Introduction

1. Psychophysiological indices of patients with psychotic major depression as compared with delusional misidentification syndromes: A P300 study.Ch. Papageorgiou1, E. Ventouras2, G.N. Christodoulou11 Department Of Psychiatry, Eginition Hospital, Medical School, Uninersity of Athens, Greece 2Department of Medical Instrumentation Technology, Tecnological Educational Institution of Athens, Greece

2. Introduction • A variety of considerations indicate a close association between psychotic major depression (PMD) and delusional misidentification syndrome (DMS). Parenthetically, the delusional misidentification syndromes (DMS) including the Capgras, the Frégoli, and intermetamorphosis syndrome, are characterized by a misidentification delusion of the self or others (Christodoulou 1991). • Both entities are presened with delusions (Munro, 2000) and dopamine overactivity is an essential biological substrate of delusional symptoms, for both disorders(Roane et al., 1998; Wood et al., 2002), while antipsychotic medication is effective in treating this symptomatology (Mulsant et al., 1997; Zanker, 2000). • In a clinical level of analysis both entities demonstrate frequently aggression (Silva et al., 1995; Silva et al., 1997; Brdsky et al., 2001). • The right hemispheric function and/or interhemispheric transmission has been implicated in the pathogenesis of both nosological entities (Taiminen et al., 2000; Dejode et al., 2001). • Psychological and especially psychodynamic viewpoints attribute a decisive pathogenetic role to the defence mechanisms splitting and projection for both entities, hypothesizing that this results from ambivalent feelings, induced by overintense affect towards significant others. (Zanker, 2000) • Here it should be emphasized that recently the significance of psychodynamic suggestions has been weakened owing to the fact that a high proportion of cases of both disorders exhibit significant brain pathology. • Thus, it seems to be a need for a differential diagnosis in such cases.

3. Event-related potentials (ERPs) provide a valuable means for studying brain-behavior relations (Fabiani et al., 2000). • The P300 component of ERPs is thought to reflect attentional operation resource when working memory (WM) updating is engaged (Kok, 2001). • In this context it is worth noting that contemporary neuropsychological views define WM as the capacity to keep information ‘on-line’, as necessary for an ongoing task (Baddeley, 1998; Collette and Van der Linden, 2002). • In other words, WM is not for ‘memorizing’ per se. It is rather in the service of complex cognitive activities, such as reasoning, problem solving and decision making (Miyake and Shah, 1999; Glassman, 2000).

4. Concerning ERP measures in PMD, Santosh et al., (1994), using an ‘oddball’ paradigm, reported that PMD patients showed an attenuation of the P300 amplitude varying in accordance with the severity of psychotic features. They suggested that smaller P300 amplitude may be a state marker in depression and a trait marker in schizophrenia. It is notable in this regard that there are studies reporting that PMD patients exhibit deficits of working memory (Pelosi et al., 2000; Slade et al., 2000)

5. We reported recently (Papageorgiou et al., 2003), that DMS patients, as compared to healthy controls, showed reduced P300 amplitude at right prefrontal region and prolonged latency of P300 located at central midline brain area. These findings suggest that surface-recorded event-related potentials may be useful for detecting and monitoring the changes in brain function associated with DMS.

6. In view of the above considerations, it was thought that electrophysiological brain activity, as reflected by the P300, in association with WM operations, could be of value in identifying or discerning possible common pathophysiological mechanisms involved in PMD and DMS, and also in evaluating the extent to which such mechanisms may differentiate these two conditions.

7. Materials and methods

8. The DMS patients were studied during their delusional episode. The sample of patients included four patients suffering from Capgras syndrome, two patients from Frégoli syndrome, two from coexisting Capgras and Frégoli syndrome and one patient suffering from Frégoli syndrome and intermetamorphosis. All patients were psychotics of paranoid type according to DSM-IV criteria • * Medicated DMS patients have taken medication as follows: The first patient trifluoperazine (30mg/day) + carbamazepine (600mg/day), the second patient risperidone (8mg/day) + gabapentin (800mg/day) and the third patient olanzapine (20mg/day) + oxcarbazepine (600mg/day). • ** Three PMD patients have taken medication as follows: the first patient risperidone (8mg/day) + paroxetine (20mg/day), the second patient olanzapine (10mg/day) + venlafaxine (150mg/day), and the third (olanzapine 20mg/day) + fluoxetine (20mg/day).

9. F D E A B C Experimental procedure

10. Grand average ERP waveforms of the DMS group (red line), the PMD group (blue line) and the normal controls group (black line), at each lead.

11. Mean values (±S.D.) in microVolts of the P300 amplitudes for the three groups at each lead. Groups which differ significantly (post-hoc Bonferroni pairwise comparisons, p<0.05) are indicated by the different letters.

12. Comparison of P300 amplitudes • Stepwise discriminant analysis applied for the distinction of the three groups, based on the P300 amplitude values, revealed two canonical discriminant functions, which correctly classified 80% of the cases. • The first function is correlated with lead F4 (r=0.806) and, discriminates the control group from both patient groups. • The second function correlates with lead C4 (r=0.941) and discriminates the psychotic depressive group from the DMS group. • Post-hoc Bonferroni comparisons of the discriminant scores derived from the two functions confirm the above results.

13. Mean values in microVolts of the P300 amplitudes for the three groups at each lead.The first group are the controls (white bars), the second group are the PMD group (spotted bars), and the third group are the DMS group (striated bars). An asterisk denotes statistically significant difference between the controls and the PMD group, a triangle indicates the differences between the controls and the DMS group, and a rhombus that between PMD and the DMS groups. Statistically significant differences were computed on the basis of Bonferroni pairwise comparisons.

14. Mean values (±S.D.) in msec of the P300 latencies for the three groups at each lead..If two groups do not differ significantly at a specific lead then they have the same letter (a or b) next to their values, while different letters indicate groups which differ significantly (post-hoc Bonferoni paiwise comparisons, p<0.05).

15. Comparison of P300 latencies • The same stepwise discriminant analysis, applied to distinguish the three groups based on the P300 latency values, revealed only one canonical discriminant function, which however correctly classified 71.4% of the cases. • The function is formed from the latency values of Cz alone. This is due to the fact that latencies are highly correlated with each other. Post-hoc Bonferroni comparisons of the discriminant scores derived from the function revealed statistically significant differences between the DMS group and the two other groups.

16. Mean values in msec of the P300 latencies for the three groups at each lead.The first group are the controls (white bars), the second group are the PMD group (spotted bars), and the third group are the DMS group (striated bars). An asterisk denotes statistically significant differences between the controls and the PMD group, a triangle indicates the difference between the controls and the DMS group and a rhombus that between PMD and the DMS groups. Statistically significant differences were computed on the basis of Bonferroni pairwise comparisons.

17. Comparison of memory performance Post-hoc tests revealed that both patient groups had significantly attenuated memory performance compared with healthy controls (p < 0.001, F = 9.31, d.f. = 32), whereas there were no significant differences between the two patient groups. The mean values and the standard deviation (S.D.) for the three groups, i.e. DMS, PMD and control, were 54.4 ± 7.2, 56.06 ± 9.96 and 68.0 ± 4.5, respectively. More than 149 digits were presented.

18. Discussion • The amplitude of P300 component is considered as sensitive measure of attentional operation when WM updating is engaged (Coull, 1998; Kok, 2001). • It is believed that frontal generators are more involved in automated orienting, while temporoparietal generators are more responsive in effortful responding to evoked stimuli (Winterer et al., 2001). • The reduction in P300 amplitude is also thought to reflect gray matter abnormalities (Martin-Loeches et al., 2001).

19. Consequently, the obtained pattern of differences in the amplitude of P300 could imply that both DMS patients and patients suffering from PMD may be associated with defects in the WM, being connected to the automatic nature of information processing and mediated by the right frontal area.

20. With regard to PMD patients, our results appears to be in agreement with recent studies (Santosh et al., 1994; Pelosi et al., 2000; Slade et al., 2000), indicating that the dysfunction of these brain areas may be implicated in PMD. Within this framework, it is worth noting that current brain models of emotion processing hypothesize that positive (or approach-related) emotions are lateralized towards the left hemisphere, whereas negative (or withdrawal-related) emotions are lateralized towards the right hemisphere (Fossati et al., 2003). Similarly, as far as the DMSs are concerned, there are also studies providing evidence of dysfunctional connections among frontal cortex, multimodal association areas and paralimbic structures, resulting in cognitive-perceptual-affective dissonance, which under specific conditions may lead to positive delusional formation (Fleminger and Burns, 1993; Paillere-Martinot et al., 1994; Mentis et al., 1995; Feinberg, 1997; Joseph et al., 1999).

21. The two disorders appear to be distinguishable with regard to the ‘effortful’ nature of information processing involving or affecting the right parietal area.In this case the DMS group is afflicted. The importance of this finding may be better understood considering anatomicoclinical evidence indicating that activation of this region during working memory tasks has conceived responsible for the coordination of concurrent processing of disparate sensory and cognitive events [Collette F& Van der Linden, 2002]. In this context it is reasonable to keep in mind that lesion studies [Karnath, 2001] indicate that this region plays a crucial role in spatial neglect.

22. However, it would be useful to discuss the specificity of the attenuation of the P300 amplitude with respect to other psychiatric disorders. Alcoholics also exhibit attenuated P300 (Enoch et al., 2001), as do schizophrenics (Mathalon et al., 2000) and Alzheimer patients (Daffner et al., 2001). An alternative explanation may be that these nonspecific abnormalities are mediated by complex brain networks, requiring the integration of multiple cognitive activities involving multiple brain areas (Tracy, 1995). Moreover, these nonspecific findings may indicate that, in addition to disease-specific processes, disease general processes exist, which could represent ‘an ordered pathway in the brain’s adaptation to many central nervous system diseases’ (Tracy, 1995).

23. The P300 latency is considered to be a measure of stimulus classification speed (Polich, 1986), reflecting the rapidity of allocation of attentional resources for memory processing (Polich and Martin, 1992; Reinvang, 1999). Thus, it has been argued that prolonged P300 latency may reflect a failure to allocate attention resources to a stimulus (Coull, 1998; Polich, 1998). From a neurobiological point of view, prolonged latency may also suggest the involvement of a neurodegenerative process (O’Donnel et al., 1995; Wang et al., 2003), affecting callosal size and the efficiency of inter-hemispheric transmission (Hoffman and Polich, 1999).

24. Therefore, the differences reported here could imply that DMS patients may have difficulties in allocating attention resources to a stimulus, possibly due to a neurodegenerative process, involving or affecting an impaired interhemispheric transmission. This assumption seems to be broadly consistent with the study from Shah et al. (2001), who, exposing healthy volunteers to familiar and unfamiliar faces and voices and employing functional MRI technique, recorded increased activity in the posterior cingulate cortex and the bilateral retrosplenial cortex. Based on these findings they suggested that this brain circuitry would account for the judgment of familiarity, which is a substantial issue of DMS.

25. Our hypothesis is also compatible with observations in the classic disconnection syndrome called pure word blindness or alexia without agraphia,resulting fromdisruption of the corpus callosum, which interconnects the two hemispheres(Nolte, 1999). Patients with this rare condition can write (thus no agraphia) but are unable to read (alexia) even words they have just finished writing. Additionally, this assumption is supported by the study of Sergent (1990), who found that callosal defects may be involved in DMS processes.

26. The memory performance of the two groups was significantly compromised. This agrees with studies reporting that both DMS patients and PMD patients show memory deficits (Feinberg et al., 1999; Verdoux and Liraud, 2000).

27. Conclusion • Our results should be interpreted with caution due to the smallness of the test sample and that post-hoc assignation of psychological function to regional activation is hypothetical. • Future studies attending to these issues are warranted to build on these initial findings indicating that PMD and DMS patients share similar psychophysiologic alterations connected to the right frontal region, mediating automatic processes, while DMS are associated with dysfunction of effortful mechanisms and allocation of attentional resources involving the right parietal and the interhemispheric circuitry.