راهگاهی حسی و حرکتی و پیامدهای بالینی بدنبال رفتاردرمانی شناختی برای روان پریشی

Background Prepulse inhibition (PPI) of the startle response refers to the ability of a weak prestimulus to transiently inhibit the response to a closely following strong sensory stimulus. PPI provides an operational index of sensorimotor gating and is reduced, on average, in people with schizophrenia, relative to healthy people. Given the variable response to Cognitive Behaviour Therapy for psychosis (CBTp) and positive associations between pre-therapy brain and cognitive functions and CBT outcome across disorders, we examined whether pre-therapy level of PPI is associated with clinical outcome following CBTp. Method Fifty-six outpatients stable on medication with at least one distressing symptom of schizophrenia and willing to receive CBTp in addition to their usual treatment were assessed on acoustic PPI. Subsequently, 28 patients received CBTp (CBTp + treatment-as-usual, 23 completers) for 6–8 months and 28 continued with their treatment-as-usual (TAU-alone, 17 completers). Symptoms were assessed (blindly) at entry and follow-up. Results The CBTp + TAU and TAU-alone groups did not differ demographically, clinically or in PPI at baseline. The CBTp + TAU group showed improved symptoms relative to the TAU-alone group, which showed no change, at follow-up. Pre-therapy PPI level correlated positively with post-CBTp symptom improvement. Conclusions Relatively intact sensorimotor gating is associated with a good clinical response following a 6–8 months course of NICE compliant CBTp in schizophrenia. Pharmacological or psychological interventions capable of improving PPI may enhance the effectiveness of CBTp in people with schizophrenia, particularly in those who fail to show clinical improvement with currently available antipsychotic drugs and adjunctive CBTp.

Despite marked symptom improvement with the use of antipsychotics in acutely ill patients with schizophrenia (Kasper, 2006), the long-term outcome for up to 40% of patients remains unsatisfactory as they continue to suffer from one or more distressing symptoms despite remaining medication compliant (Conley and Kelly, 2001 and Potkin et al., 2009). Additional benefits of cognitive behaviour therapy for psychosis (CBTp) have been reported for such patients (reviews, Pilling et al., 2002, Zimmermann et al., 2005, Pfammatter et al., 2006 and Wykes et al., 2008), and symptom improvement may continue even after therapy is terminated (Sensky et al., 2000 and Sarin et al., 2011). CBTp is now recommended for the treatment of psychosis in both the National Institute for Health and Clinical Excellence (NICE) updated guidelines in the UK (NICE, 2009) and the Schizophrenia Patient Outcomes Research Team (PORT) Treatment Recommendations in the US (Dixon et al., 2010). The beneficial effects of CBTp, however, are seen with modest effect sizes and to a meaningful degree in only about 50% of patients who undergo this therapy (Pilling et al., 2002, Pfammatter et al., 2006 and Wykes et al., 2008). Uncovering the determinants of effective CBTp may a) help to maximise its benefits by targeting the most relevant population, and b) to identify methods to help those who do not show a sufficient response with current antipsychotic medications and CBTp. A number of studies have focussed on specific predictors of clinical response to CBTp (Garety et al., 1997, Kumari et al., 2009, Kumari et al., 2010, Penades et al., 2010, Premkumar et al., 2010 and Premkumar et al., 2011). Cognitive flexibility about delusions (Garety et al., 1997), better cognitive insight (Perivoliotis et al., 2010), and lower conviction scores (Brabban et al., 2009) have all been found to be predictors of a good outcome on delusional thinking. More recently, Penades et al. (2010) reported a positive association between verbal memory and clinical outcome following CBTp. Although we did not find a direct association between symptom improvement following CBTp and pre-therapy cognitive performance, assessed with a number of tests commonly employed in schizophrenia research (Premkumar et al., 2011), we did observe greater hippocampal grey matter volume in CBTp responders, compared to CBTp non-responders in the same sample (Premkumar et al., 2009). This latter finding can be regarded consistent with that of Penades et al. (2010), given the positive association between hippocampal volume and memory in schizophrenia observed across a number of previous studies (review, Antonova et al., 2004). Furthermore, our functional magnetic resonance imaging (MRI) studies have demonstrated that pre-therapy brain activity and functional connectivity between brain regions involved in cognitive flexibility and self-other distinction predict clinical outcome following CBTp (Kumari et al., 2009 and Kumari et al., 2010). Specifically, we found a positive association between CBTp responsiveness and dorsolateral prefrontal cortex (DLPFC) activity and its connectivity with the cerebellum (Kumari et al., 2009), most likely mediated by PFC–cerebellum contributions to executive processing (Bellebaum and Daum, 2007). The present study aims to further advance this field by investigating the relationship between pre-CBTp level of sensorimotor gating function, as assessed by prepulse inhibition (PPI) of the acoustic startle response, and the clinical outcome following CBTp. PPI refers to a response reduction in reaction to a strong startling stimulus, ‘pulse’, if this is preceded shortly by a prestimulus, ‘prepulse’, too weak to evoke a measurable startle response itself (Graham, 1975). PPI provides an operational index of sensorimotor gating: while information processing resources are targeted at the prepulse, any incoming information (i.e. the pulse) is attended to at reduced level, thereby protecting the processing of the initial stimulus (i.e. the prepulse) (Geyer et al., 1990). Since the first demonstration by Braff et al. (1978), a large number of studies have shown reduced PPI, on average, in people with schizophrenia (e.g. those reviewed in Braff et al., 2001, Meincke et al., 2004, Swerdlow et al., 2006 and Kumari et al., 2007), especially in those who have thought disorder (Perry and Braff, 1994 and Perry et al., 1999), hear uncontrollable voices (Kumari et al., 2008a) or have poor global functioning (Swerdlow et al., 2006). Some studies also report small-to-moderate positive associations between reduced PPI and poor performance on measures of attention (Karper et al., 1996 and Kumari et al., 2007) and executive function, in particular cognitive flexibility (Butler et al., 1991 and Kumari et al., 2007), in schizophrenia, suggesting that deficient gating may interfere with higher order cognitive function. Given these observations, and previous findings indicating that relatively intact (pre-therapy) executive processing is associated with good clinical responsiveness to CBT across many disorders, including depression (Moorey et al., 2001 and Julian and Mohr, 2006) and generalized anxiety disorder (Mohlman and Gorman, 2005), we hypothesised that there would be a positive association between pre-therapy PPI level and clinical response to CBTp in patients with schizophrenia. In addition, we explored the relationship between pre-therapy level of startle habituation and CBTp response. Reduced habituation has been found in people with schizophrenia (e.g. Geyer and Braff, 1982, Braff et al., 1992 and Takahashi et al., 2008); it is thought to reflect their inability to ignore the repetitive functionally insignificant stimuli and to result in sensory overload (Geyer and Braff, 1987 and Geyer et al., 1990).

As shown in Table 1, the final CBTp + TAU and TAU-alone groups, after the loss of some patients from each group, did not differ in age, education, IQ, age at illness onset, baseline symptoms, antipsychotic dose (all p values > 0.15) . The two groups showed comparable amplitude and habituation of the startle response over pulse-alone trials as demonstrated by a significant main effect of Block [F (3, 114) = 14.77, p < 0.001] indicating habituation of the startle response over four blocks [Linear F (1, 38) = 18.60, p < 0.001] in both groups, but no significant Group [F (1,37) = 2.25, p = 0.14] or Group × Block effect [F (1,111) = 0.52, p = 0.70]. For PPI too, there was no effect of Group [F (1,38) = 0.01; p = 0.96] indicating comparable PPI in the two groups. There was, as found in previous PPI studies, a significant main effect of Trial type [F (2, 76) = 16.18, p < 0.001], reflecting a linear increase in PPI from 30-ms through 60-ms to 120-ms prepulse trials [Linear F (1, 38) = 34.41, p < 0.001], but no Group × Trial Type interaction [Group × Trial type: F (2, 76) = 1.45, p = 0.24]. Finally, the two groups did not differ in the latencies to peak over the four trial types as there was only a main effect of Trial Type [F (3, 114) = 3.86, p = 0.01] and no Group [Group: F (1,38) = 1.58, p = 0.22] or Group × Trial type effect [F (1,114) = 1.91, p = 0.13]. Mean (s.e.m) startle amplitudes for blocks 1–4, PPI for 30-ms, 60-ms, and 120-ms trials, and mean latencies to peak over the pulse-alone and prepulse trials in the CBTp + TAU and TAU-alone groups are presented in Table 2.