*3.1. Literature Search*

The search yielded 181 papers. One additional paper was added after checking the reference lists of included papers [12]. Based on the title and/or abstract, 154 of these were excluded because of the following reasons: animal studies (*n* = 14), not referring to OCD (*n* = 61), not referring to DBS (*n* = 15), not referring to CBT (*n* = 28), not in English (*n* = 10) and other reasons (including the absence of an abstract) (*n* = 17). The remaining 28 papers were read in full. An additional 19 of these were excluded due to the following reasons: not referring to CBT (*n* = 11), not referring to DBS (*n* = 1) and other reasons (*n* = 7). Eventually, 9 papers were included in the review: three randomized controlled trials (RCTs) [13–15], one cohort study [16], one case series [12], one qualitative study [17], one systematic review [18] and 2 narrative reviews [19,20]. These reviews were focused on the efficacy of DBS for OCD and not on the efficacy of CBT after DBS for OCD. Two of the included papers were based on the same RCT [13,14] (see Figure 1 for a PRISMA flowchart). The quality assessment of these studies are displayed in supplementary Table S1. The included systematic and narrative reviews are not discussed in the 'results' section since they did not include other relevant papers than the ones discussed below.

**Figure 1.** PRISMA flow diagramme. Abbreviations: OCD = obsessive compulsive disorder; DBS = deep brain stimulation; BT = behavioral therapy.

### *3.2. Description of Included Studies*

The first RCT, by Denys et al. (2010) was a double-blind, sham–controlled, clinical trial of DBS of the nucleus accumbens (NA) that included 16 therapy resistant OCD patients [13]. In this study, refractoriness was defined as no or insufficient response to treatment with at least 2 different selective serotonin reuptake inhibitors (SSRIs) at maximum dosage for at least 12 weeks, treatment with clomipramine hydrochloride for at least 12 weeks with adequacy of treatment established by plasma levels, one augmentation trial with an atypical antipsychotic for 8 weeks in combination with an selective serotonin reuptake inhibitor, and at least 16 sessions of CBT [13].

Design: The study had 3 sequential treatment phases: an initial open phase, starting immediately after electrode implantation and lasting for 8 months, in which stimulation parameters were optimized and CBT was started. DBS was administered per protocol, with restricted stimulation settings at 90 μs, 130 Hz and a maximum stimulation intensity of 5.0 V. The effects of DBS were assessed with the Y-BOCS for obsessions and compulsions, with the Hamilton Anxiety Rating Scale (HAMA) for anxiety symptoms, and with the Hamilton Depression Scale (HAMD) for depression. After this open phase, a 1-month, double blind, sham-controlled phase started in which patients were randomly allocated to 2 periods of 2 weeks with the stimulators blindly turned 'on' (active stimulation) or 'off' (sham stimulation). CBT was continued throughout this phase. The double-blind phase was followed by a 12-month maintenance phase in which the stimulator was turned on for all patients and settings adjusted as required. Patients were allowed to use psychopharmacological medication during the trial.

Effectiveness: Stimulation in the initial open phase resulted in a mean decrease of 46% in Y-BOCS score from 33.7 (baseline) to 18.0 points; a mean decrease of 52% on the HAMA score from 20.9 (baseline) to 10.1 points, and a mean decrease of 46% in HAMD scores from 19.5 (baseline) to 10.5 points. Without stimulation, the improvement gained with the addition of CBT disappeared rapidly, suggesting that efficacy of CBT depends on stimulation. In this double-blind phase, the mean difference in Y-BOCS score between the active and sham condition after correction for period effects was 8.3 (*p* = 0.04). The mean difference in HAMA scores was 12.1 (*p* = 0.1) and the difference in HAMD scores was 11.3 (*p* = 0.01). It was reported that CBT was particularly effective in decreasing compulsions and avoidance behavior.

Mantione et al. (2014) performed a secondary analysis of this same RCT that was aimed at quantifying the added treatment effect of CBT after DBS, as well as to discuss the methodology of the CBT programme used (see above) [11]. The average decrease on the Y-BOCS after optimization of stimulation settings was 25%. With the addition of 24 weeks of CBT to ongoing DBS treatment, there was an additional 22% decrease of total Y-BOCS score (*p* = 0.021), without any additional effects on the HAMA or HAMD scores. The number of responders after CBT increased from 6 to 9 out of 16.

Timing: CBT was added when three conditions were fulfilled: an initial and substantial decrease (on average 6 points) in Y-BOCS score had to be obtained, there had to be no further decrease in Y-BOCS during three consecutive visits (which was usually after 8 weeks of stimulation), and it had to be observed that patients avoided resisting their compulsions or avoided anxiety-provoking exposure situations.

Procedural aspects: The CBT program consisted of 24 weekly individual face-to-face sessions of 60 min each. The protocolized treatment started with an extensive evaluation of the patient's motivation. Once motivation was established, therapy started with ERP and gradually introduced more cognitive elements at later stages [14,21].

Tyaghi et al. (2019) performed a randomized, double-blind counterbalanced comparison of DBS of the anteromedian subthalamic nucleus (STN) and ventral capsule/ventral striatal (VC/VS) stimulation in 6 patients [12]. In this study, treatment resistance was defined as no sustained benefit from treatment with at least two SSRIs for a minimum of 12 weeks at optimal doses, augmentation of SSRI treatment with an antipsychotic or extension of the SSRI dose beyond recommended limits, and at least two trials of CBT with a minimum of 10 sessions, of which one as inpatient.

Design: the study consisted of two phases: an initial randomized phase of 12 weeks with stimulation of either the STN or the VC/VS, followed by an open phase in which both targets were stimulated. Stimulation was started after a mapping session at 60 μs and 130 Hz, without restrictions for stimulation intensity and also allowing stimulation of di fferent contact points, both monopolar and bipolar. Next, there were two additional 12-week open phases: in the first one stimulation settings were optimized using data from previous phases. In the second phase, CBT was added to optimized DBS using the combined VC/VS and STN targets.

E ffectiveness: Psychopharmacological treatment was allowed and kept constant during the trial. Overall, the score on the Y-BOCS reduced by 60%, from 36.2 at baseline to 14.3 when optimal stimulation settings were administered. Adding in-patient CBT resulted in an additional decline of the Y-BOCS score by 35% to 9.3 (*p* = 0.09; total decline from baseline 74%). Although obsessions and compulsions improved significantly from baseline to optimal stimulation, there was no statistically significant added improvement after CBT. Scores on the Montgomery–Asberg Depression Rating Scale (MADRS) declined from 28 at baseline to 13 during optimal stimulation settings and further reduced to 7 after CBT (information from the authors). The authors conclude that there is no further improvement in obsessions and compulsions due to CBT after optimal stimulation settings, and that this reflects a 'floor e ffect' of DBS on OCD. With 'floor e ffect' they intend to say that no further improvement of OCD symptoms would be possible after optimization of stimulation settings.

Timing: CBT was started standard after 24 weeks

Procedural aspects: CBT, including ERP, was applied in an inpatient unit while optimal stimulation settings were maintained.

Greenberg et al. (2006) report on the long-term (>3 years) follow-up of 10 therapy-resistant OCD patients being treated with VC/VS DBS [16].

Effectiveness: The average Y-BOCS score declined by 35% from 34.6 preoperatively to 22.3 after three years of DBS. All pharmacotherapy was allowed, but kept constant up to three months after the start of DBS treatment. The information provided in the paper does not allow to calculate the added e ffect of behaviour therapy to DBS on OCD symptoms. Clinically, the authors describe a 'notably enhanced motivation to engage in goal directed activities' during DBS, which also included enhanced motivation for CBT, which all patients had attempted unsuccessfully before the procedure. They consider that this increased motivation may have been a key factor in the patients' clinical progress.

Timing: If patients had had behavior therapy immediately prior to DBS, this was allowed to continue after the start of DBS; if behavior therapy was newly indicated, it was allowed to start only six months after the start of DBS. No details on the number of patients that received behavioral therapy postoperatively is given, nor details about the type, frequency, duration and way of delivery of the behavioral therapy.

Procedural aspects: There is no information on procedural aspects.

Abelson et al. (2005) reported a case series of 4 therapy resistant OCD patients being treated with DBS of the anterior limb of the internal capsula, with the tip of the electrode adjacent to the nucleus accumbens [12]. After operation, a 12-week double-blind testing stage was followed by an open-ended, open stimulation phase, with e fforts to optimize results by adjusting stimulation settings and by pharmacotherapy and CBT. No further details on the e ffectiveness, timing and procedural aspects of CBT is given.

The qualitative study by van Westen et al. (2019) reports on the results of interviews with 8 professionals involved in DBS treatment of OCD patients, as well as experiences from embedded patient observation of the author [17]. These professionals identified the process in which patients become increasingly engaged in their process of improvement as an important predictor of e ffect. As the patient changes, new possibilities emerge, one of which is renewed treatment with CBT, to reduce remaining symptoms and expand healthy behavioral repertoires [17].
