Burnett et al. 1 noted that certain chronic schizophrenic. Does Tardive Dysmentia Really Exist? CLINICAL AND RESEARCH REPORTS

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1 CLINICAL AND RESEARCH REPORTS Does Tardive Dysmentia Really Exist? Sagar Lavania, M.B.B.S, M.D., D.P.M. Samir Kumar Praharaj, M.B.B.S, M.D., D.P.M. Hariender Singh Bains, M.R.C.P. (Psych.) Sudhir Kumar, M.B.B.S, M.D. Dinesh Malkan Singh Rathore, M.B.B.S, M.D. Sandhya Mohanty, Ph.D. Madhu Nayak, M.B.B.S, M.D. Tardive dysmentia has been described as the behavioral equivalent of tardive dyskinesia in patients with schizophrenia. Its association with tardive dyskinesia and psychopathology has been controversial. The authors assessed 123 inpatients with chronic schizophrenia for presence of tardive dysmentia symptoms/signs. Psychopathology and tardive dyskinesia were also assessed. Of the group, 24 patients (19.5%) had at least one tardive dysmentia symptom/sign, whereas only 1 patient (0.8%) fulfilled the syndromal criteria for tardive dysmentia. Those with tardive dysmentia had higher psychopathology scores, higher Abnormal Involuntary Movement Scale total scores, higher number of women and family psychiatric illness, and higher rates of persistent tardive dyskinesia. Tardive dysmentia symptoms/signs are frequently seen in chronic schizophrenia, but the complete syndrome may be rare. (The Journal of Neuropsychiatry and Clinical Neurosciences 2013; 25:58 62) Burnett et al. 1 noted that certain chronic schizophrenic patients with severe tardive dyskinesia presented with behavior resembling that of hypomania as well as schizophrenia. These patients tended to be loquacious and to speak in a loud voice. Wilson et al. 2 studied this phenomenon in 29 schizophrenia patients and coined the term tardive dysmentia as the behavioral equivalent of tardive dyskinesia. It is described as a behavioral syndrome in schizophrenia characterized by a triad of symptoms/signs: alteration in 1) affect; 2) activation level; and 3) interpersonal interaction. Since the time term tardive dysmentia was coined by Wilson et al., 2 research papers have been published questioning the validity of the term. Mukherjee 3 reassessed the concept of tardive dysmentia and discouraged the use of dysmentia on phenomenological grounds. Also, the association with tardive dyskinesia was challenged, based on the observation that such syndrome was absent in bipolar patients with tardive dyskinesia after long-term exposure to antipsychotics. 3 Mukherjee and Bilder 4 reported that there is no evidence that the syndrome is tardive or iatrogenic in nature and that it may be a manifestation of schizophrenia. Perenyi et al. 5 found this phenomenon to be very rare and suggested retaining the term tardive dysmentia until a better characterization is found. Tardive dysmentia has been associated with various risk factors. Studies have related tardive dysmentia with the severity of tardive dyskinesia, 2 duration of antipsychotic exposure, 2 and phenomenology and pathophysiology of schizophrenia. 3 There is lack of consensus on whether the tardive dysmentia is primarily related to disease process or is iatrogenic in origin. Furthermore, although various risk factors for tardive dysmentia have been suggested in patients with schizophrenia, only a small proportion develops this condition. Understanding these risk factors would have far-reaching implications on prognosis, treatment, and understanding of the disorder. Only a handful of studies on tardive dysmentia have been systematically done todate. Therefore, we aimed to assess the prevalence of tardive dysmentia and its relationship with tardive dyskinesia and psychopathology in patients with chronic schizophrenia. Received February 6, 2012; revised June 17, 2012; accepted July 10, From the Dept. of Psychiatry, Sarojini Naidu Medical College, Agra, India; Dept. of Psychiatry, Kasturba Medical College, Manipal, Karnataka, India; Nottinghamshire Healthcare NHS Trust, Kingsfield Resource Centre, Surrey, UK; Institute of Mental Health & Hospital, Agra, India; Department of Paediatrics, Netaji Subhash Chand Bose Medical College, Jabalpur, Madhya Pradesh, India. Send correspondence to Dr. Samir Kumar Praharaj, M.B.B.S, M.D., D.P.M., Dept. of Psychiatry, Kasturba Medical College, Manipal, Karnataka, India; samirpsyche@yahoo.co.in Copyright 2013 American Psychiatric Association 58 J Neuropsychiatry Clin Neurosci 25:1, Winter 2013

2 LAVANIA et al. METHODS Sample This was cross-sectional, hospital-based study conducted at Institute of Mental Health (IMH) and Hospital, Agra, India. The study was approved by the institutional ethics committee. The sample consisted of male and female inpatients fulfilling criteria for schizophrenia according to ICD-10 Diagnostic Criteria for Research, 6 having chronic illness (duration of illness of 2 years or more) and giving written informed consent. Those with comorbid mental retardation or major medical or neurological illness were excluded from the study. Assessment Tools A datasheet specially designed for the study was used to collect sociodemographic and clinical details of the patients. To diagnose tardive dysmentia, Wilson et al. 2 criteria were used. Emotional behavior was rated on five symptoms/signs: 1) depressed-to-euphoric mood; 2) stable-to-labile or unstable mood; 3) quiet-to-loud speech; 4) paucity-to-excess of words; and 5) retreat-to-approach to the examiner, using 100-mm line tests as described by Wilson et al. 2 To assess schizophrenic psychopathology, the 30-item Positive and Negative Syndrome Scale (PANSS) 7 was used. The PANSS is based on the premise that schizophrenia has two distinct syndromes, a positive syndrome including delusions, hallucinations, and so forth, and a negative syndrome, involving features such as affective flattening and alogia. To characterize tardive dyskinesia, the Abnormal Involuntary Movement Scale (AIMS), 8 a 12-item instrument utilized to provide a numeric measure to the observed abnormal movements in different parts of the body, was used. The information is scored on a 5-point scale (0: none; 4: severe). Test retest reliability ranges from 0.40 to 0.82 for individual items and is 0.71 for overall severity. Research diagnoses for tardive dyskinesia 9 were used to classify tardive dyskinesia subtype. These has been suggested to help study the epidemiology, etiology, and treatment of tardive dyskinesia patients. Tardive dyskinesia is divided into six groups: probable tardive dyskinesia, masked probable tardive dyskinesia, transient tardive dyskinesia, withdrawal tardive dyskinesia, persistent tardive dyskinesia, and masked persistent tardive dyskinesia. 9 Procedures Case record files of inpatients of the IMH, Agra were screened to identify patients with schizophrenia. For those fulfilling inclusion criteria, a detailed mental status examination was done to confirm the diagnosis, after obtaining written informed consent. Sociodemographic and clinical details were recorded in the semistructured datasheet. Detailed physical and neurological examination was done to rule out medical comorbidity. Tardive dysmentia was assessed using Wilson et al. 2 criteria to characterize two groups: schizophrenia patients with and without tardive dysmentia. All the patients were rated on PANSS, AIMS, and Global Assessment of Functioning (GAF). Tardive dyskinesia was classified using Schooler and Kane criteria. 9 The ratings were done by two authors, SL and DMSR. To assess interrater reliability, the first 25 patients were assessed by both raters. Statistical Analysis Data obtained were analyzed with the Statistical Package for Social Sciences (SPSS) Version 10.0 for Windows. Normality of data were examined with the Shapiro-Wilk test statistic. To examine interrater reliability, Spearman s rank correlation coefficient was calculated for 25 patients. To compare patients with or without tardive dysmentia, the Mann-Whitney U test and Pearson s chi-square test were used for continuous and categorical variables, respectively. A p value of,0.05 (two-tailed) was considered significant. RESULTS Sample characteristics as described by the Mann- Whitney U test and Pearson s chi-square (with effect size) test are summarized in Table 1 and Table 2. The mean age of patients was (standard deviation [SD]: 9.42; range: 19 62) years, and mean illness duration was 9.32 (SD: 6.36; range: 2 40) years. Mean level of formal education was 8.23 (SD: 4.69) years. Ninety-one patients (74%) were men; 53 (43.1%) were single; 34 (27.6%) were unemployed before admission to the hospital; 84 (68.3%) were of lower socioeconomic status; and 75 (61%) were from a rural background. Interrater reliability, as seen using Spearman s rank coefficient of correlation, was the following: PANSS Positive score, 0.97 (p,0.001); PANSS Negative score, 0.96 (p,0.001); PANSS General psychopathology score, 0.89 (p,0.001); PANSS Total score, 0.93 (p,0.001); AIMS total score, 0.70 (p,0.001); euphoria, 0.97 (p,0.001); unstable mood, 0.95 (p,0.001); loud speech, 0.90 (p,0.001); J Neuropsychiatry Clin Neurosci 25:1, Winter

3 DOES TARDIVE DYSMENTIA REALLY EXIST? TABLE 1. Comparison of Socio-Demographic and Clinical Characteristics Without TDm (N=99) With TDm (N=24) Mann- Whitney U (Z) p Age, years (9.10) (10.76) 1, Median (range) 34 (42) 34 (38) (20.39) Education years 8.13 (4.56) 8.63 (5.31) 1, Median (range) 8 (17) 9 (17) (20.51) Illness duration, years 9.09 (6.45) (5.98) 1, Median (range) 7 (38) 9.50 (23.5) (21.19) PANSS Positive 9.93 (4.30) (5.47) 815.5* Median (range) 8 (20) 12 (25) (22.47) PANSS Negative (7.77) (6.04) 1, Median (range) 8 (28) 8.5 (20) (20.17) PANSS General psychopathology (7.67) (5.07) Median (range) 18 (43) 20.5 (16) (21.72) PANSS Total (17.80) (14.15) Median (range) 35 (97) 43 (56) (21.66) AIMS Total 0.42 (1.86) 0.96 (2.49) 1, Median (range) 0 (10) 0 (9) (21.89) Antipsychotics dose (chlorpromazine equivalent) (214.95) (208.86) Median (range) 300 (1400) 300 (850) (21.25) Values are mean (standard deviation), unless otherwise indicated. TDm: Tardive dysmentia. *p,0.05 (two-tailed). excessive words, 0.87 (p,0.001); and approach to examiner, 0.89 (p,0.001). Mean PANSS Positive scores were significantly higher in patients with tardive dysmentia symptoms/signs than those without (p=0.014), and there was a trend toward higher scores in PANSS Total score and General psychopathology scores. A trend toward higher mean AIMS total scores was also seen in patients with tardive dysmentia symptoms/signs than those without (p=0.059). There was no difference in illness duration and antipsychotics dose between the two groups. Women were significantly more frequent among those with tardive dysmentia symptoms/signs than those without (p=0.014), although the effect size was small. Also, family psychiatric TABLE 2. Comparison of Socio-Demographic and Clinical Characteristics, N (%) Without TDm (N=99) With TDm a (N=24) x 2 p Effect size (f) Sex Male 78 (78.8) 13 (54.2) 6.08* Female 21 (21.2) 11 (45.8) Marital status Single 43 (43.4) 10 (41.7) 0.03 NS Married 56 (56.6) 14 (58.3) Occupation Unemployed 24 (24.2) 10 (41.7) Employed 75 (75.8) 14 (58.3) SES Lower 68 (68.7) 16 (66.7) 0.04 NS Middle 31 (31.3) 8 (33.3) Family type Nuclear 25 (25.3) 6 (25) 0.01 NS Joint 74 (74.7) 18 (75) Domicile Rural 59 (59.6) 16 (66.7) 0.41 NS Urban 40 (40.4) 8 (33.3) Schizophrenia subtype Paranoid 58 (58.6) 15 (62.5) 0.12 NS Nonparanoid 41 (41.4) 9 (37.5) Comorbid substance dependence Absent 53 (53.5) 18 (75) Present 46 (46.5) 6 (25) Family psychiatric illness Absent 83 (83.8) 12 (50) 12.58**, Present 16 (16.2) 12 (50) TD (Schooler & Kane) 9 Absent 96 (97) 20 (83.3) 6.69* Persistent 3 (3) 4 (16.7) TDm: Tardive dysmentia; TD: Tardive dyskinesia; Having at least one symptom of TDm; SES: socio-economic status. a Having at least one symptom of TDm. *p,0.05. **p,0.001 (two-tailed) J Neuropsychiatry Clin Neurosci 25:1, Winter 2013

4 LAVANIA et al. illness was higher in the tardive dysmentia symptoms/ signs group (p,0.001), with moderate effect size. Furthermore, trend toward a higher (16.7%) rate of persistent tardive dyskinesia was noted in those with tardive dysmentia symptoms/signs than those without (p=0.1), with small effect size. The frequency of tardive dysmentia symptoms/signs were the following: 9 (7.3%) had euphoria; 7 (5.7%) had unstable mood; 17 (13.8%) had loud speech; 12 (9.8%) had excessive words; and 3 (2.4%) had approach to examiner. Ninety-nine (80.5%) had no symptoms/signs; 24 (19.5%) had at least one symptom/sign; 16 (13%) had at least two symptoms/signs; 6 (4.9%) had at least three symptoms/signs; 2 (1.6%) had four symptoms/signs; and none had all five symptoms/signs. Only one patient (0.8%) fulfilled the Wilson et al. 2 criteria for tardive dysmentia, that is, having all three symptoms/signs: unstable mood, loud speech, and approach to the examiner. Spearman s rank correlation between individual tardive dysmentia symptoms/signs with psychopathology showed a significant positive correlation of PANSS Positive symptoms with unstable mood (r s =0.57; p=0.004) and excessive words (r s =0.52; p=0.009; Figure 1[A] and Figure 1[B]), and a trend toward positive correlation with loud speech (r s =0.39; p=0.06) and approach to examiner (r s =0.37; p=0.074). There was no correlation with PANSS Negative, General psychopathology, or Total score, and AIMS total score with any of tardive dysmentia symptoms/signs. There was no correlation of tardive dysmentia symptoms/signs with duration of illness or antipsychotics dose. FIGURE 1. Unstable Mood Excessive Words A B Scatterplot Showing Correlation of PANSS Positive Score With Tardive Dysmentia Symptoms (With Regression Line) (N=24) PANSS Positive Score DISCUSSION Results of our study show that tardive dysmentia symptoms/signs are fairly common in chronic schizophrenia patients, whereas, tardive dysmentia, as defined by Wilson et al., 2 is uncommon. Our study supports the hypothesis that these symptoms/signs are related to positive symptoms of schizophrenia, 3 with moderate-tohigh effect sizes. Although these symptoms/signs were not related to antipsychotic dose, a trend toward higher symptoms/signs was noted in those with tardive dyskinesia, with small effect size. Moreover, these symptoms/signs correlated with higher level of persistent tardive dyskinesia by Schooler and Kane 9 criteria. These findings are in contradiction to the reports of association of tardive dyskinesia with negative symptoms PANSS Positive Score [A] With Unstable Mood; [B] With Excessive Words of schizophrenia, 10,11 although, in recent studies, 12 they show correlation with positive symptoms, as well. It is also interesting to note that the symptoms/signs of tardive dysmentia have a superficial resemblance to hypomanic or manic symptoms. There have been reports of a possible association between tardive dyskinesia and affective disorders. 13 It also raises the possibility of the usefulness of mood stabilizers in the treatment of such symptoms/signs. Furthermore, tardive dysmentia symptoms/signs were more common in women and J Neuropsychiatry Clin Neurosci 25:1, Winter

5 DOES TARDIVE DYSMENTIA REALLY EXIST? those with a family history of psychiatric illness, with small-to-moderate effect sizes, respectively. Similar female predominance has also been reported in tardive dyskinesia studies. 14 The mechanisms of these symptoms/signs are poorly understood. Dopamine receptor supersensitivity after prolonged antipsychotics exposure, as proposed for tardive dyskinesia, may be an underlying mechanism for tardive dysmentia. 2,15,16 Jones 17 argued against such hypothesis and introduced the concept of cholinergic system dysfunction in tardive dysmentia. Correlation with positive symptoms suggests a common psychopathological mechanism for tardive dysmentia symptoms/ signs. The common pathway for expression of both these conditions could probably be through involvement of cortico subcortical circuits. 18,19 Interestingly, dopamine receptor supersensitivity has been suggested as the final common state resulting from multiple pathways that converge to elevate the dopamine levels in various brain areas. 20 Alternatively, the etiology of tardive dysmentia may be multifactorial, with one mechanism predominating in a subset of such patients. Neurobiological studies in these patients would reveal further insights into this phenomenon and the possible treatment strategies. In summary, tardive dysmentia symptoms/signs are frequently seen in patients with schizophrenia, but the complete syndrome may be rare. Besides correlation with psychopathology and tardive dyskinesia, which may provide clues to the neurobiological mechanisms, there are clinical implications also. The symptoms/signs of tardive dysmentia may lead to misdiagnosis of patients with schizophrenia by an unwary examiner as bipolar or schizoaffective disorder. Although our study had a large sample size, it may not be sufficient to characterize the true prevalence of this syndrome, and further studies are required. Another limitation is that all patients were chronically institutionalized, and, hence, these findings cannot be generalized to other population. Future studies may be designed to include schizophrenia patients from the community to overcome the effects of institutionalization and characterize the true prevalence of these symptoms/signs. This work was carried out at the Institute of Mental Health & Hospital, Agra, India. References 1. Burnett GB, Prange AJ Jr, Wilson IC, et al: Adverse effects of anticholinergic antiparkinsonian drugs in tardive dyskinesia: an investigation of mechanism. 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Schizophr Bull 1992; 18: Andrew HG: Clinical relationship of extrapyramidal symptoms and tardive dyskinesia. Can J Psychiatry 1994; 39(Suppl 2):S76 S Kostrzewa RM, Kostrzewa JP, Brown RW, et al: Dopamine receptor supersensitivity: development, mechanisms, presentation, and clinical applicability. Neurotox Res 2008; 14: Jones BD: Tardive dysmentia : further comments. Schizophr Bull 1985; 11: Deutch AY: Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson s disease. J Neural Transm 1993; 91: Bonelli RM, Cummings JL: Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 2007; 9: Seeman P, Schwarz J, Chen JF, et al: Psychosis pathways converge via D2 high dopamine receptors. Synapse 2006; 60: J Neuropsychiatry Clin Neurosci 25:1, Winter 2013