (for example, 'hoarding') and comorbidities (for example, severe mood disorders and other anxiety disorders) and bipolar-related temperaments, could also account for the therapeutic outcome.
Nonetheless, it remains unclear if and how the presence of impaired circadian rhythms such as sleep disruption (or even other features as seasonal course of illness) might influence the therapeutic response of OCD especially considering the lack of objective neurophysiological monitoring. In fact, in this report agomelatine appeared effective for those SRI-refractory OCD patients who also subjectively reported impaired sleep (none of them had TEMPS-A findings, but there was 'anxious temperament' in one case (patient 2), and the presence of a cyclothymic temperament in the absence of impaired circadian rhythm (patients 1 and 4)) was associated to refractoriness to agomelatine within 3 months of 50 mg/day therapy. This appears to be consistent with evidence in the current literature pointing out a lack of response to antidepressants (usually to SRIs) among those (OCD and/or MDD) patients with 'soft bipolar' characteristics, including 'cyclothymic sensitiveness' and 'interpersonal sensitivity' (inability to accept refusal from the ex-fiancé) or 'sensation seeking behavior' (cocaine use) . Other clinical features such as behavioral addictions, substance abuse, impulse control disorders, bulimia, comorbidity with PD (for example, patient 6), sexual/religious obsessions, late onset of OC symptoms after grief (for example, patient 3), concomitant depression (high scores on the HAM-D) might also be accounted for by potential 'hidden bipolar' signs or as generic factors responsible to antidepressant refractoriness among OCD patients.
As consequence, even the consideration of a SRI switch in favor of agomelatine among OCD refractory patients should prompt for attentive evaluation of subthreshold bipolarity and eventually suggest an early administration of lifetime screening instruments such as TEMPS-A along with a more accurate clinical interview or a prompt consideration of mood stabilizers such as lithium, antiepileptic drugs and atypical antipsychotics. Nonetheless, further investigations should assess whether agomelatine might be less prone to induce (hypo)mania in comparison to standard antidepressants, as indirectly suggested by criteria '2a' and '2b' for 'rhythm regulator' recently proposed by Fountoulakis .
Among those with impaired circadian rhythms prior switching to agomelatine (all were remitters at week 12), it should be noted that agomelatine has already been associated with early recovery of sleep disruption when associated with MDD . Circadian rhythm restoration usually precedes the 'antidepressant' response in comparison to other classes of antidepressants, which in turn might be associated with circadian rhythm disruption . Nonetheless, considering the absence of objective recording and the intrinsic limitations of current rating instruments  it is difficult to discriminate whether the subjective amelioration of circadian rhythm should also be perceived as an improvement of affective and/or anxious symptoms (this might be the case of patients 2, 5 and 6), as this remains a major task to be assessed by further controlled investigations.
Other concerns regard the augmentation strategy adopted for patient 2: in fact, it is difficult to understand if and how the presence of an incisive D2 blocker, first generation antipsychotic (pimozide) could have favored (or eventually induced per se) the response during agomelatine treatment in the presence of PI-OCD.
Gender and age could also influence the OCD response to SRIs  and this should be valid also for agomelatine, as potentially occurred in patient 3. Similarly, life stress may lead to mood and/or anxiety disorders (including OCD) by causing disruptions in individuals' social routines and, in turn, their biological rhythms according to the 'social zeitgeber' theory , eventually representing OCD features more favorably responding to MT1 and MT2 agonists such as agomelatine (patient 5) .
Indeed, many other factors may influence the clinical presentation of OCD and its putative response to agomelatine. Among others, the role of concomitant psychotherapy (CBT) might be better investigated. However, in this case series it does not appear to be a confounding factor influencing the outcome of agomelatine treatment, since patient 6 receiving psychotherapy had already been treated with CBT for at least 6 months in the course of SRI treatment(s).
With regard to the side effects experienced during agomelatine treatment, weight gain (patient 1) appears to be an unexpected occurrence. In fact, agomelatine is considered generally safe regarding weight gain, especially versus SRIs , which the patient had already been taking for about 4 years prior to the agomelatine switch without experiencing significant weight gain. Also, patient 1 showed a slight reduction of body weight just after 1 month of therapy with lithium carbonate and quetiapine, an atypical antipsychotic drug which also blocks the 5-HT2C receptors via its principal active metabolite (norquetiapine) and also acts as an antihistamine and 5-HT2A blocker . However, the effective role of 5-HT2C blockade on weight gain is still under debate as it may also observed that the use of 5-HT2C stimulants has been proposed for obesity, which on turn appears to occur more frequently among individuals reporting sleep disturbances . Nonetheless, in this case the effect of mood stabilization appeared to be the most effective antiobesity therapeutic intervetion.
Concerning dizziness, experienced by patient 6, this appears to be a known issue potentially occurring with the beginning of an agomelatine trial . Nonetheless, when it occurs, it is supposed to be due to a 'flu-like' syndrome (for example, dizziness, general malaise, fever, diarrhea) associated with sudden serotonergic (especially SSRI) withdrawal and consequent rebound syndrome, hypothetically due to abrupt interruption of 5-HT2A postsynaptic stimulation (in the presence of SRI-upregulated receptors) as it may happen even with agomelatine, which is proof of (direct) 5-HT2A stimulating action malaise . However, in case 6, the patient was prudently downtitrated from the SNRI venlafaxine and the BDZ clonazepam so that dizziness appeared as an unexpected occurrence, which in this case was speculated to be due to a peculiar cerebellar sensitivity of MT1 and MT2 neurons. Remarkably, the degree of severity of transient, self-remitting dizziness did not preclude continuation of agomelatine.
Finally, despite a number a methodological and clinical constraints and the very preliminary nature of the results, further controlled studies are warranted to assess the efficacy of agomelatine in course of OCD, with more accurate methodological investigation od the eventual role of circadian rhythm imbalance, even in the course of drug-naïve cases with no other relevant comorbidities.
Written informed consent was obtained from the patients for publication of this article.
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