|Ahead of print publication
Are there neuropsychological predictors for response and nonresponse in first-episode drug naïve patients with OCD? A 12 weeks interventional study
Jasmine Brar, Ajeet Sidana, Nidhi Chauhan, Manoj Kumar Bajaj, Sumeesha Jaswal
Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India
|Date of Submission||10-Jun-2022|
|Date of Decision||16-Jul-2022|
|Date of Acceptance||07-Jul-2022|
|Date of Web Publication||19-Jan-2023|
Department of Psychiatry, Government Medical College and Hospital, Chandigarh
Source of Support: None, Conflict of Interest: None
Background: Obsessive–compulsive disorder (OCD) is a common, chronic debilitating disorder. A detailed neuropsychological assessment at baseline might help us to identify the various neuropsychological predictors for response and nonresponse. Aim: The identification of neuropsychological predictors for response and nonresponse in patients with OCD. Materials and Methods: Patients with a diagnosis of OCD (Diagnostic and Statistical Manual 5th edition), first episode, and treatment naïve were evaluated for neuropsychological functioning with the National Institute of Mental Health and Neurosciences Neuropsychological Battery-2004, and the severity of OCD on the Yale-Brown Obsessive–Compulsive Scale (YBOCS). After baseline assessment, patients received either sertraline or fluvoxamine at a maximum tolerable therapeutic dose and were reassessed after 12 weeks for a response. Results: A total of 50 patients (25 in sertraline and 25 in the fluvoxamine group) were included in the 12 weeks study. The majority of the patients had adequate baseline neuropsychological functioning except for inadequacy in the category and verbal fluency, and the mean baseline total Y-BOCS score was 23.48 (standard deviation = 6.29). Out of 50 patients, 36 (72%) patients showed a response to the treatment. The correlation analysis showed that except for the N-1 hits variable, in the Verbal N Back test for working memory, which correlated significantly with a reduction in YBOCS score across 12 weeks, none of the other neuropsychological domain scores were correlated with the outcome. Conclusion: The index study concludes that working memory is significantly correlated with the response at 12 weeks. However, there are no other neuropsychological predictors for response and nonresponse in patients with OCD.
Keywords: Neuropsychological predictors, nonresponse, obsessive–compulsive disorder, response, selective serotonin reuptake inhibitors
|How to cite this URL:|
Brar J, Sidana A, Chauhan N, Bajaj MK, Jaswal S. Are there neuropsychological predictors for response and nonresponse in first-episode drug naïve patients with OCD? A 12 weeks interventional study. Ann Indian Psychiatry [Epub ahead of print] [cited 2023 Feb 3]. Available from: https://www.anip.co.in/preprintarticle.asp?id=368088
| Introduction|| |
Obsessive–compulsive disorder (OCD) is a common, chronic debilitating disorder with a lifetime prevalence of 1%–3%. Although the progress in the management of OCD has resulted in many pharmacological and non-pharmacological methods, the issue of response rate in OCD remains worrisome. As per estimates, approximately 40%–70% of patients show an adequate response to the first trial of SSRI, the first-line drug therapy in OCD, with a remission rate of 10%–40%. The response rate to the subsequent trial of SSRI decreases further to 0%–20%. This has motivated researchers to investigate factors, that might predict future responses to treatment. Many studies have reported certain clinical parameters such as age at illness onset, illness severity, total illness duration, past hospitalizations, gender, insight, subtypes of OCD, presence of other psychiatric comorbidities such as tics, family history, and others, that could predict response to treatment in OCD.,,,
There is evidence that neuropsychological functions in patients with OCD are poorer than the general population with impairments in more than one domain of neuropsychological functions., Impairments in response inhibition, set-shifting, fluency, processing speed, and working memory have been reported.,,,, Although a few studies report no significant difference in neuropsychological functions between patients with OCD and matched healthy controls.,, Various studies have looked for associations between these functions and illness-related variables. Some studies reported no correlation between neuropsychological functions and duration and course of illness, average dose of drug, symptom severity,, comorbid psychiatric conditions. Furthermore, according to research, cognition might be an area of particular vulnerability to the negative effects of the anti-obsessional drugs and the neuroanatomically-based approaches (neurosurgery and deep-brain stimulation). Although there is literature to refute this and reports a strong correlation between neuropsychological functions and symptom severity in early-onset OCD. It is important to evaluate this association between neuropsychological functions and response treatment as it might play a mediating role in clinical symptomatology and treatment response. Hence, the current study was planned with the aim to assess detailed neuropsychological functions at baseline in drug naïve first-episode patients with OCD, to evaluate the correlation between neuropsychological functions and treatment response, and to thereby assess if any of these neuropsychological parameters predict response/nonresponse to treatment.
| Materials and Methods|| |
The study was undertaken at the Department of Psychiatry of a tertiary-care teaching hospital in Northern India. The Department of Psychiatry runs daily Walk-in-Clinic (WIC) for patients coming to OPD for the first time. The Principal Investigator (JB) contacted the Senior Resident in WIC for the enrolment of patients with a diagnosis of OCD according to the Diagnostic and Statistical Manual 5th edition. In addition, these patients were ought to be of the first episode, drug naïve, in the age range of 18–55 years, and willing to give written informed consent for participation in the study. Verbal inquiry from the patient as well as family members with regard to the previous episode of illness as well as any previous consultation taken, or medications taken, was made. Patients having other comorbid psychiatric illnesses of diagnosable severity, intellectual disability, neurological disorder, organic brain syndrome, epilepsy, dementia, substance dependence except for caffeine and nicotine, pregnant and lactating females, actively suicidal patients, and those with severe/unstable medical or surgical illnesses were excluded. Electrocardiography and various laboratory investigations, including hemogram, renal function tests, liver function tests, thyroid profiles, and metabolic profiles were carried out to screen patients for any undiagnosed medical illness.
The study participants were recruited through consecutive sampling methods from January 2019 to November 2020. A total of 64 participants have included in the study and out of which 50 participants completed the 12 weeks study period. Lifetime prevalence of OCD in the Indian population is around 0.6%. Since there was no study on neuropsychological predictors of response and non-response in OCD from India, a conservative sample of 50 patients with the first episode of OCD was taken. A final analysis of 50 participants was performed.
Sociodemographic and clinical characteristics of participants were recorded in a semi-structured pro forma developed for the study. The Yale-Brown Obsessive–Compulsive Scale (YBOCS) and YBOCS checklist were used to assess baseline illness severity and obsessive–compulsive symptom subtypes. The baseline neuropsychological functioning of participants in the domains of mental speed, sustained attention, verbal fluency, category fluency, working memory, response inhibition, and set shifting were assessed using tests of Digit Symbol Substitution Test, Digit Vigilance Test, Controlled Oral Word Association Test, Animal Names Test (ANT), N back tests, Stroop Test, and Wisconsin Card Sorting Test, respectively, from the National Institute of Mental Health and Neurosciences (NIMHANS) Neuropsychological Battery-2004. Following this, participants were randomized using computer-generated random number table to receive either sertraline or fluvoxamine, on an initial dose of 50 mg/day, which was gradually escalated to achieve the maximum tolerable therapeutic doses by the end of 4–6 weeks. Thereafter, participants were continued on the same dose, till the completion of the study period, i.e., 12 weeks. Verbal inquiry from the patient as well as family members was made to assess the compliance with medications. At 12 weeks, participants were assessed for response to treatment, defined as ≥35% reduction in their YBOCS scores. At this point, the sample was divided into two groups to achieve the objectives laid down for the study, "responders" (i.e., achieving at least a 35% reduction in Y-BOCS score) and "non-responders" to pharmacological treatment. The scores of more than 15 percentiles of the norms as per the NIMHANS battery were taken as adequate. The Institutional Ethics Committee approved the study. The confidentiality of patient information was maintained, and principles laid down by the Declaration of Helsinki and the Indian Medical Council of Research were adhered to., Study was registered with the Clinical Trial Registry of India (CTRI/2020/01/022890).
The sociodemographic and clinical characteristics of responders and nonresponders were compared using an independent t-test and Chi-square test for the continuous and categorical variables, respectively. The baseline neuropsychological scores were correlated (Pearson correlation) with a mean percentage reduction in the YBOCS scores across 12 weeks. Significant correlations, if any, were intended to be analyzed with linear regression to investigate the possible neuropsychological predictors of drug response. All statistical analyses were conducted using the Statistical Package for the Social Science (SPSS for Windows, Version 16.0. Chicago, SPSS Inc.).
| Results|| |
The total sample consisted of 50 participants, including 26 females (52%) and 24 males (48%). The mean age was 31.90 (standard deviation [SD] = 8.53) years, the mean age at onset of OCD was 25.33 (SD = 8.66) years, and the mean duration of OCD was 6.64 (SD = 5.61) years. The mean baseline total Y-BOCS score was 23.48 (SD = 6.29), indicating moderate severity of OCD. Out of the total sample, 86% of participants had insidious onset, with more than half (58%) having a continuous course and almost all (96%) had full insight into their illness. A small percentage of patients (2%) had a history of hypertension, which was well controlled on anti-hypertensives. Family history was significant in 4% of the participants who had a history of OCD in their first-degree relatives. At baseline, the majority of the participants had adequate neuropsychological functioning in all domains except verbal and category fluency.
At the study endpoint, i.e., 12 weeks postinduction into the study, 36 (72%) participants showed response to the treatment, defined as ≥35% reduction in the YBOCS scores. The comparison of sociodemographic and clinical details of responders and nonresponders is depicted in [Table 1].
There were no significant differences in any of the sociodemographic and clinical characteristics of the two groups, as shown in [Table 1].
Almost half of the study participants (54%) had obsessive doubts about contamination and an equal number (54%) had cleaning/washing compulsions. Obsessions with a need for symmetry/exactness were the least common present in 2% of participants. Counting compulsions were present in 6% of participants. There were no significant differences between responders and nonresponders on clinical subtypes of OCD.
The number of responders was significantly higher in the fluvoxamine group (22 patients) as compared to the sertraline group (14 patients) at 12 weeks (Pearson Chi-square = 6.39; P = 0.012). The average maximum tolerable therapeutic dose of sertraline and fluvoxamine was 196.00 mg and 284.00 mg per day, respectively.
There was also a statistically significant difference (P ≤ 0.001) in the reduction of the mean Y-BOCS score on comparing the baseline mean YBOCS score (23.48 ± 6.29) and at 12 weeks (12.88 ± 8.37). The differences observed in the mean reductions in YBOCS scores, between the two drug groups, were found to be statistically insignificant at all assessment points. Furthermore, the neuropsychological functioning after 12 weeks of treatment was comparable between the two drug groups, with no significant difference observed.
The study results compared the baseline neuropsychological functioning of responders and nonresponders and found that there was no significant difference between the two groups and also no significant association between adequacy of neuropsychological test performance, defined as ≥15 percentile scores on neuropsychological tests as per normal population norms, and outcome of treatment across 12 weeks, as shown in [Table 2].
|Table 2: Comparison of baseline neuropsychological test findings of responders and nonresponders|
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The correlation analysis between baseline neuropsychological test scores of the responders and nonresponders, with the mean percentage reduction in the YBOCS scores across 12 weeks of treatment, showed that none of the neuropsychological domain scores was linearly related to the outcome, as shown in [Table 3].
|Table 3: Summary of correlation results between neuropsychological performance and clinical response|
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The only single variable, N-1 hits, in the Verbal N Back test for working memory, correlating significantly with reduction in YBOCS score across 12 weeks, in the responder group, was analyzed using linear regression. The results showed an R2 = 0.001.
| Discussion|| |
The current study was carried out with the research question of, are there neuropsychological predictors for response and nonresponse in the first episode drug naïve patients with OCD? To get the answer, the baseline neuropsychological functioning was carried out and correlated with a reduction in severity scores on YBOCS, across 12 weeks of treatment with selective serotonin reuptake inhibitors in an open-label trial.
The mean age of patients and mean age at onset of illness in the current study are consistent with the known bimodal distribution in the age at onset. Slight female preponderance, majority of patients having insidious onset and continuous course of illness and having insight in the index study is consistent with findings in the literature.,, The most common types of obsession observed in the current study were those relating to dirt and contamination and cleaning/washing compulsions were present in the majority of participants. This is well in line with the previous analyses of the phenomenology of OCD. The majority of the participants showed adequate functioning at baseline on most of the neuropsychological domains, except for those of category and verbal fluency. This is in contrast to research findings that indicate a neuropsychological deficit in OCD,,, and even to those studies which report no neuropsychological impairment in OCD.,, The two groups, i.e., responders and nonresponders did not differ concerning their sociodemographic variables, clinical variables, and baseline neuropsychological functioning. Although, there was a significant association between testing variables for working memory and reduction in YBOCS scores across 12 weeks in the responder group. However, none of the other baseline neuropsychological functions correlated with mean Y-BOCS score reduction at 12 weeks. Thus, baseline working memory could exert an influence, such that it could predict future responses in patients with OCD and which substantiate observation of another study.
A study by Ravizza et al. evaluating 53 patients with OCD for 6 months, showed that nonresponders to treatment had a longer duration of illness, earlier age of onset, followed a chronic course with multiple hospitalizations, had a higher frequency of compulsions, washing rituals and had a concomitant schizotypal personality disorder. Similar results have been shown in a study by Alarcon et al. The current study findings do not resonate with any of these studies as the responders and nonresponders had comparable sociodemographic and clinical characteristics. The potential reasons could be the inclusion of a highly selected patient population with a single psychiatric diagnosis of OCD, shorter study duration, and most importantly, the patients were drug as well as treatment naïve. The latter factor is important as it automatically rules out variables like previous hospitalizations and leads to comparatively shorter illness duration before these could establish themselves as predictors to the response. The results showed no predominance of a specific clinical subtype of OCD, concerning responders and nonresponders and understandably could not qualify as predictors.
A 12 weeks study by D'Alcante et al. showed that better scores on tests of verbal working memory, response inhibition, and cognitive flexibility were predictors of good response to either CBT or fluoxetine in 38 patients with OCD. Another study by Hamatani et al. reported that diminished working memory and poor communication skill were associated with poor response to CBT in 42 nontreatment naïve OCD patients. However, patients with comorbid depression, anxiety were not excluded from these studies. Altogether, the results of our study that the level of working memory might influence treatment outcome, is somewhat similar to the findings of these studies., Other than this, there were no other neuropsychological predictors for response and nonresponse in patients with OCD.
Overall, the potential explanation for these results might also lay in the clinical characteristics of participants of the current study. These include the moderate illness severity, treatment naïve status, presence of no other axis 1 disorder, and relatively lesser duration of illness that usually affect neuropsychological functioning, which could, in turn, influence the treatment outcome. These factors also accentuate the strength of this study as these tend to reduce confounding. There is also variability in the type of tests chosen for assessing neuropsychological functions that might have resulted in the disparity between results when compared to results from the referred studies.
Although the index study was planned with a reliably sound methodology and use of standardized neuropsychological tasks, still has a few limitations. These include a small sample size, shorter study duration, lack of allocation concealment, and incidental inclusion of participants with moderate illness severity. Further, the control group was not included, and multiple analyses have been computed, which increases the chance of Type I error. The study thus invites further research in drug and treatment naïve OCD patients, with larger sample sizes, to confirm or refute these findings.
| Conclusion|| |
It can be concluded from the index study that the majority of the patients with OCD had adequate pretreatment neuropsychological functioning except for category and verbal fluency. Baseline higher level of working memory is a good predictor of response at 12 weeks. However, there are no other neuropsychological predictors for response and nonresponse in patients with OCD. Although there is a need to conduct the study in a population with severe OCD and longer duration of illness with and without axis 1 disorders and with various treatment modalities.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]