Review
THEMED ARTICLE ❙ Schizophrenia
Insights into hallucinations in schizophrenia: novel treatment approaches Expert Rev. Neurother. 11(7), 1007–1015 (2011)
André Aleman†1 and Frank Larøi2 Department of Neuroscience, University Medical Center Groningen, University of Groningen, The Netherlands 2 Cognitive Psychopathology Unit, University of Liège, Liège, Belgium † Author for correspondence:
[email protected] 1
Novel strategies are needed in the treatment of hallucinations as a subgroup of patients with pathological hallucinations (>30%) do not respond to antipsychotics or are not compliant with medication. We review recently developed biological and cognitive treatments. Repetitive transcranial magnetic stimulation concerns neuromodulation targeted at aberrant activity in regions shown to be hyperactive in neuroimaging studies. Repetitive transcranial magnetic stimulation has been shown to reduce auditory hallucinations in several studies. However, not all studies have confirmed such effects, and a number of questions remain. With regard to cognitive therapeutic approaches, new proposals include attention training, acceptance and commitment therapy, and competitive memory training. After a brief discussion of these approaches, we take stock of recent advances and discuss avenues for future research. KEYWORDS : acceptance and commitment therapy • cognitive–behavioral therapy • hallucinations • schizophrenia • transcranial magnetic stimulation
Hallucinations are a prevalent symptom in schizophrenia and are experienced by 50–70% of patients at some point of the illness [1,2] . However, the presence of hallucinations is not necessary for diagnosis [3] . The pathophysiology of hallucinations needs to be fully elucidated, but advancements have been made in recent decades regarding the development of cognitive hypotheses. The advent of neuroimaging techniques has fueled research that tests such hypotheses, for example, concerning the involvement of monitoring systems or language areas. Novel treatment methods for hallucinations are also being developed. Although treatment may be primarily aimed at reducing the frequency of hallucinations, improvement can also be achieved by a reduction in the distress caused by the hallucinations. Therefore, it is also important to assess these aspects when assessing treatment efficacy. Most treatment strategies involve the treatment or management of auditory hallucinations, which are more frequent and debilitating in schizophrenia patients than hallucinations in visual or other modalities. In other words, few strategies have been developed for nonauditory hallucinations. Thus, there is clearly a need to develop treatment strategies specifically for nonauditory hallucinations, such as visual hallucinations, www.expert-reviews.com
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which may occur in up to 20% of patients with schizophrenia, and may also prove to be highly distressing and problematic for both patients and their families. Although pharmacotherapy is generally effective in treating acute psychosis and in preventing the frequency of relapse [4] , a significant proportion of patients continue to experience symptoms. Approximately 30% (estimates range from 10 to 60%) of patients who adhere to drug treatment may still experience psychotic symptoms [5,6] . Indeed, there is evidence that hallucinations can persist in 25–50% of patients even after adequate levels of medication have been prescribed [7] . Another problem with medication concerns compliance. For example, in a meta-ana lysis of studies examining the prevalence of medication nonadherence in patients with schizophrenia, Lacro et al. found a mean rate of nonadherence ranging from 41 to 50% in studies with a strict set of study inclusion criteria [8] . Thus, although antipsychotic medication remains the mainstay of psychosis treatment, the inclusion and further development of other treatment strategies is warranted. In this article, we focus on new developments in the treatment of hallucinations with transcranial magnetic stimulation (TMS) and novel cognitive therapeutic
© 2011 Expert Reviews Ltd
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approaches. As TMS is a brain-based neurostimulation technique, we will first briefly review neuroimaging findings on hallucinations in schizophrenia. Neural substrate
For auditory hallucinations, structural, as well as functional studies point to a pivotal role for the temporal lobe (see the review by Allen et al. [9]). Functional MRI (fMRI) studies have shown increased activation of the superior and middle temporal gyri. For visual hallucinations, activity has consistently been observed in the secondary visual cortex. However, it is essential to consider the fact that activation studies found a distributed network of cortical and subcortical areas implicated in an individual’s experience of hallucinations, which may also include the anterior cingulate, basal ganglia and thalamus. Integrity of the left auditory cortex has also been associated with frequency of auditory hallucinations [10] . A question of interest with regard to auditory hallucinations, which are generally verbal (i.e., involving speech), concerns the role of abnormal activation of speech circuitry. Special attention has been directed to Broca’s area, which subserves language production. Despite the fact that neuroimaging-based research has repeatedly demonstrated that primary and association auditory areas are involved, it is important to consider that several neuroimaging studies have not necessarily found auditory hallucinations to be associated with brain activation in language production areas or have only found this association to exist in a subgroup of patients [11–15] . Activation in right hemisphere homotopic language regions may also be characteristic of auditory–verbal hallucinations (AVHs) [14,16] . With regard to the phenomenological characteristics of hallucinations, sense of reality has been related to activation strength of the inferior frontal gyri (IFG), including the Broca’s language region [17] . Experienced reality may also be associated with reduced language lateralization [18] . Subjective loudness of hallucinations has been shown to be correlated with reduced task-related activity in the bilateral angular gyrus, anterior cingulate gyrus, left inferior frontal gyrus, left insula and left temporal cortex. This could potentially be due to a competition for shared neural resources [18] . A recent meta-ana lysis of ten neuroimaging studies published by 2010 integrated evidence regarding AVH-related activity from studies using PET or fMRI [19] . For meta-analysis, Jardri et al. used activation likelihood estimation by combining foci of activation reported across studies. In total, the aggregated studies included 68 patients with schizophrenia spectrum disorders and stereotaxic coordinates of 129 foci, reported to be significant activations in the source studies. Patients experiencing AVHs demonstrated significantly increased activation likelihoods in a bilateral neural network, including the Broca’s area, anterior insula, precentral gyrus, frontal operculum, middle and superior temporal gyri, inferior parietal lobule and hippocampus/para hippocampal region. Although the network was bilateral, it was more pronounced on the left, with six out of eight clusters lateralized to the left hemisphere. The authors concluded that, in addition to frontotemporal speech areas, medial temporal areas known to be important for verbal memory may also be involved in AVHs. 1008
In another meta-ana lysis, Kühn and Gallinat suggested that the neural substrate for state versus trait aspects of AVHs would differ [20] . ‘State’ studies refer to the studies that attempt to capture the precise neural signature of hallucinations by comparing periods of patient-reported presence of hallucinations versus periods of absence of hallucinations in a within-subjects ana lysis (e.g., with the button-press method). By contrast, ‘trait’ studies refer to studies that compared brain activation between groups of patients with and without hallucinations, often during a cognitive task involving verbal material. Kühn and Gallinat included ten state and eight trait studies, and after meta-analytic integration of the results concluded that state studies were associated with activation in the bilateral inferior frontal gyrus, bilateral postcentral gyrus and left parietal operculum [20] . By contrast, trait studies showed decreased activation in the left superior temporal gyrus, left middle temporal gyrus, anterior cingulate cortex and left premotor cortex. They suggest that the state of experiencing AVHs is primarily related to speech production regions, such as Broca’s area, whereas the trait that makes people prone to hallucinations is more related to brain regions involved in auditory processing and speech perception. It is not clear how the hyperactivity of temporo-parietal cortical areas in auditory hallucinations arises. Excessive dopamine neurotransmission could contribute to this, as well as increased levels of stress and arousal, which can prime perceptual areas. Frith [21] and Ford et al. [22] have suggested that hallucinations may involve dysfunction of a predictive model, in which sensory areas are primed with regard to self-generated actions, such as speaking, which enables detection and correction (if necessary) of one’s actions. That is, synchronization of neural activity preceding self-generated actions is thought to reflect the operation of the forward model, which acts to dampen sensations resulting from those actions. According to this model, pre-action synchrony should be related to subsequent sensory suppression. Deficits in such a mechanism may lead to aberrant activation of sensory areas, as the dampening does not occur, which may eventually lead to symptoms such as auditory hallucinations. Search strategy
In order to identify relevant studies with novel treatment approaches for hallucinations in schizophrenia, we searched PubMed and Web of Science from 1998 (when the latest comprehensive review on psychosocial treatments for hallucinations was published [23]) to January 2011. Search words used were “hallucinations”, in combination with “schizophrenia”, and one of the following, “treatment”, “therapy”, “cognitive behavioral” and “transcranial magnetic stimulation” or “rTMS”. We also based our selection of strategies on a recent edited volume on treatment of hallucinations [24] . Magnetic brain stimulation
Transcranial magnetic stimulation, and in particular TMS at frequencies of 1 Hz or higher, also referred to as repetitive TMS (rTMS), has been suggested as a treatment for hallucinations in schizophrenia. This treatment consists of a time-varying magnetic Expert Rev. Neurother. 11(7), (2011)
Novel treatments for hallucinations in schizophrenia
field that is generated by a current pulse through a stimulator coil that is placed at a particular locus on the scalp. The rapid switches in the magnetic field induce a flow of current in the brain tissue underneath (diameter of a2–3 cm), which causes membrane depolarization and neural activation [25,26] . In the context of hallucination treatment, 1-Hz (or slow) rTMS is usually used because it reduces brain excitability (for a review, see [27]). More specifically, the rationale is that where rTMS coils are placed, excitability of these brain areas (e.g., speech perception areas) will be reduced. By contrast, fast rTMS (>5 Hz) may enhance brain excitability and has been used in treatment for depression to boost activation of the left dorsolateral prefrontal cortex. Being one of the first treatment strategies in psychiatry that is directly inspired by neuroimaging studies, in rTMS for hallucinations the coil is generally targeted at speech perception areas located at the temporoparietal junction, which have been shown to be hyperactive in neuroimaging studies. Thus, the aim of the rTMS approach is to reduce baseline excitability in speech perception areas, which is too high according to neuroimaging studies, by applying slow rTMS – that is, stimulation at a frequency of 1 Hz. The first studies were reported by Hoffman et al. [28,29] , who found a significant reduction of hallucinations in a study that included 50 schizophrenia patients with treatment-resistant auditory hallucinations [30] . Other studies found even stronger improvements (e.g., [31]), but some failed to find significant amelioration (e.g., [32]). Most studies used rTMS over the temporoparietal junction, which is generally defined as the position halfway between the T3 and P3 electrode positions of the International 10–20 system (following Hoffman et al. [29]). In regard to the intensity of stimulation, a motor threshold of between 80 and 100% is commonly utilized, and all of the studies used a frequency of 1 Hz. Motor threshold refers to the strength of the stimulus provided, which is the percentage of the total machine output that is required to instill movement of thumb or fingers. In a meta-ana lysis of the studies up to 2007, Aleman et al. were able to include ten small sham-controlled studies, with a total number of patients of 216 [33] . All studies included a sham rTMS control condition or control group. In sham rTMS, the coil is rotated by 90°, which precludes the magnetic field from entering the brain. Length of stimulation varied between studies, but generally ranged between 15 and 20 min, and the duration of treatment varied from between 4 and 10 days. The results revealed a mean standardized gain effect size of 0.76 (95% CI: 0.36–1.17), which gives support for the efficacy of this treatment in reducing the severity of auditory hallucinations in schizophrenia. Notably, the observed effect was specific to auditory hallucinations and rTMS did not improve positive symptoms in general. Four studies of rTMS for hallucinations in schizoprhrenia have been reported after this meta-analysis. Vercammen et al. reported modest effects of rTMS, which were also present in the placebo condition [34] . Although real TMS was statistically superior to placebo, it was only marginally so. This study compared the classical 1-Hz rTMS over the left temporoparietal cortex (located as in Hoffman et al. [29]) to a bilateral condition in which rTMS was delivered over the left www.expert-reviews.com
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and right temporoparietal location. The rationale for stimulating the left and right hemisphere was based on neuroimaging studies that reported activation of both sites during hallucinations (for a review, see [9]). In addition, the authors hypothesized that the bilateral rTMS might reduce the emotional distress associated with hallucinations to a larger extent, as the right hemisphere has been implied to a stronger extent in emotional processing. Both active conditions were compared with a sham condition, in which a MagStim® placebo coil was used. The trial involved random assignment of 36 patients with schizophrenia to the three conditions, which involved 12 sessions of 20-min 1-Hz rTMS at 90% of the motor threshold over 6 days of treatment. However, the bilateral condition was not superior to the left hemisphere condition. A recent study used 20 Hz instead of 1 Hz to improve AVHs in schizophrenia patients [35] . The high frequency was used in order to deliver a large number of pulses in a brief period. A total of 11 patients were studied, rTMS was delivered over only 2 days, and they were then followed for 6 months. The target area was identified by fMRI activation during a language task, as the highest activation cluster along the posterior part of the left superior temporal sulcus. The authors reported a significant reduction in global severity and frequency of AVHs between baseline and posttreatment day 12. Auditory hallucinations disappeared entirely at 6-month follow-up in two patients. A major limitation of this study was the lack of a sham-control group. The use of fast rTMS at 20 Hz was surprising, as such high frequencies are generally considered to increase excitability of the cortex. However, a recent study in cats reported that TMS pulse trains elicited initial activation (a1 min) and prolonged suppression (5–10 min) of neural responses, which was observable for both slow and fast rTMS [36] . In one of the largest studies to date, Slotema et al. reported on 62 patients with medication-resistant AVH who were randomized over three conditions [37] . In an fMRI-guided rTMS group, rTMS was targeted at the area of maximal hallucinatory activation calculated from individual fMRI scans during AVH. The second group received rTMS directed at the left temporoparietal junction, and the third group received sham treatment. Patients recieved rTMS during 15 sessions of 20 min each during 3 weeks, at 1 Hz and 90% of the individual motor threshold. The authors reported reductions in hallucination severity in all three groups, with effect sizes ranging from 0.2 to 0.5. There were no significant differences, however, between the three groups. A number of issues regarding rTMS of hallucinations will need further clarification in future research. First, although the effect sizes in Aleman et al. were demonstrated to be in a positive direction [33] , some studies did not clearly support the therapeutic efficacy of rTMS for hallucinations (e.g., [38–40]). Why some individuals respond to rTMS treatment, whereas others do not needs to be investigated. Indeed, there is evidence of considerable individual variation regarding treatment effects. Several factors may affect responder status, for example, chronicity, beliefs associated with hallucinations (e.g., patients that ascribe the voices to be omnipotent might be less responsive), frequency of hallucinations, the degree that patients wish to give up their voices and the use of 1009
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benzodiazepine and anticonvulsant medications (which may limit TMS effects). The duration of treatment effects may vary considerably. Hoffman et al. reported that of the patients treated, 52% maintained improvement in symptoms for at least 15 weeks [29] . It should be noted that all of the reviewed studies included treatment-resistant patients. Given the favorable side-effect profile of rTMS, it should also be considered in other patient groups, for example, those with primarily hallucinations that do not want to use medication. Using larger multicenter studies, future research should systematically evaluate different rTMS parameters, such as duration of treatment, number of sessions per week, intensity of stimulation relative to motor threshold (e.g., is stimulation at 110% of motor threshold more effective than stimulation at 90%) and frequency (e.g., 1 vs 10 or 20 Hz). W-burst rTMS should also be explored. W-burst may be more powerful as it more closely resembles natural correlates of neural plasticity. The use of novel placebo coils that mimic real rTMS better by simulating the scalp sensation induced by real TMS, in addition to the visual impact and acoustic sensation [41] , should be encouraged. Finally, novel TMS coils are being developed that may allow for deeper stimulation than the typical 1–2-cm depth of current coils. Using such a coil, Rosenberg et al. reported a 30% reduction in hallucination severity in eight patients with schizophrenia [42] . Their study did not include a sham-control group. It goes without saying that more research using such coils, with attention to issues of safety, should be conducted. Cognitive-based psychotherapeutic approaches to treating & managing auditory hallucinations
Research over the past 20 years has shown that cognitive appraisals and perceptions concerning the nature of psychotic symptoms, including hallucinations, will influence the maintenance or recurrence of these symptoms. This research has also emphasized the central role of emotional dysfunction as a precursor and consequence of psychosis and psychotic symptoms, such as hallucinations (for a review, see [2]). Based on this large body of research, a wide variety of intervention methods have been proposed in the literature to treat and manage hallucinations. Furthermore, many of these methods have been scientifically tested in regard to their efficacy. It is not possible to present all of these and in detail. Therefore, for those readers who wish for an exhaustive presentation of these intervention strategies, the edited volume by Larøi and Aleman may be consulted [24] . Important to note is that the majority of studies have not tested the efficacy of these interventions specifically for hallucinations but, rather, for positive psychotic symptoms (i.e., hallucinations and delusions) as a whole. Furthermore, the majority of interventions are for AVHs, and rarely for hallucinations in other modalities, such as visual, olfactory and tactile. Whereas the step from the putative neural basis of hallucinations (as revealed by functional neuroimaging studies) to the rTMS treatment was rather straightforward (i.e., hyperactive temporoparietal areas should be dampened), such a relationship is less apparent for psychosocial approaches. However, one could argue that psychotherapy may focus on gaining control of the 1010
function of particular circuits, such as changes in appraisal, control of attention, modulation of interoceptive processes and so on, which all involve neuroadaptations in circuits. Such circuits could involve key nodes, such as anterior cingulate and medial prefrontal areas (involved in conflict monitoring and error detection), dorsolateral prefrontal areas (involved in working memory and cognitive control) and insula (interoceptive sensitivity). However, more research is needed to delineate this circuits and the effects of psychotherapy in more detail. Cognitive–behavioral therapy
In general, cognitive–behavioral therapy (CBT) in the context of psychosis aims to achieve a number of therapeutic goals, including a reduction of the distress and emotional disturbance (e.g., anxiety and depression) caused by the symptoms, and helping to provide the person with a sufficient understanding of psychosis (e.g., through psychoeducation) to promote the active participation of the individual in order, for instance, to reduce the risk of relapse and social disability [43] . In the context of hallucinations, a basic premise in CBT is that the hallucination is seen as an activating agent, that is then appraised by the individual in the context of their belief system, and that finally leads to emotions and safety behaviors [44] . The numerous studies that have examined the effects of individual CBT on psychotic symptoms have, on the whole, observed that CBT is effective in alleviating psychotic symptoms [45–55] . For instance, in the most recent meta-ana lysis that included 14 controlled studies (including 1484 patients) examining the effectiveness of CBT on the positive symptom of schizophrenia, Zimmerman et al. reported a mean weighted effect size of 0.37, representing a small-to-moderate effect size [55] . Furthermore, there was a higher benefit of CBT for patients suffering an acute psychotic episode versus those with a chronic condition (effect size of 0.57 vs 0.27, respectively). Group CBT for psychotic symptoms has also been proposed [56] . There are a number of advantages with this form of CBT. One obvious example is that in treating groups, one is able to treat more people compared with individual treatment. Discussing these experiences together in a group with others who have similar experiences may also combat feelings of isolation that voice hearers often report, and they may share natural (effective) coping strategies with each other in order to increase their coping repertoire [54] . Early, uncontrolled studies of group treatment for voices have shown beneficial effects, and although there are few, more rigorous studies in the literature, these studies report that group CBT reduces the severity of hallucinations, especially if therapy is provided by experienced CBT therapists. In addition, group CBT has been shown to improve social functioning and self-esteem, and reduce hopelessness (for a review of these studies, see [56]). Acceptance & commitment therapy
Newer approaches to treating hallucinations have, for instance, explored the utility of adding mindfulness or acceptance-based techniques to treat psychotic symptoms [57] . Briefly, acceptance Expert Rev. Neurother. 11(7), (2011)
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and commitment therapy (ACT) encourages individuals to accept and experience internal events in a nonjudgmental manner (i.e., mindfully) while simultaneously working toward the pursuit of personally defined goals. In general, the desired outcome in ACT is psychological flexibility rather than direct symptom reduction. In the context of AVHs, the ACT approach considers these symptoms to be similar to other private experiences (such as thoughts, emotions, urges and memories), and furthermore that it is not the presence of AVHs that results in distress and disability but, rather, it is when efforts to control, eliminate or avoid these experiences lead to poor functioning [57] . There is emerging evidence to suggest that ACT is a promising intervention for psychosis, both based on randomized controlled trials [58,59] and correlational studies [60,61] . Gaudiano and Herbert examined the efficacy of an ACT-based CBT [59] . Psychotic inpatients were randomly assigned to two groups: either a control group (who underwent typical treatment) or a treatment group (typical treatment, as well as individual sessions of ACT). At the time of discharge, the results implied that there were short-term advantages in the ACT group in affective symptoms, overall improvement, social impairment and distress associated with hallucinations. A 4-month follow-up revealed a reduction in the believability of hallucinations in the ACT group – a change that was strongly associated with reduced levels of distress. A recent RCT study examined the efficacy of CBT augmented with ACT for command hallucinations [Shawyer F et al. Manuscript submitted] . In total, 43 participants with problematic command hallucinations were randomized to receive either the target (CBT with ACT) or a control intervention (befriending), and were followed-up at 6 months. The results showed that although patients who received the target intervention subjectively reported greater improvement in command hallucinations compared with patients in the control intervention, there were no significant group differences in primary and secondary outcome measures. Attentional training technique
Attention training technique (ATT) is a treatment technique that aims to alleviate psychological problems via the enhancement of metacognitive control of attention. ATT is a technique and as such should be embedded into larger therapeutic frameworks, such as metacognitive therapy [62] or CBT. Briefly, patients are asked to focus and maintain their attention on several different extraneous sounds in the environment. They are then asked to switch their attention between different sounds. Thereafter, they are asked to practice to divide their attention by listening to all of the sounds at the same time. After mastering these neutral sounds, patients are asked to switch their attention between the voices and other sounds, and to divide their attention between the voices and other sounds. This technique is particularly interesting in the context of AVHs as it directly targets attentional processes underlying excessive attentional self-focus, which is characteristic of psychotic symptoms, such as AVHs (e.g., [63]). www.expert-reviews.com
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Preliminary evidence, albeit limited to case studies, suggests that ATT is a promising intervention technique for AVHs. At post-treatment, Valmaggia et al. reported a 56% reduction in the patient’s AVHs (based on scores on the Auditory Hallucinations subscale of The Psychotic Symptom Rating Scales), with the strongest effects on increased perceived controllability of voices, decreased duration of voices, reduced amount of negative voice content and reduced distress related to voices [64] . Similarly, in another case study, Valmaggia and Morris revealed a decrease in the patient’s voices’ intensity and duration, in addition to the voices becoming less negative [57] . Furthermore, at 6-month follow-up, many of these results were maintained, resulting in the patient no longer needing to use ATT in his/her daily life. Competitive memory training
Competitive memory training (COMET) is a relatively novel (transdiagnostic) intervention form that is based on the idea that, since psychopathology often involves dysfunctional meanings that are too often triggered in the wrong circumstances, therapy should influence the retrieval competition so that the chances of functional meanings being retrieved are increased. This is achieved via a number of different techniques, all of which attempt to make the positive and incompatible meanings emotionally more salient. Competitive memory training has been administered to a number of different psychopathologies, including panic disorder, obsessive–compulsive disorder and generalized anxiety disorder, and only very recently for treating AVHs (for a review of some of these studies, see van der Gaag and Korrelboom [65]). In terms of AVHs, findings from a recent RCT including 77 patients with schizophrenia with AVHs (39 were given COMET and 38 treatment as usual) suggest that COMET can be helpful in reappraising the meaning and changing the emotional impact of AVHs [van der Gaag M et al. Manuscript submitted] . Results revealed that, compared with the treatment-as-usual group, patients in the COMET group attributed less power to the voices, accepted voices more and became less submissive on the social ranking scale. In addition, COMET revealed improvements in depression and self-esteem. Although there was no significant change in total scores for AVHs (as measured by the Auditory Hallucinations subscale of The Psychotic Symptom Rating Scales), an inspection of subscale scores revealed that the cognitive interpretation subscale improved in the COMET condition, whereas the physical characteristics and negative emotional content subscales stayed unaffected. Appraisals
Chadwick and Birchwood and collaborators have observed that both emotional reactions (e.g., distress, depression and anxiety) and voice-driven behavior (e.g., coping strategies) in the context of hallucinations appear to be mediated by people’s beliefs about the voice (for a review, see [66–68]). These beliefs include the voice’s identity (who is the voice?), purpose (why is the voice talking to me and not someone else?), degree of omnipotence (how powerful is the voice?) and control. For instance, studies show that AVHs 1011
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believed to be malevolent incite fear and anger and are resisted, whereas benevolent voices elicit a positive effect and are engaged with, and AVHs interpreted as benign are associated with a greater diversity of coping strategies [69] . Interventions based on this approach, therefore, examine how the individual attributes the experiences on the basis of underlying beliefs. Techniques may involve undermining the patient’s central beliefs about AVHs, as research has shown that weakening maladaptive (core) beliefs and strengthening more adaptive ones has positive effects (e.g., reduced distress and improved coping) in patients [67] . Disputing a belief’s veracity may implicate a number of commonly used cognitive techniques; for instance, hypothetical contradiction (e.g., where the patient is questioned as to whether a hypothetical, but contradictory, occurrence would change their belief) and verbal challenge (e.g., where the patient is asked to question the evidence for his or her beliefs and to generate other plausible explanations). Later in treatment, beliefs are challenged more directly by, for example, pointing out irrational arguments and inconsistencies, and are then tested empirically by the patient. In addition to being a form of individual therapy, appraisal-based interventions have also been shown to be effective in a group format [70] .
neurobiological pathways that contribute to the emergence and maintenance of hallucinations [2] . One is at the level of sensorimotor processing, exemplified by low-frequency TMS delivered to Wernicke’s area (or perhaphs even Broca’s area) whereby one depresses directly localized hyperactivity. The second strategy is to promote executive cognitive function in the service of enhancing prefrontal executive control mechanisms for guiding bottom-up processes. Presumably this path would unite the efficacy of the CBT, ACT and possibly even high-frequency TMS delivered to the dorsolateral prefrontal cortex. Certainly, more research is needed to prove the specific efficacy of some of these strategies in the context of hallucinations. Individual differences are likely to play a role, which suggests that treatment should be individualy tailored. TMS may help to reduce the frequency of hallucinations, whereas cognitive approaches can be effective in assisting with coping and with reducing affective connotations that interfere with daily functioning. The use of neuroimaging to localize target regions for rTMS needs further exploration, and neuroimaging could also be used to assess effects of cognitive therapies on normalizing brain function. It would also be of interest to study direct comparisons of medication versus nonpharmacological methods with regard to hallucination treatment.
Conclusion & expert commentary
Novel approaches towards the treatment of hallucinations are being developed. Antipsychotic medication may be sufficiently effective in approximately half of patients with schizophrenia. Additional approaches are needed to help patients in which medication is not effective, or that for some reason do not use medication. There is evidence that TMS of brain areas involved in speech perception can reduce hallucinations. With regard to psychosocial therapies, attention training, ACT and COMET may be promising, but need further evaluation. It is safe to conclude that, besides antipsychotic medication, several other intervention strategies are available to clinicians that have been shown to alleviate or reduce hallucinations. Cognitive and neurobiological studies suggest that there may be two
Five-year view
As there is no prospect of improved antipsychotics (e.g., with less side effects and therefore better compliance) in the short term, nonpharmacological approaches to the treatment and management of hallucinations will be necessary. We foresee that more hospitals will offer TMS as a treatment for patients with resistant hallucinations, although this will depend on larger trials showing positive effects of rTMS. New coils for rTMS are being developed, and the next few years will reveal whether they can be instrumental in safe neurostimulation of deeper areas. Studies will increasingly investigate the neural effects of this treatment (e.g., with fMRI). fMRI may also be used for coil positioning over functionally defined areas.
Key issues • Hallucinations are a disturbing symptom that are prevalent in patients with schizophrenia. • Antipsychotic medication is the treatment of choice, but it is not effective in all patients, and a substantial proportion of patients do not adhere to drug treatment. • Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment strategy for auditory hallucinations in schizophrenia. • In rTMS, 1-Hz stimulation is generally used over speech perception areas, in order to reduce excitability of this region. • Meta-analyses have shown beneficial effects of rTMS for the treatment of auditory hallucinations, but a number of studies did not find improvement. Larger studies are needed. • Recently, acceptance and commitment therapy has been proposed for the management of chronic hallucinations. Acceptance and commitment therapy encourages individuals to accept and experience internal events in a nonjudgmental manner (i.e., mindfully), while simultaneously working toward the pursuit of personally-defined goals, and has been shown to reduce distress. • Competitive memory training is a relatively novel (transdiagnostic) intervention form that is based on the idea that, since psychopathology often involves dysfunctional meanings that are triggered too often in the wrong circumstances, therapy should influence the retrieval competition so that the chances of functional meanings being retrieved are increased. • It is safe to conclude that, besides antipsychotic medication, several other intervention strategies are available to clinicians that have been shown to alleviate or reduce hallucinations, although further development is possible and necessary.
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However, this is a time-consuming and costly approach and research is needed in order to determine whether it can yield gains in specific patient groups based on clinical characteristics. Further development of psychosocial (more specifically, cognitive–behavioral) approaches is also warranted. A combination of cognitive–behavioral approaches and mindfulness- or acceptance-based approaches might prove to be fruitful. Two other aspects of hallucinations could be further expanded on in therapies: the sensory aspects (e.g., the training of sensory discriminaton) and the metacognitive aspects (e.g., differentiating reality and imagination, but also addressing the role of References 1
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insight in psychosis). With regard to the methodology of trials investigating these novel therapeutic approaches, there is a need for trials that include larger samples. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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