Assessment of subjective cognitive and emotional effects of antipsychotic drugs. Effect by defect?

Neuropharmacology 72 (2013) 179e186

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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm

Assessment of subjective cognitive and emotional effects of antipsychotic drugs. Effect by defect? Steffen Moritz a, *,1, 2, Christina Andreou a,1, 2, Stefan Klingberg b, 3, Teresa Thoering a,1, Maarten J.V. Peters c, 4 a b c

University Medical Center Hamburg Eppendorf, Department of Psychiatry and Psychotherapy, Martinistraße 52, 20246 Hamburg, Germany University of Tuebingen, Department of Psychiatry and Psychotherapy, Calwerstraße 14, D-72076 Tübingen, Germany Maastricht University, Faculty of Psychology and Neuroscience, Clinical Psychological Science, P.O. Box 616, 6200 MD Maastricht, The Netherlands

a r t i c l e i n f o

a b s t r a c t

Article history: Received 16 November 2012 Received in revised form 11 March 2013 Accepted 23 April 2013

Antipsychotic medication represents the first-line treatment for schizophrenia. While it is undisputed that antipsychotics ameliorate positive symptoms, the exact cognitive and emotional pathways through which the effect is exerted has remained unclear. The present study investigated the subjective effects of antipsychotics across various domains of cognition and emotion in both patients with psychotic symptoms and patients with other psychiatric diagnoses. A total of 69 patients with a probable history of psychosis or psychotic symptoms and 26 patients with psychiatric diagnoses other than psychosis participated in a survey conducted over the Internet. Multiple control measures aimed to secure response validity. All patients were currently or had previously been treated with antipsychotic agents. A questionnaire comprising 49 items and measuring possible effects of antipsychotics on cognition and emotion was administered. For 30 out of 49 items a clear response pattern emerged, which was similar for patients with psychotic disorders and patients with other diagnoses. Factor analysis of these items revealed three main effects of antipsychotic medication related to doubt and self-doubt, cognitive and emotional numbing, and social withdrawal. Antipsychotic treatment appears to be connected to a number of negative subjective effects on cognition and emotion. Further studies are warranted to assess how these effects impact on the patients’ subjective well-being and quality of life, as well as their association with antipsychotic efficacy on one hand, and adherence rates on the other. Induction of doubt and dampening of emotion may be one reason why antipsychotics work and at the same time offer an explanation why they are experienced as rather unpleasant and are eventually discontinued by many patients. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Antipsychotics Psychosis Compliance Cognition Emotion

1. Introduction In the 1950s the discovery of antidopaminergic medication led to a paradigm shift in the treatment of schizophrenia. Its introduction replaced less effective, often hazardous and invasive methods such as insulin shock (Doroshow, 2007) or leucotomy (Feldman and

* Corresponding author. Tel.: þ49 40 7410 56565; fax: þ49 40 7410 57566. E-mail addresses: [email protected], [email protected] (S. Moritz), [email protected] (C. Andreou), [email protected] (S. Klingberg), [email protected] (T. Thoering), [email protected] (M.J.V. Peters). 1 Tel.: þ49 (0)40 7410 56565; fax: þ49 (0)40 7410 57566. 2 The first two authors split first authorship. 3 Tel.: þ49 (0)7071 2982330; fax: þ49 (0)7071 294141. 4 Tel.: þ31 (0) 433884026; fax: þ31 (0) 433884196. 0028-3908/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropharm.2013.04.039

Goodrich, 2001). Until today, antipsychotic medication remains the unrivalled treatment of choice for schizophrenia. While the efficacy of dopamine antagonists on positive symptoms is well-documented a recent meta-analysis indicates that antipsychotic medication reduces symptoms merely at a moderate effect size (Leucht et al., 2009). Moreover, they are associated with adverse side effects. While most of the first-generation agents are associated with extrapyramidal symptoms, the newer second-generation antipsychotics have been found to induce somatic (especially metabolic) side effects, which are regarded as equally troubling by many patients (Schimmelmann et al., 2005). Not surprisingly, non-compliance constitutes a major obstacle in treatment (Dolder et al., 2002; Voruganti et al., 2008), occurring in 50e75% of the schizophrenia patients (Byerly et al., 2007; Kahn et al., 2008; Lieberman et al., 2005).

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S. Moritz et al. / Neuropharmacology 72 (2013) 179e186

1.1. How do antipsychotics work and affect cognition?

1.2. Methodological problems

Our understanding about the biological pathways through which antipsychotic medication exerts its effect has expanded over the years but is still fragmented. Antipsychotics ameliorate positive symptoms (i.e., hallucinations and delusions) via both mesolimbic and mesocortical dopamine pathways (e.g., Sadock and Sadock, 2003; Stahl, 1999). Although these drugs also impact on other neurotransmitter systems, the antidopaminergic potential seems to represent the common denominator of all available first- and second-generation antipsychotic drugs (Kapur and Remington, 2001; Lambert and Naber, 2009; Sadock and Sadock, 2003). In contrast, assumptions relating to the cognitive and psychological mechanisms underlying antipsychotic effects have not yet fertiled to solid models. Elucidating these mechanisms may help to delineate pathogenetic models and the development of new therapeutic strategies for the treatment of positive symptoms. The present study aimed to explore subjective cognitive and emotional effects of antipsychotic medication. Before we turn to the methodology of our investigation, research findings and theories on biological mechanisms of antipsychotic medication and their impact on cognition and affect will be summarized first. A recent model about the interconnections between dopamine and psychotic symptoms (Kapur, 2003) postulates a triangular relationship among behavior, dopamine and schizophrenia symptomatology. Specifically, it is assumed that positive symptoms of schizophrenia are caused by a dysregulated dopaminergic activity that leads to excessive or random salience of stimuli: Certain stimuli “stick out” (i.e., receive overly weight), thereby fostering delusional ideation. According to Kapur, hypersalience is dampened by antipsychotics. In favor of this hypothesis are early observations suggesting that antipsychotics induce a state of “indifference” (Delay et al., 1952; Laborit and Huguenard, 1951), as well as studies reporting dysphoria (de Haan et al., 2004; Voruganti et al., 2001), often referred to as neuroleptic-induced negative syndrome (NIDS; Lader, 1993), and a certain emotional detachment under antipsychotic medication (Kapur et al., 2005; Mizrahi et al., 2006). A plethora of studies have investigated the impact of antipsychotic medication on neuropsychological domains like executive functioning, memory and attention. These studies have produced somewhat conflicting findings (e.g., Mishara and Goldberg, 2004). Prior reports about beneficial effects of second-generation drugs on neurocognition (Keefe et al., 1999), have been increasingly called into question by recent reports asserting either no or merely weak effects on cognition (Keefe et al., 2007, 2004). Another line of research that might provide insights into the psychological mechanisms of action of antipsychotic drugs is the examination of cognitive biases, such as jumping to conclusions (i.e., the tendency to make strong judgments on the basis of poor evidence, e.g. Garety et al., 1991), overconfidence in memory errors (Moritz et al., 2008, 2003), or a bias against disconfirmatory evidence (i.e., a strong tendency to stick to previously held opinions even in the face of substantial counter-evidence, Woodward et al., 2007, 2006, 2008). For example, in some of our studies we have collected tentative evidence that higher antipsychotic medication dosage is associated with decreased overall response confidence in memory tasks (Moritz et al., 2008, 2003). Conversely, the administration of L-Dopa seems to augment response confidence (Lou et al., 2011). Based on these preliminary findings, we have postulated that antipsychotic medication increases doubt and hesitance, which may extend to the psychopathological domain by attenuating delusional conviction (Moritz et al., 2008).

Studies that have investigated how cognitive factors are modulated by antipsychotics are often hampered by several methodological difficulties. First, non-compliance and pretended compliance (i.e., the patients claim to be taking the medication when in fact they are not) is a problem in schizophrenia. Secondly, if psychotic symptoms attenuate over time and so do cognitive biases and deficits, this does not prove a causal relationship: observed effects might be due to other factors such as practice or the passage of time. Alternatively, cognitive biases and deficits may decrease over time parallel to a decline of symptoms other than productive psychotic phenomena (e.g., negative symptoms or impulsivity). Trials with patients on and off antipsychotics would be clearly desirable but are hard to conduct for obvious reasons (So et al., 2010), and very few antipsychotic-naïve patients or those who refuse intake are willing to undergo research. Correlational studies pose another problem, as it is hard to find a consensual way to express the effect of antipsychotic agents: equivalent dosages largely vary across different algorithms and are especially difficult to establish for secondgeneration antipsychotics (Taylor et al., 2009, p.11). One way to shed light on the issue of how antipsychotics act on cognition and emotion is to directly enquire patients who are prescribed antipsychotic medication. The reliability of self-report measures in psychotic patients for the measurement of side effects has been demonstrated before (see Awad et al., 1995). For reasons pertaining to reliability, we recruited both a sample of patients with psychosis (schizophrenia or bipolar disorder with psychotic symptoms) and a non-psychosis group of patients prescribed antipsychotic agents in the context of augmentation strategies (Fountoulakis et al., 2004). The questionnaire used for the present study included questions relevant to the theoretical models summarized in section 1.1. Following Kapur (2003) we included items on (dampened) perceptual and emotional processing, and also formulated items on doubt and subjective confidence, as our prior results (see above) suggest that confidence is modulated by antipsychotic medication as well (Moritz et al., 2008, 2003). We also considered items of the Subjective Well-Being under Neuroleptics scale (SWN; Naber et al., 2001). Further, questions relating to jumping to conclusions, cognitive inflexibility, attribution style, theory of mind, and emotion processing were posed. This was done because numerous studies suggest that these (partially overlapping) cognitive biases are involved in the formation and maintenance of schizophrenia positive symptoms and may thus be sensitive to the effects of antipsychotic agents. We were especially interested in cognitive flexibility,5 as a review by So and coworkers (2010) tentatively suggests that antipsychotics may improve this function (however see also So et al., 2012). Based on previous research by Kapur and coworkers (2003), we expected that patients would report a dampening of affect under antipsychotic medication. Furthermore, we expected that these drugs would also slow their thinking and decision-making (decreased jumping to conclusions), and would induce more doubt. The study was conducted over the Internet. We favored this strategy over a face-to-face interview, as the latter approach likely inflates socially desirable responses (Byerly et al., 2007; Klingberg et al., 2008). We aimed to recruit a mixed patient group including those

5 Belief flexibility is a heterogeneous construct that can be examined in different ways, for example by self-report, neuropsychological tests like the trail-making test B or cognitive bias test like the so-called “bias against disconfirmatory evidence” paradigm (Woodward et al., 2007, 2008). Results from the latter domain suggest that incorrigibility is a state rather than a trait. In the present study it was defined as being able to question own opinions and attitudes.

S. Moritz et al. / Neuropharmacology 72 (2013) 179e186

who were non-help seeking, as this subgroup differs from (clinical) in- or outpatient samples on important aspects (Brett et al., 2009). 2. Methods 2.1. Participants and procedure The overall goal of our investigation was to assess subjective cognitive and emotional effects of antipsychotic medication. To this end, we conducted an online survey via www.unipark.de and approached several moderated German discussion forums for psychosis and other psychiatric disorders. Many of these forums have collaborated with us for other studies (Moritz and Jelinek, 2013; Moritz and Laroi, 2008). Parts of the project that are unrelated to the present topic have been published previously (Moritz et al., 2009). The invitation on the forums contained a web-link providing access to our Internet survey. The introductory page repeated the rationale of the study at length; participants were informed that the study investigated the subjective effects of antipsychotic medication beyond diagnostic boundaries as well as adherence (the latter results are presented elsewhere). We made explicit that the survey was only devoted to patients who were currently or previously prescribed antipsychotic agents. Examples of first-generation/conventional (e.g. HaldolÒ) and secondgeneration/atypical antipsychotic agents (e.g. ZyprexaÒ) were provided so that subjects did not confuse antipsychotics with other psychotropic agents. Participation was strictly anonymous, in order to ensure unbiased responses. Cookies prevented multiple access attempts from the same computer. 2.2. Background information First, information about the sociodemographic status of subjects was collected (e.g., age, gender, current work situation). Subsequently, questions relating to mental health were posed. Participants were asked if they had ever sought psychological treatment and, if this was the case, to enter the date of the first contact and the context of the initial treatment (i.e., counseling, outpatient treatment, inpatient treatment, other) as well as the overall frequency of treatments so far. Furthermore, diagnoses determined during treatment were inquired [more than one diagnosis could be endorsed: depression, bipolar disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia/psychosis, other (to be specified), no psychiatric diagnosis at all]. Participants were then asked if they were currently prescribed any medication and, if so, to specify the type and dosage of medication. Subsequently, the present therapeutic setting was inquired (e.g., inpatient, outpatient treatment). Patients were then asked which antipsychotic(s) had been previously prescribed, about the longest duration of intake, and the symptom for which this type of medication was prescribed according to their recollection. 2.3. Effect of Antipsychotic Medication on Emotion and Cognition (EAMEC) questionnaire The survey proceeded with the Effect of Antipsychotic Medication on Emotion and Cognition (EAMEC) questionnaire, which is presented here for the first time. The original version of EAMEC contains 49 items on subjective effects of antipsychotics. One goal of the study was to extract a subset of items that showed a consistent association with antipsychotic medication and are largely independent of psychopathology. Items were administered on a 7-point Likert scale with extreme responses at either end (e.g., 1 ¼ fewer creative ideas versus 7 ¼ more creative ideas). A rating of 4 corresponded to no change/unclear. Ratings of 1 or 7 meant strong agreement to either option, ratings of 2 or 6 meant medium agreement to either option and 3 or 5 meant slight agreement to either option. Five additional items served as lie items (rare but highly publicized or pseudo-psychotic symptoms: vision turns yellow; feet grow vs. shrink; deaf vs. can hear for miles; loss of ability to write vs. can write backwards; heightened eye pressure vs. low eye pressure) aimed at identifying and excluding subjects with unreliable responses. As laid out in the introduction, the questionnaire contained items relevant to the measurement of hypersalience, confidence, neurocognition, social cognition as well as cognitive biases (e.g., jumping to conclusions, cognitive inflexibility), as many studies suggest that these variables are involved in the emergence and maintenance of schizophrenia positive symptoms (Bell et al., 2006; Freeman, 2007; Moritz et al., 2010; van der Gaag, 2006) and/or are modulated by antipsychotics (So et al., 2010). The EAMEC also covered aspects of the SWN, especially pertaining to well-being and mood (Naber et al., 2001). 2.4. Illness insight and psychopathological assessment The survey proceeded with the 8-item insight scale (Birchwood et al.,1994) which provides independent indices of awareness of illness, need for treatment and attribution of symptoms. The psychometric properties of the English version (Birchwood et al., 1994) are satisfactory, and have been confirmed for other language versions (Camprubi et al., 2008). Additionally, the 42-item CAPE scale was administered (Konings et al., 2006), a self-report instrument which assesses psychotic experiences across three syndromes: positive, negative and depressive symptoms.

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At the end of the survey, participants were asked if they had honestly responded to the questions (yes/no). They were then given the possibility to leave comments and their email address if they were interested to participate in future studies or would like to be informed about the study results. The postal and email address of the first author (S.M.) was displayed in case of queries. The entire study is described in detail elsewhere (Moritz et al., 2009).

3. Results 3.1. Participants We adopted rather strict inclusion criteria to ensure reliability of the data. In a first step, we retained those participants who completed the questionnaire (N ¼ 129). In a second step, participants were considered for the analyses only if they met all of the following criteria: (1) affirmed intake of antipsychotic medication, (2) provided the name of an existing antipsychotic agent when asked for current or previous antipsychotic medication, (3) confirmed the presence of at last one psychiatric disorder, (4) did not endorse more than 2 out of 5 implausible/impossible antipsychotics side effects (e.g. yellow vision, see above), (5) did not show a stereotypal response pattern (same value entered throughout the survey) (6) affirmed that their responses had been made truthfully at the end. The final sample comprised 95 patients, 69 of whom had a probable diagnosis of psychosis (schizophrenia spectrum disorders, three patients were diagnosed with bipolar disorder but reported antipsychotic treatment due to psychotic symptoms), and 26 had a probable diagnosis of another psychiatric disorder (12 patients had been diagnosed with major depression, 7 with OCD, the rest had diverse diagnoses including anxiety disorders). 3.2. Background and illness-related variables The two samples were comparable regarding age and gender distribution (see Table 1). As expected, the psychosis group scored higher on the CAPE positive dimension and the non-psychosis group scored somewhat higher on depressive symptoms. However, insight was not different between groups. Table 1 Background characteristics, insight and psychopathology of the psychosis and nonpsychosis groups. Means and standard deviations. Variable

Psychosis (n ¼ 69)

Non-psychosis (n ¼ 26)

Statistics

Sociodemographic characteristics Age 35.13 (9.56)

36.92 (11.39)

Gender (male/female)

33/36

9/17

t(93) ¼ 0.77, p > .4 c2(1) ¼0.25, p > .2

Insight scale Awareness of symptoms

3.13 (1.10)

3.16 (1.08)

Awareness of illness

3.22 (1.44)

3.54 (0.95)

Need for treatment

5.17 (1.24)

5.04 (1.18)

Current medication (atypical/conventional/ antidepressant) Past treatment with antipsychotics

85%/12%/25%

62%/17%/62%

t(93) ¼ 0.09, p > .9 t(93) ¼ 1.05, p > .2 t(93) ¼ 0.48, p > .6 e

100%

100%

e

CAPE Positive

1.82 (0.49)

1.51 (0.30)

Negative

2.30 (0.47)

2.36 (0.49)

Depressive

2.31 (0.47)

2.59 (0.54)

t(87) ¼ 3.66, p < .001 t(87) ¼ 0.56, p > .5 t(87) ¼ 2.37, p ¼ .02

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S. Moritz et al. / Neuropharmacology 72 (2013) 179e186

3.3. Subjective cognitive effects of antipsychotics Table 2 summarizes the subjective effects of antipsychotics (sorted in ascending order according to the mean values of the psychosis patients). The two groups displayed similar scores on all items except one (item #20): Psychotic patients reported less

control over their life in conjunction with antipsychotic treatment than non-psychotic patients. Table 2 also indicates for each item whether deviations from the midpoint (4 ¼ no change/unclear) achieved significance (one-sample t-test). Moreover, the proportion (in percent) of subjects tending to either pole of the scale (i.e., 1e3 versus 5e7) is provided for each item.

Table 2 Effect of Antipsychotic Medication on Emotion and Cognition (EAMEC) questionnaire. Means, standard deviations, significant difference against midpoint and proportions of subjects who lean to either side of the scale (1e3 vs. 5e7, see text). Items for which the same response tendency emerged in both groups have been highlighted in bold. Item

1. 2. 3. 4.

Fewer creative ideas versus more creative ideas Emotions impoverished versus too many emotions Respond more slowly versus respond more quickly Experience my environment as dampened versus Experience my environment more intensively 5. Poor memory for new information versus good memory for new information 6. Feel indifferent versus passionate 7. External stimuli are processed worse vs. perceptual flooding 8. More hesitant versus impulsive 9. Impoverished fantasy versus enhanced fantasy 10. Depressed versus happy 11. Thoughts are sticky versus thoughts are rushing 12. Less sociable versus more sociable 13. “Empty head” versus head full of ideas 14. Lower self-esteem versus higher self-esteem 15. Poor attention versus good attention 16. Forgetting of prior events versus improved recollection of prior events 17. Worsens thinking versus improves thinking 18. Narrow-minded vs. open to other ideas 19. Worsen flow of thinking versus improve flow of thinking 20. Control over my life versus feel like being controlled 21. Memories are blurry versus memories are very sharp 22. Low bodily well-being versus improved bodily well-being 23. Avoid other people versus search for contact with other people 24. Higher self-doubt versus lower self-doubt 25. Indecisive versus decisive 26. Anxious versus courageous 27. Heightened self-attention versus lower self-attention 28. More doubtful even for little things versus over-confident 29. Feel like a different person versus feel how I want to be 30. Seek blame in myself versus blame others 31. Worsens mood versus improves mood 32. Seek exchange with other less frequently versus seek exchange with others more frequently 33. Indecisive about what is right or wrong versus decisive about what is right or wrong 34. Mistrust my thinking versus trust my thinking 35. Think less frequently about positive things versus think more frequently about positive things 36. Problems to imagine things visually vs. improved ability to imagine things visually 37. Lack of interest for other people or hobbies versus higher interest for other people or hobbies 38. People talk bad about me versus people talk good about me 39. Sick versus healthy 40. Numbness of upper limbs versus increased sensitivity to touch 41. Increased rumination versus less rumination 42. Worse decision-making versus better decision-making 43. More problems in daily life versus improved coping with daily life 44. Helpless and vulnerable versus having control 45. Refer more things to myself (e.g., certain looks) versus refer less things to myself 46. Less self-critical versus more self-critical 47. Dream less intensively versus dream more intensively 48. Thinking is more disorganized versus thinking is clearer 49. Poor sleep versus better sleep

Psychosis (n ¼ 69)

Non-psychosis (n ¼ 26)

Statistics (two-group comparison)

M (%1e3/5e7)a

SD

M (%1e3/5e7)a

SD

t

2.37 2.48 2.48 2.49

(75/12) (77/11) (78/3) (78/8)

(1.63) (1.46) (1.24) (1.25)

2.73 2.50 2.64 2.48

(69/19) (71/0) (64/8) (78/4)

(1.69) (1.14) (1.35) (1.20)

.94 .07 .54 .05

p p p p

2.53 **** (73/12)

(1.50)

2.69 **** (65/15)

(1.49)

.47

p > .6

2.55 2.63 2.85 2.91 2.92 2.92 2.92 2.97 2.97 3.01 3.05

(79/12) (77/10) (69/10) (63/11) (57/14) (60/11) (55/17) (61/11) (60/18) (67/27) (49/6)

(1.31) (1.37) (1.42) (1.63) (1.49) (1.42) (1.64) (1.51) (1.62) (1.80) (1.31)

3.00 *** (64/16) 2.77 **** (69/11) 3.38 * (54/21) 3.00 *** (68/16) 2.88 **** (62/25) 2.76 **** (68/8) 3.42þ (46/29) 2.85 **** (54/8) 2.83 *** (62/25) 2.92 **** (65/15) 3.00 *** (58/12)

(1.41) (1.42) (1.50) (1.44) (1.56) (1.36) (1.69) (1.38) (1.71) (1.41) (1.56)

1.44 .43 1.53 .25 .13 .48 1.25 .36 .35 .23 .14

p> p> p> p> p> p> p> p> p> p> p>

.1 .6 .1 .8 .8 .6 .2 .7 .7 .8 .8

3.06 **** (57/21) 3.09 **** (51/12) 3.11 **** (64/17) 3.13 **** (62/22) 3.15 **** (52/11) 3.18 **** (58/21) 3.20 **** (51/27) 3.25 **** (53/23) 3.28 **** (48/20) 3.34 *** (49/26) 3.34 *** (49/26) 3.36 **** (48/23) 3.37 *** (53/23) 3.40 *** (46/17) 3.46 * (45/32) 3.46 * (45/28)

(1.61) (1.49) (1.61) (1.81) (1.35) (1.82) (1.85) (1.68) (1.41) (1.47) (1.73) (1.42) (1.65) (1.54) (1.73) (1.77)

3.12 *** (60/16) 3.04 **** (56/12) 3.19 **** (61/8) 3.88 (33/29) 3.48þ (48/9) 2.80 *** (76/16) 3.22 * (52/22) 2.75 *** (62/17) 3.32 * (56/24) 3.42þ (46/23) 3.91 (35/35) 3.78 (39/30) 3.04 * (54/25) 2.74 **** (52/9) 4.04 (29/42) 3.40þ (48/20)

(1.39) (1.34) (1.10) (1.23) (1.34) (1.71) (1.48) (1.75) (1.41) (1.68) (1.47) (1.17) (1.83) (1.63) (1.57) (1.55)

.16 .15 .25 2.22 1.01 .91 .05 1.23 .12 .24 1.42 1.28 .79 1.73 1.43 .15

p> p> p> p¼ p> p> p> p> p> p> p> p> p> p¼ p> p>

.8 .8 .8 .03 .3 .3 .9 .2 .9 .8 .1 .2 .4 .09 .1 .8

3.46 ** (41/24)

(1.61)

3.00 *** (61/13)

(1.51)

1.19

p > .2

3.53 * (44/28) 3.56 * (39/31)

(1.60) (1.59)

3.36þ (52/32) 3.76 (32/36)

(1.68) (1.66)

.45 .52

p > .6 p > .6

3.60 þ (40/20)

(1.64)

3.52 (43/14)

(1.33)

.19

p > .8

3.60 þ (42/36)

(1.73)

3.16 * (60/32)

(2.03)

1.03

p > .3

3.66 3.71 3.79 3.83 3.84 3.85 3.89 3.92

* (33/11) (47/37) þ (18/5) (44/45) (37/37) (43/37) (41/40) (35/43)

(1.28) (1.89) (0.89) (1.93) (1.70) (1.97) (1.78) (1.92)

3.52 3.15 3.68 3.58 3.83 3.69 3.36 4.17

(43/17) * (61/35) (26/10) (42/37) (33/29) (38/35) * (60/24) (30/48)

(1.38) (1.89) (1.11) (1.79) (1.27) (1.76) (1.41) (1.44)

.42 1.26 .40 .55 .03 .35 1.33 .57

p p p p p p p p

> > > > > > > >

.6 .2 .6 .5 .9 .7 .1 .5

4.05 4.17 4.18 4.54

(33/33) (35/41) (31/47) * (33/54)

(1.47) (1.87) (1.80) (2.07)

3.78 3.65 4.18 4.36

(35/30) (42/35) (41/41) (36/56)

(1.35) (1.96) (1.65) (2.29)

.75 1.18 .00 .36

p p p p

> > > >

.4 .2 .9 .7

**** **** **** ****

**** **** **** **** **** **** **** **** **** **** ****

**** **** **** ****

p > > > >

.6 .9 .5 .9

Notes. þ p  .1 *p  .05,**p  .01; ***p  .005, ****p  .001 for one-sample t-test against baseline. a Proportion (in percent) of responses on either pole of the scale (1e3 vs. 5e7). The proportions do not sum up to 100% as the proportions of the medium score (¼4) are not displayed. Response options are set in bold type, if they showed a strong response shift in both psychosis (p  .05) and non-psychosis patients (p  .1). Please note that mean scores (first line of each item) and proportional scores (second line) do not fully correspond for some items, as the proportional score weights each response option of each side of the scale similarly (1e3 or 5e7).

S. Moritz et al. / Neuropharmacology 72 (2013) 179e186

3.4. Factor analysis Next, we extracted all items showing a clear dominance for either side of the scale both in psychotic (i.e., scores significantly different from zero at p  .05) and non-psychotic patients (scores different from zero at p  .1). We choose a somewhat more liberal criterion for non-psychotic patients because of the small size of this group. A total of 30 items fulfilled these criteria (i.e., substantial deviation from midpoint) and were submitted to a factor analysis with varimax rotation (if the alpha-level had been Bonferroniadjusted for psychosis patients and the p-level lowered to <.05 for non-psychotic patients, 23 items would have fulfilled the criteria). According to Pawlik (1976) a factor analysis necessitates at least 3 subjects for each item, a criterion which is met (N ¼ 95 subjects for 30 items). The KaisereMeyer Olkin index revealed a score of .83, which is satisfactory. As expected, the Bartlett test of sphericity was significant at p < .001. Scree-plot inspection suggested a three-dimensional solution (i.e., a steep dip emerged after the fourth factor). The three-dimensional solution explained 51.4% of the variance, with Factor 1 ((self)doubt) explaining 20% of the variance. The following items loaded on Factor 1 (loadings > .6, see Table 3): mistrust my thinking, feel like a different person, indecisive about what is right or wrong, depressed, higher self-doubt, low bodily well-being, and being indecisive. The second dimension was named “cognitive and emotional numbing” and explained 19%, receiving highest loadings from the following items: impoverished

Table 3 Rotated factor matrix for those items where psychosis and non-psychosis patients displayed a similar response tendency (item scores were reversed). Loadings  .5 are set in bold type. Item (dominant tendency)

Mistrust my thinking (item 34) Feel like a different person (item 29) Indecisive about what is right or wrong (item 33) Depressed (item 10) Higher self-doubt (item 24) Low bodily well-being (item 22) Indecisive (item 25) Experience my environment as dampened (item 4) Lower self-esteem (item 14) Worsens thinking (item 17) Anxious (item 26) Respond more slowly (item 3) Impoverished fantasy (item 9) “Empty head” (item 13) Emotions impoverished (item 2) Thoughts are sticky (item 11) External stimuli are processed worse (item 7) Feel indifferent (item 6) Fewer creative ideas (item 1) Poor memory for new information (item 5) Memories are blurry (item21) Narrow-minded (item 18) Worsens flow of thinking (item 19) Poor attention (item 15) Forgetting of prior events (item 16) Avoid other people (item 23) Seek exchange with other less frequently (item 32) Less sociable (item 12) Seek blame in myself (item 30) More hesitant (item 8)

Self (doubt)

Emotional and cognitive numbing

Social withdrawal

.79 .77 .73

.08 .23 .20

.09 .11 .21

.68 .68 .67 .62 .57

.23 .12 .24 .17 .40

.25 .31 .18 .14 .03

.57 .53 .52 .49 .12 .25 .08 .39 .10

.07 .49 .11 .47 .73 .70 .69 .68 .65

.50 .11 .44 .00 .21 .22 .16 .01 .09

.10 .01 .22

.63 .57 .55

.22 .43 .13

.18 .14 .28 .37 .37

.51 .51 .46 .46 .38

.08 .36 .39 .20 .00

.17 .25

.25 .14

.80 .78

.23 .29 .05

.34 .07 .38

.76 .58 .40

183

fantasy, “empty head”, emotions impoverished, sticky thoughts, external stimuli are processed worse, problems to visualize things, and feeling indifferent. The third dimension explained 12% of the variance and related to “social withdrawal”. Items loading on this factor were: avoid other people, seek exchange with other less frequently, and less sociable. We saved the factor scores to the matrix and explored whether psychotic and non-psychotic patients differed on any of the dimensions, which was not the case (all comparisons t < 1.2, p > .2). 3.5. Correlations The factor scores of the three dimensions [(self)doubt, cognitive and emotional numbing and social withdrawal] were correlated with background and illness-related variables like illness insight and psychopathology (see Table 4). All correlations were jrj  .2 and none of the 27 correlations achieved significance. Interestingly, (self)doubt was not correlated with depressive symptoms, suggesting that these two dimensions are independent. Only between age and social withdrawal there was a trend toward a significant positive correlation (however, before any corrections for multiple comparisons). 4. Discussion The present study explored the subjective cognitive and emotional effects of antipsychotic medication. We were especially interested to examine whether antipsychotics ameliorate certain cognitive biases that are implicated in the pathogenesis of psychosis, especially cognitive inflexibility (So et al., 2010), overconfidence (Moritz et al., 2008, 2003) and jumping to conclusions. Moreover, we investigated the hypothesis proposed by Kapur that antipsychotics dampen emotions and reduce hypersalience (Kapur, 2003; Kapur et al., 2005). To meet this aim, we administered a selfrating scale covering cognitive biases, emotion and subjective neuropsychological (dys)functions. Items from the newly developed Effect of Antipsychotic Medication on Emotion and Cognition (EAMEC) questionnaire were measured on a scale with (semantically) opposing endpoints, enabling the detection of both positive and negative effects. Our hypotheses were partially confirmed. For 30 out of 49 items of the scale, patients clearly favored one end of the pole (if stricter criteria were applied, 23 items remained). Negative effects largely prevailed. Factor analysis of the 30 items revealed three dimensions: (self)doubt, cognitive and emotional numbing, and social withdrawal. Regarding the first factor, patients reported that they were more doubtful due to antipsychotics, a finding in line Table 4 Correlations between the three dimensions of the EAMEC. Variables/Factors

Self (doubt)

Cognitive and emotional numbing

Social withdrawal

Background variables Age in years Number of admissions

.05 .02

.02 .02

.20 (þ) .04

Insight scale Awareness of symptoms Awareness of illness Need for treatment Total score

.10 .06 .09 .12

.00 .14 .12 .13

.12 .05 .02 .09

CAPE syndromes Positive Negative Depressive

.12 .01 .17

.07 .00 .00

.15 .02 .04

Notes. þp < .1.

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with prior experimental findings of our group (Andreou et al., in press; Moritz et al., 2008, 2003). Importantly, none of the EAMEC subscales were correlated with CAPE scores, which supports the claim that the EAMEC factors reflect neuroleptic-induced symptoms and not psychopathology. In line with a recent study, cognitive inflexibility was subjectively not improved (So et al., 2012). On the contrary, the majority of patients reported somewhat greater hardheadedness under antipsychotics (both groups predominantly endorsed the response option “narrow-minded and not open to other ideas”). However, this was tapped by a single item so that no solid conclusions can be drawn. Results regarding the second factor are in line with the hypersalience account of schizophrenia (Kapur et al., 2005): patients reported that antipsychotics decreased their emotionality, creativity and also exerted a detrimental effect on their cognitive faculties. Results accord to another online study which investigated the subjective effects of antipsychotic medication in 439 patients, mainly prescribed atypical antipsychotics (Moncrieff et al., 2009): The predominant subjective effects elicited by all drugs were “sedation, cognitive impairment and emotional flattening or indifference” (p. 102). Case reports (Belmaker and Wald, 1977) as well as experimental trials (Saeedi et al., 2006) have shown similar effects in healthy subjects as well. For the third factor, social withdrawal, one may argue that this represents a secondary consequence of the other two dimensions. If replicated, our findings are disquieting with respect to the second and third factor: Across groups, patients strongly and rather consistently attributed a dampening of emotion, clouding of cognitive faculties and decreased joy to antipsychotic treatment. For these clinical manifestations, the term neuroleptic-induced deficit syndrome has been coined (Lader, 1993). Clearly, our questionnaire did not cover every single cognitive domain, and/or positive effects might not have been perceived by patients or misattributed to other factors. Moreover, these cognitive effects might reflect the well-established primary cognitive deficits of schizophrenia, which patients mistakenly misattribute to medication, although this possibility is less likely, since non-psychotic patients also reported the same effects. The issue certainly warrants further research. However, one should also keep in mind the possibility that the adverse events and negative cognitive effects of antipsychotics are in fact an intrinsic part of their main mechanism of action, that is, one of the reasons why antipsychotics are effective. If the amelioration of positive symptoms and reduction of cognition and emotion are two sides of the same coin, this may explain why antipsychotics are disliked despite their effectiveness by both patients with psychosis and those with, for example, obsessive-compulsive disorder (Voderholzer et al., submitted for publication). This is especially pertinent for research on antipsychotic drug development: If replicated, it would be very relevant to investigate whether the desired (i.e. antipsychotic effect) and unwanted effects (i.e. numbing of thinking and emotions) of antipsychotic drugs occur through the same or different pathophysiological mechanisms, and whether they can be avoided with use of new agents. This is highly important, since it has been repeatedly shown that subjective side effects compromise treatment satisfaction, which in turn can significantly influence long term adherence and treatment outcomes, including the achievement of life goals (Nasrallah and Lasser, 2006). Knowing how antipsychotics work on a cognitive and emotional level may also help us devise more targeted non-pharmacological treatments. Various non-pharmacological approaches, such as psycho-education (for a meta-analysis see Lincoln et al., 2007) and family therapy (for a meta-analysis see Pharoah et al., 2010) have been shown to reduce relapse rates in patients with schizophrenia, and a recent cross-sectional study showed that the likelihood of

symptomatic remission is greater among patients engaged in current or past psychotherapy (San et al., 2007). Moreover, evidence from two psychotherapeutic approaches exists that indicates a direct positive effect on symptoms of schizophrenia. First, cognitive behavioral therapy (CBT; Klingberg et al., 2010b; Lincoln et al., 2008; Sarin et al., 2011; Wykes et al., 2008) focuses on challenging beliefs associated with delusional ideas and hallucinations as well as on stress reduction and emotion regulation (Klingberg et al., 2010a). Second, a increasing body of literature shows that cognitive bias modification programs such as Metacognitive training (MCT; Moritz et al., 2010), Reasoning Training (Waller et al., 2011) and Social and Cognition Interaction Training (SCIT; Combs et al., 2007; Roberts and Penn, 2009), which target cognitive biases, social cognition deficits and depressive cognitions in an educational context, show some promise to reduce symptoms over and above the effects of antipsychotics. Since both treatment strategies are presumably related to the first and second factors of the EAMEC questionnaire, it would be interesting to investigate whether a combination of both strategies (for favorable but preliminary evidence see Moritz et al., 2011) may not only be a useful adjunct to antipsychotics, but also prove a viable treatment alternative for patients who refuse to take (or who are non-responsive to) medication. A recent study shows that CBT may be efficient even for patients who refuse to take antipsychotics (Morrison et al.,2012). We have to refrain from bold conclusions in view of several limitations. First, our results need independent replication: A shortcoming of the present study is that self-report assessments might be problematic in psychosis patients, as they have been consistently shown to lack metacognitive awareness (e.g., Moritz et al., 2004). Relatedly, an Internet population is probably different from a clinical population as it contains a subgroup of subjects who are not willing to undergo treatment and are thus less compliant with the psychiatric health care system. As mentioned before, some patients were not able to perceive favorable effects of antipsychotics, or misattributed these to alternative factors. Still, results were comparable in the group of nonpsychotic patients, who are considered to be more capable to perceive and describe their own cognitive processes. Another limitation relates to the fact that the construct validity of the EAMEC remains to be confirmed in comparison to other scales, for example the Subjective Well-Being under Neuroleptics scale (SWN; Naber et al., 2001) and, preferably, to objective measures of emotion and cognition as well. For example, the present study did not investigate whether the effects of antipsychotics assessed with the EAMEC questionnaire correlated with patient satisfaction, adherence rates, or quality of life. Further, although results indicate a negative effect of antipsychotics, at this point it is not known whether these effects are associated with subjective distress, as most items of the scale were phrased in a rather neutral manner. It might be that, as is the case with other (side)effects, the clinicians’ perception of negative effects differs from that of patients (Nasrallah and Lasser, 2006). Finally, while our sample size (N ¼ 95) met the requirements for a factor analysis according to Pawlik (1976), other authors suggest that at least 5 subjects are needed per variable and some studies demand at least 100 subjects to arrive at solid conclusions. Thus, our sample was rather small for this type of analysis, rendering the results preliminary. However, at least two of the three components showed good saturation which is a vital fit index according to some researchers (Guadagnoli and Velicer, 1988). Hence, we intend to replicate our findings in an independent and larger sample. In our view, the present study also possesses a number of strengths that are worth highlighting. First, we included a nonpsychosis sample controlling for possible psychosis-specific

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effects. Speaking for the solidity of the findings, a discrepancy between the responses of psychotic and non-psychotic patients occurred only in one out of 49 items, which is below chance level. This study confirms claims by Awad, Naber and Vorungati that the responses of schizophrenia patients are more reliable than commonly thought and represent an important source that should not be neglected (Awad et al., 1995; Naber et al., 2001; Voruganti and Awad, 2004). Secondly, the study was conducted as an anonymous survey, thus maximizing the likelihood of unbiased appraisals in patients. A number of studies confirm the reliability of this line of research (Jones et al., 2008; Ritter et al., 2004; Riva et al., 2003), even for severely impaired psychiatric patients (Chinman et al., 2004; Moritz and Laroi, 2008). In clinical contexts, patients may not disclose negative aspects of treatment or low compliance with medication, fearing that this might, for example, have a negative impact on their treatment (Moritz et al., 2012). To illustrate this point, a recent study found that patients disclosed negative side effects of psychotherapy in face-to-face interviews very rarely, while the majority did so in an online study (Nestoriuc et al., 2011). Another strength of the present study is the usage of multiple precautions, including lie items, in order to ensure a high quality of the data (this to the exclusion of six subjects). The CAPE scores of our sample are largely in line with prior studies collected in clinical samples (Myin-Germeys and Collip, unpublished data on 311 mainly remitted patients: positive score M ¼ 1.66, SD ¼ .49; negative score: M ¼ 1.98, SD ¼ .54; depression score: M ¼ 2.00, SD ¼ .55). In addition, we have recently gathered evidence (Moritz et al., submitted for publication) that subjects who try to simulate psychosis, including mental health experts, show a tendency to over-report symptoms (i.e., much higher CAPE positive scores). To conclude, antipsychotic treatment was associated with a number of negative subjective effects regarding cognition and affect in the present study. This effect was not limited to patients with psychotic disorders, but also applied to patients with other psychiatric diagnoses, and was independent of insight and the coexistence of depressive symptoms. The induction of doubt and the dampening of emotion may be one reason why antipsychotics reduce positive symptoms, and at the same time might constitute another reason for their discontinuation. Conflict of interest statement None declared. References Andreou, C., Moritz, S., Veith, K., Veckenstedt, R., Naber, D. Dopaminergic modulation of probabilistic reasoning and overconfidence in errors: a double-blind study. Schizophrenia Bulletin, in press. Awad, A.G., Hogan, T.P., Voruganti, L.N.P., Heslegrave, R.J., 1995. Patients subjective experiences on antipsychotic medications: implications for outcome and quality of life. International Clinical Psychopharmacology 10, 123e132. Bell, V., Halligan, P.W., Ellis, H.D., 2006. Explaining delusions: a cognitive perspective. Trends in Cognitive Sciences 10, 219e226. Belmaker, R.H., Wald, D., 1977. Haloperidol in normals. British Journal of Psychiatry 131, 222e223. Birchwood, M., Smith, J., Drury, V., Healy, J., Macmillan, F., Slade, M., 1994. A selfreport insight scale for psychosis: reliability, validity and sensitivity to change. Acta Psychiatrica Scandinavica 89, 62e67. Brett, C.M.C., Johns, L.C., Peters, E.P., McGuire, P.K., 2009. The role of metacognitive beliefs in determining the impact of anomalous experiences: a comparison of help-seeking and non-help-seeking groups of people experiencing psychoticlike anomalies. Psychological Medicine 39, 939e950. Byerly, M.J., Nakonezny, P.A., Lescouflair, E., 2007. Antipsychotic medication adherence in schizophrenia. Psychiatric Clinics of North America 30, 437e452. Camprubi, N., Almela, A., Garre-Olmo, J., 2008. Psychometric properties of the Spanish validation of the insight scale. Actas Espanolas De Psiquiatria 36, 323e330. Chinman, M., Young, A.S., Schell, T., Hassell, J., Mintz, J., 2004. Computer-assisted self-assessment in persons with severe mental illness. Journal of Clinical Psychiatry 65, 1343e1351.

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