- Email: [email protected]
Characteristics, treatments and outcome of psychosis in Thai SLE patients
Journal of Psychosomatic Research 73 (2012) 448–451
Contents lists available at SciVerse ScienceDirect
Journal of Psychosomatic Research
Characteristics, treatments and outcome of psychosis in Thai SLE patients Pongsatorn Paholpak a,⁎, Poonsri Rangseekajee a, Chingching Foocharoen b a b
Department of Psychiatry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Department of Internal Medicine, Division of Rheumatology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
a r t i c l e
i n f o
Article history: Received 13 February 2012 received in revised form 9 August 2012 accepted 10 August 2012 Keywords: Neuropsychiatric systemic lupus erythematosus (NPSLE) Psychotic disorders Lupus vasculitis Lupus psychosis
a b s t r a c t Objectives: To study the clinical characteristics and outcomes of psychosis and its clinical correlation with disease activity in Thai systemic lupus erythematosus (SLE) patients. Methods: From 750 SLE patients, 36 episodes of psychosis or psychotic depression in SLE patients were retrospectively identified between June 1999 and June 2009 at Srinagarind Hospital, Khon Kaen University. The clinical characteristics, laboratory analyses, disease activity, treatments and outcomes were studied. Results: A total of 35 SLE patients had 36 psychotic episodes that consisted of 29 psychotic episodes and 7 psychotic depressive episodes. Eleven episodes (30.6%) occurred during the first manifestation of lupus. Psychotic symptoms included persecutory delusion (50%), bizarre delusion (44.4%), third person auditory hallucinations (44.4%) and visual hallucinations (36.1%). Twenty four episodes (67%) were associated with active lupus in CNS and other organs. All patients received immunotherapy and psychotropic treatments. Psychosis and depressive psychosis were treated with antipsychotics and antidepressants for a mean duration of 71 and 410 days. One death resulted from suicide, and one of thirty four cases (2.9%) had a reoccurrence within a mean follow-up period of 44 months. Conclusion: About one-third of the psychotic episodes occurred during the first manifestation of lupus. Persecutory delusion, bizarre delusion, third person auditory hallucination, and visual hallucination were common. During psychotic episodes, lupus activity was active in other parts of CNS and organs in 67% of patients. Depressive psychosis required psychotropic treatment longer than psychosis alone. The psychiatric outcome was very favorable. Most of psychotic episodes (97.1%) were fully remitted and rarely showing recurrences. © 2012 Elsevier Inc. All rights reserved.
Systemic lupus erythematous (SLE) is an autoimmune disorder which manifests with systemic inflammation. It can cause abnormalities to either the central or the peripheral autonomic system and can result in a wide range of neuropsychiatric (NP) disorders. In 1999, American College of Rheumatology (ACR) presented neuropsychiatric systemic lupus erythematosus (NPSLE) as a standardized group of SLE-induced NP disorders [1]. NPSLE which required psychiatric attention included acute confusional state (delirium), affective disorders, cognitive impairment, and psychosis. Since clinical presentations and laboratory findings varied widely among each of the NPSLE patients, further study was warranted for each individual disorder. Psychosis and seizure were the only 2 NP manifestations in which ACR included in diagnostic criteria for SLE [2]. Psychosis is a mental state which is characterized by hallucination, thought disturbance and disorganized behavior. The clinical condition is probably mediated by autoantibodies, microvasculopathies and the intracranial production of inflammatory mediators [3]. Many studies have found that the prevalence of psychosis ranged from 1 to 22.3% [4–14] in the SLE population. Psychosis may be influenced by disease-related psychological stressors ⁎ Corresponding author. Tel.: +66 43 348384; fax: +66 89 422 1147. E-mail addresses: [email protected], [email protected] (P. Paholpak). 0022-3999/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2012.08.006
[15] and it usually has occurred during an aggravation of lupus activity, especially skin rashes and vasculitis [12,13]. Treatment options for psychosis in lupus patients included the use of immunosuppressive agents to control disease activity and supportive management with psychotropic medications [16]. However, characteristic, treatment and outcomes of this rare syndrome are not well established. Furthermore, none of the previous publications have mentioned psychotic depression which appears to be an overlap syndrome between depression and psychosis. By using the definition of NPSLE from ACR, this group of SLE patients who had been diagnosed with either psychosis or psychotic depression were studied in order to report the following: 1) their clinical characteristics and laboratory data, 2) treatment options for patients, and 3) and long term outcomes of patients. Patients and methods This study was approved for all research procedures by the Ethics Committee in Human Research of the Khon Kaen University (EC code: HE521089). From 1 June 1999 to 1 June 2009, a total of 750 SLE patients were registered in the database at Srinagarind hospital, Faculty of Medicine, Khon Kaen University, Thailand. The database was coded in the
P. Paholpak et al. / Journal of Psychosomatic Research 73 (2012) 448–451
ICD-10 format. As ACR has previously proposed, mental disorders which have occurred from a direct consequence of SLE can be considered under two categories: “mental disorder due to general medical condition” in the Statistical Manual of Mental Disorders 4th edition (DSM-IV) [17] and “organic mental disorder” category in the International Statistical Classification of Diseases 10th Revision (ICD-10) [18] nomenclatures. The database was scrutinized using the ICD code as above and a total of 76 inpatients and outpatients records were found. All records were included in this study. The clinical information of each visit of every patient was collected, and then all of the psychiatric episodes were carefully reviewed. Since the main objective was to study real NP episodes, the criteria ensured that all of psychotic episodes did not occur as a result of other metabolic or medication-induced conditions. The majority of steroid-induced psychosis usually occurred within 5–14 days [19] after initiating and increasing corticosteroid dosage, and these episodes were likely to respond after the dose had been tapered within a week. Therefore, psychotic episodes which occurred within 5–14 days after initiating and increasing steroid therapy, and the psychotic episodes which responded to dose tapering within 7 days were excluded due to a high possibility that the episodes were actually steroid induced psychosis [20,21]. Overall, a total of 40 records were excluded for the following reasons: 1) 12 records were incomplete, 2) 10 records did not meet at least four of ACR 1997 criteria for SLE [2], and 3) 18 episodes were likely to be steroid-induced psychosis. None of patients have had a preexisting primary psychotic disorder. From the 36 remaining records, 17 patients had not had complete follow up by the end of June 2009. In order to detect any psychotic episode during loss of follow up, one psychiatrist performed the Mini International Neuropsychiatric Interview, Thai version 5 (MINI Thai version 5), module L (psychotic disorders) [22], via phone calls with all patients and knowledgeable caregivers. Thus, it was very unlikely that any psychotic episode would have been missed. Patient data were retrospectively reviewed from medical records. Demographic data collected were the age of onset of SLE, clinical manifestations of SLE, laboratory findings of SLE during each psychotic episode, characteristics of psychotic episode, duration, treatments and outcomes of each episode. Hematologic involvement was defined by having the autoimmune hemolytic anemia (AIHA) blood picture with a positive direct Coomb's test. Renal involvement was defined by evidence of protein in the urine of more than 0.5 g/day, or presenting of red blood cells, or confirmation via renal biopsy. Central nervous system (CNS) involvement was defined by diagnosis of other neurological disorders than psychosis. In the investigations, the most significant result of the repeated evaluations done during each psychotic episode like complete blood count and serum complement level, that could explain the temporal relationship with the NP symptoms, was used. A complete resolution of positive symptoms and a return of function reported by caregivers were considered as remission. Results Patients All of the patients were Thai. Thirty five patients had a total of thirty six psychotic episodes. There were 29 psychotic episodes and 7 psychotic depressive episodes; only 1 patient in the psychosis group had a recurrence of psychosis. Average ages were 29.97 (SD ± 12.77) and 26.14 (SD ± 7.96) years for psychosis and psychotic depression group, respectively. Most of the patients were female with only three males (11%) in the psychosis group.
SLE manifestations, characteristic of psychotic episodes and psychotic depression episodes In the psychosis group, an average delay of psychosis from SLE onset was 35.9 months (SD ± 52). In 9 patients (32.1%), psychosis appeared in first visit of SLE. Twenty-two (75.8%) patients were being treated with corticosteroids at an average dose of 27.7 mg/day (SD ± 23.4). For the psychotic depressive group, 2 episodes (29%) appeared in first visit of SLE. All patients (100%) were being treated with
449
corticosteroids at an average dose of 45 mg/day (SD ± 21.4). The average delay from lupus onset was 40.1 months (SD ± 44.6). From the total subjects of both groups, active organs involvement occurred in 24 episodes (67%). Active organ involvement included renal (39%), hematologic (36%), skin rashes (22%), central nervous system (19%), arthritis (8%), vasculitis (5%), and cardiac (3%). Central nervous system involvement, other than psychosis, was comprised of 4 cerebral ischemia, 2 seizures and 3 encephalopathies. Twenty nine patients (80.6%) were being treated with corticosteroids at an average dose of 31.1 mg/day (SD ± 23.8). All of demographic data and SLE manifestations that occurred during psychotic episodes are summarized in Table 1. Psychotic elements of both groups included persecutory delusion (50%), bizarre delusion (44.4%), third person auditory hallucinations (44.4%), complex visual hallucinations (36.1%), auditory and visual hallucinations (17%), and controlled delusions (17%). From the 7 depressive psychotic episodes, guilty delusion occurred 3 times (43%). According to DSM-IV criteria, the average severity of depression was moderate by 5.5(SD ± 1.4). The characteristics of psychosis in each group are detailed in Table 2.
Investigation During psychotic episodes, the average blood levels of both C3 and C4 were normal in both groups. ANA was positive in 33 patients (92%), antiphospholipid antibody was positive in 3 patients, but we were unable to perform anti-ribosomal P antibody testing. Neuroimaging (CT or MRI) was done in 21 episodes (72%) during psychosis, and abnormal findings were described in 15 of the 21 patients (72%). Seven of the fifteen (47%) patients had mild to moderate brain atrophy while other abnormalities included 4 ischemic processes at frontal lobe and basal ganglia, 1 leptomeninges involvement and 4 white matter hyperintensities. Lumbar puncture was performed in 15 patients, and elevated protein levels (above 45 mg/dL) were found in 6 samples. EEG was performed on 3 patients and all three demonstrated encephalopathy by exhibiting a diffused slow wave, while 2 of them had co-existing epileptic activity.
Neuropsychiatric treatment and outcome All 36 psychotic episodes required hospitalization and both immunotherapy and symptomatic treatments were also required. Patients were treated with methylprednisolone 1 g daily for 3 days (58.3%) or cyclophosphamide 500 mg every 2 weeks (8%) or with both (19.4 %). All of psychotic episodes required antipsychotic treatment; haloperidol, risperidone, and quetiapine were used in 23, 4 and 2 episodes. All episodes were fully remitted with an average haloperidol dose and duration of treatments of 5.9 (SD±7.7) mg/day and 71 (SD±61) days. Depressive psychotic patients required both antidepressant and antipsychotic treatment. A combination of fluoxetine and haloperidol was used in six (85%) patients with an average dose of 30 mg/day and 5 mg/day. The mean duration of treatment in depressive psychosis was 410 days (SD±379 days) due to the prolonged use of antidepressant. Another patient (15%) was successfully treated with a combination of paroxetine and risperidone. One death occurred from suicide by a drug resistant patient in the psychosis group. One (2.9%) of thirty four remaining patients had a recurrence of psychosis after 4 years of remission while other psychotic episodes remitted completely during the mean follow up of 44 (SD ± 29.7) months.
Table 1 Demographic data and clinical manifestations of lupus during psychotic episodes. Demographic data
Age (years) Appear in first visit of SLE Previous episode of lupus psychosis Delay of psychotic presentation (months) Organ involvement Any organ involvement Renal Vasculitis Pulmonary Cardiac Serositis Hematologic CNS (other than psychosis) Skin rash, vasculitis Arthritis Medications Corticosteroid Average corticosteroid (mg/day)
Psychosis episodes
Depressive psychotic episodes
(N = 29)
(N = 7)
29.97 ± 12.77 9 (32.1%) 1 35.9 ± 52
26.14 ± 7.96 2 (28.6%) 0 40.1 ± 44.6
20 (69%) 11 (37.9%) 1 (3.4%) 0 (0%) 1 (3.4%) 0 (0%) 12 (41.4%) 6 (20.7%) 6 (20.7%) 2 (6.9%)
4 (57.1%) 3 (42.9%) 1 (14.3%) 0 (0%) 0 (0%) 0 (0%) 1 (14.3%) 1 (14.3%) 2 (28.6%) 1 (14.3%)
22 (75.8%) 27.7 ± 23.4
7 (100%) 45 ± 21.40
450
P. Paholpak et al. / Journal of Psychosomatic Research 73 (2012) 448–451
Table 2 Common symptoms in psychosis and depressive psychotic groups. Characteristic of NP episodes
Hallucination Auditory (third person) Visual (complex) Both auditory and visual Other Delusion Bizarre Persecutory Control Other
Psychosis episodes
Depressive psychotic episode
(N = 29)
(N = 7)
13 (45%) 12 (42%) 6 (21%) 1 Tactile (4%)
3 (43%) 1 (14%) 0 0
16 (55%) 14 (48%) 4 (14%) 3 TB (10%), 1 TI (3.5%), 1 TW (3.5%)
0 4 (57%) 2 (29%) 3 Guilty delusions (43%)
TB = thought broadcasting, TI = thought insertion, TW = thought withdrawal.
Discussion This case series reports a total of 36 psychotic episodes, a prevalence of 4.8%, which included 29 episodes of psychosis and 7 of depressive psychotic episodes. Patients with depressive psychosis tended to receive higher doses of corticosteroids than the pure psychosis group, but without statistical significance (p > 0.05). The mean severity of depressive symptoms in depressive psychosis was moderate. Most of the psychotic episodes remitted completely, except for the one death from suicide. In the long duration of the follow up, only one recurrence occurred. It was found that lupus psychosis resembled psychosis in the primary psychotic disorders e.g. schizophrenia and steroid induced psychosis. All of these patients presented with bizarre delusions along with either visual or auditory hallucinations [12,13]. Third person auditory hallucination, persecutory delusion and bizarre delusion were the three most common psychotic symptoms in this case series; and they are also very common in schizophrenia. Since one-third of psychotic episodes appeared in the first diagnosis of SLE and all of them had positive ANA (unpublished data); this encourages psychiatrists to screen for ANA in the first visit of psychotic female patients. However, it is not recommended to use phenotypes of psychosis to distinguish between lupus psychosis and psychosis from other causes. Our prevalence was relatively low compared to other studies; this might have arisen from differing methods of inclusion and exclusion criteria utilized among studies. Although we tried to exclude psychosis from the other causes, we could not totally exclude steroid-induced psychosis, which in some cases could occur later than 2 weeks after initiating and increasing the dose. The Brazil [12], UK [13], US [23] and this case series found that psychotic episodes usually occurred with florid activity of lupus. From the laboratory aspect, renal and hematologic involvements were predominant and lymphopenia was found in nearly half of psychotic episodes (unpublished observations). This differs from the previous UK study in which malar rash and hematologic manifestations were the two most common lupus exacerbations while renal involvement was less evident [13]. This difference could not be explained, however, from our observation, that ethnicity might have played role in neuropsychiatric manifestations. From the neurologic investigation, coexistence of nonspecific cerebral atrophy appeared in a majority of patients but ischemic or inflammatory lesions which required further treatment were not uncommon. Encephalopathy, epileptic activity and lesions at the frontal lobe or basal ganglia might explain psychosis with bizarre delusion in this series as well [24,25]. In conclusion, it is suggested that neuroimaging and electroencephalogram should be performed in every lupus psychotic episode in order to detect any missable underlying causes. Based on evidence from case series [26–28], treatment of lupus psychosis used either methylprednisolone, or cyclophosphamide, or both. In the experiences of this study, although all patients were treated
by immunotherapy, they required psychotropic treatment for rapid control of behavioral disturbances [29]. Psychosis alone required antipsychotic therapy for 2–3 months. In our series, haloperidol was used in most cases but risperidone, aripiprazole, olanzapine and quetiapine also have been reported with satisfactory results [23,30,31]. All depressive psychotic episodes were successfully treated with a combination of antidepressant and antipsychotic for a longer period of treatment than in pure psychosis. In this group, 3 patients, however, experienced prolonged 6–8 months of auditory hallucinations before the psychotic component gradually subsided. In 2 cases, psychiatrists decided to prolong antidepressants for more than 1 year to normalize their affects. As a result, this may imply a trend of showing a longer period of psychotic symptoms in depressive psychotic patients. Although psychosis caused one death from suicide, the final outcomes of other psychotic episodes were very favorable. This was unlike the UK and Brazil reports wherein the cohorts had a higher rate (31%) of corticosteroid-related recurrence [12] and 40% of chronic psychosis after 1 year [13]. It was not possible to explain the differences of psychosis outcomes among studies since knowledge of predictors and factors influencing lupus psychosis is still lacking. A recent large prospective study found that the autoantibody ribosomal P proteins (anti-P) were associated with a 3.92 fold risk of having psychosis in future [3]. Only a limited number of laboratories could perform these protein investigations and they have not been studied as a predictor of recurrence and duration of psychosis. Therefore, in terms of clinical implications, this usefulness of this autoantibody is being explored for its use in daily practice [32–34]. The number of patients in our cohort might be small but large when compared to other lupus psychosis cohorts. To the best of our knowledge, no previous publications have considered depressive psychosis and the duration of psychotropic medication. The limitations of this study were that it was a retrospective study. The results of this study seem to suggest that the numbers of patients with psychosis might be underestimated. Mild psychotic episodes, which did not cause severe distress to caregivers and did not lead patients to medical attention, might have been missed. Most of records in the database also did not contain psychological stressors and cognitive evaluations. Thus, it was not possible to report associations with stressors or cognitive impairment during psychosis. These limitations and the lack of this being a controlled trial should warrant interested researchers to conduct further studies in larger prospective design with more precise measurements and controlled management in order to develop a more comprehensive understanding of lupus psychosis. Disclosure statement This study had been supported by grants from the Faculty of Medicine, Khon Kaen University. All authors have declared no conflicts of interest. Acknowledgments The authors would like to thank Mr. Fred Burton Setzler and Professor James Will for editing this article. References [1] The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599-608 [Epub 1999/04/22]. [2] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40: 1725 [Epub 1997/10/27]. [3] Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Clarke A, et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis 2011;70:1726-32 [Epub 2011/09/07]. [4] Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-Romo D, Stallworth CL, et al. Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology 2002;58:1214-20 [Epub 2002/04/24].
P. Paholpak et al. / Journal of Psychosomatic Research 73 (2012) 448–451 [5] Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology 2001;57: 496-500 [Epub 2001/08/15]. [6] Hanly JG, McCurdy G, Fougere L, Douglas JA, Thompson K. Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance. J Rheumatol 2004;31:2156-62Epub 2004/11/02. [7] Jarpa E, Babul M, Calderón J, González M, Martínez ME, Bravo-Zehnder, et al. Common mental disorders and psychological distress in systemic lupus erythematosus are not associated with disease activity. Lupus 2011;20(1):58-66 [Epub 2010 /11/17]. [8] Kasitanon N, Louthrenoo W, Piyasirisilp S, Sukitawu W, Wichainun R. Neuropsychiatric manifestations in Thai patients with systemic lupus erythematosus. Asian Pac J Allergy Immunol 2002;20:179-85 [Epub 2003/02/18]. [9] Mok CC, Lau CS, Wong RW. Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J Rheumatol 2001;28:766-71 [Epub 2001/05/01]. [10] Mok CC, To CH, Mak A. Neuropsychiatric damage in Southern Chinese patients with systemic lupus erythematosus. Medicine 2006;85:221-8 [Epub 2006/07/25]. [11] Stojanovich L, Zandman-Goddard G, Pavlovich S, Sikanich N. Psychiatric manifestations in systemic lupus erythematosus. Autoimmun Rev 2007;6:421-6. [12] Appenzeller S, Cendes F, Costallat LT. Acute psychosis in systemic lupus erythematosus. Rheumatol Int 2008;28:237-43 [Epub 2007/07/20]. [13] Pego-Reigosa JM, Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation of the disease. Rheumatology (Oxford) 2008;47:1498-502 [Epub 2008/07/29]. [14] Chiewthanakul P, Sawanyawisuth K, Foocharoen C, Tiamkao S. Clinical features and predictive factors in neuropsychiatric lupus. Asian Pac J Allergy Immunol 2012;30:55-60 [Epub 2012/04/25]. [15] Bodani M, Kopelman MD. A psychiatric perspective on the therapy of psychosis in systemic lupus erythematosus. Lupus 2003;12:947-9 [Epub 2004/01/13]. [16] Bertsias GK, Ioannidis JP, Aringer M, Bollen E, Bombardieri S, Bruce IN, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010;69:2074-82Epub 2010/08/21. [17] American Psychiatric A, American Psychiatric Association. Task Force on D-I. Diagnostic and statistical manual of mental disorders: DSM-IV. Washington, DC: American Psychiatric Association; 1994. [18] Diseases WHOCCfCo. International Conference for the Tenth Revision of the International Classification of D. International statistical classification of diseases and related health problems, 10th revision: ICD-10. Geneva: World Health Organization; 1992. [19] Hall RC, Popkin MK, Stickney SK, Gardner ER. Presentation of the steroid psychoses. J Nerv Ment Dis 1979;167:229-36 [Epub 1979/04/01]. [20] Ayd FJ. Lexicon of psychiatry, neurology, and the neurosciences. Baltimore: Williams & Wilkins; 1995.
451
[21] Hermosillo-Romo D, Brey RL. Diagnosis and management of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Best Pract Res Clin Rheumatol 2002;16:229-44 [Epub 2002/06/04]. [22] Kittirattanapaiboon P, Mahatnirunkul S, Kongsuk T, Choovong K, Booncharoen H, Kwansanit P, Charatsingha A. Validity and Reliability of Mini International Neuropsychiatric Interview: M.I.N.I.: 5.0.0 Thai Version. J Mental Health Thai 2005;13: 125-35. [23] Muscal E, Nadeem T, Li X, Mian A, Harris TB. Evaluation and treatment of acute psychosis in children with Systemic Lupus Erythematosus (SLE): consultation-liaison service experiences at a tertiary-care pediatric institution. Psychosomatics 2010;51:508-14 [Epub 2010/11/06]. [24] Kaplan HI, Sadock BJ. Kaplan & Sadock's comprehensive textbook of psychiatry., 2. Philadelphia [u.a.]: Lippincott Williams & Wilkins; 2009. [25] Kaplan HI, Sadock BJ. Kaplan & Sadock's comprehensive textbook of psychiatry, 1. Philadelphia [u.a.]: Lippincott Williams & Wilkins; 2009. [26] Boumpas DT, Yamada H, Patronas NJ, Scott D, Klippel JH, Balow JE. Pulse cyclophosphamide for severe neuropsychiatric lupus. Q J Med 1991;81:975-84 [Epub 1991/12/01]. [27] Neuwelt CM, Lacks S, Kaye BR, Ellman JB, Borenstein DG. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med 1995;98:32-41 [Epub 1995/01/01]. [28] Ramos PC, Mendez MJ, Ames PR, Khamashta MA, Hughes GR. Pulse cyclophosphamide in the treatment of neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol 1996;14:295-9 [Epub 1996/05/01]. [29] Mok CC, Lau CS, Wong RW. Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study. Am J Med 2003;115:59-62 [Epub 2003/07/18]. [30] Muscal E, Bang L, Mian A, Harris TB. Use of aripiprazole in adolescents with a history of lupus-associated psychosis and refractory psychiatric manifestations. J Psychiatr Pract 2011;17:212-6 [Epub 2011/05/19]. [31] Pinto JP, Morais SL, Hallak JE, Dursun SM. Effectiveness of olanzapine for systemic lupus erythematosus-related psychosis. Prim Care Companion. J Clin Psychiatry 2006;8:377-8 [Epub 2007/01/25]. [32] de Macedo PA, Borba EF, Viana Vdos S, Leon EP, Testagrossa Lde A, Barros RT, et al. Antibodies to ribosomal P proteins in lupus nephritis: a surrogate marker for a better renal survival? Autoimmun Rev 2011;10:126-30 [Epub 2010/09/14]. [33] Doria A, Zen M, Canova M, Bettio S, Bassi N, Nalotto L, et al. SLE diagnosis and treatment: when early is early. Autoimmun Rev 2010;10:55-60 [Epub 2010/09/04]. [34] Rekvig OP, Putterman C, Casu C, Gao HX, Ghirardello A, Mortensen ES, et al. Autoantibodies in lupus: culprits or passive bystanders? Autoimmun Rev 2012;11: 596-603 [Epub 2011/11/02].
Contents lists available at SciVerse ScienceDirect
Journal of Psychosomatic Research
Characteristics, treatments and outcome of psychosis in Thai SLE patients Pongsatorn Paholpak a,⁎, Poonsri Rangseekajee a, Chingching Foocharoen b a b
Department of Psychiatry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Department of Internal Medicine, Division of Rheumatology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
a r t i c l e
i n f o
Article history: Received 13 February 2012 received in revised form 9 August 2012 accepted 10 August 2012 Keywords: Neuropsychiatric systemic lupus erythematosus (NPSLE) Psychotic disorders Lupus vasculitis Lupus psychosis
a b s t r a c t Objectives: To study the clinical characteristics and outcomes of psychosis and its clinical correlation with disease activity in Thai systemic lupus erythematosus (SLE) patients. Methods: From 750 SLE patients, 36 episodes of psychosis or psychotic depression in SLE patients were retrospectively identified between June 1999 and June 2009 at Srinagarind Hospital, Khon Kaen University. The clinical characteristics, laboratory analyses, disease activity, treatments and outcomes were studied. Results: A total of 35 SLE patients had 36 psychotic episodes that consisted of 29 psychotic episodes and 7 psychotic depressive episodes. Eleven episodes (30.6%) occurred during the first manifestation of lupus. Psychotic symptoms included persecutory delusion (50%), bizarre delusion (44.4%), third person auditory hallucinations (44.4%) and visual hallucinations (36.1%). Twenty four episodes (67%) were associated with active lupus in CNS and other organs. All patients received immunotherapy and psychotropic treatments. Psychosis and depressive psychosis were treated with antipsychotics and antidepressants for a mean duration of 71 and 410 days. One death resulted from suicide, and one of thirty four cases (2.9%) had a reoccurrence within a mean follow-up period of 44 months. Conclusion: About one-third of the psychotic episodes occurred during the first manifestation of lupus. Persecutory delusion, bizarre delusion, third person auditory hallucination, and visual hallucination were common. During psychotic episodes, lupus activity was active in other parts of CNS and organs in 67% of patients. Depressive psychosis required psychotropic treatment longer than psychosis alone. The psychiatric outcome was very favorable. Most of psychotic episodes (97.1%) were fully remitted and rarely showing recurrences. © 2012 Elsevier Inc. All rights reserved.
Systemic lupus erythematous (SLE) is an autoimmune disorder which manifests with systemic inflammation. It can cause abnormalities to either the central or the peripheral autonomic system and can result in a wide range of neuropsychiatric (NP) disorders. In 1999, American College of Rheumatology (ACR) presented neuropsychiatric systemic lupus erythematosus (NPSLE) as a standardized group of SLE-induced NP disorders [1]. NPSLE which required psychiatric attention included acute confusional state (delirium), affective disorders, cognitive impairment, and psychosis. Since clinical presentations and laboratory findings varied widely among each of the NPSLE patients, further study was warranted for each individual disorder. Psychosis and seizure were the only 2 NP manifestations in which ACR included in diagnostic criteria for SLE [2]. Psychosis is a mental state which is characterized by hallucination, thought disturbance and disorganized behavior. The clinical condition is probably mediated by autoantibodies, microvasculopathies and the intracranial production of inflammatory mediators [3]. Many studies have found that the prevalence of psychosis ranged from 1 to 22.3% [4–14] in the SLE population. Psychosis may be influenced by disease-related psychological stressors ⁎ Corresponding author. Tel.: +66 43 348384; fax: +66 89 422 1147. E-mail addresses: [email protected], [email protected] (P. Paholpak). 0022-3999/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2012.08.006
[15] and it usually has occurred during an aggravation of lupus activity, especially skin rashes and vasculitis [12,13]. Treatment options for psychosis in lupus patients included the use of immunosuppressive agents to control disease activity and supportive management with psychotropic medications [16]. However, characteristic, treatment and outcomes of this rare syndrome are not well established. Furthermore, none of the previous publications have mentioned psychotic depression which appears to be an overlap syndrome between depression and psychosis. By using the definition of NPSLE from ACR, this group of SLE patients who had been diagnosed with either psychosis or psychotic depression were studied in order to report the following: 1) their clinical characteristics and laboratory data, 2) treatment options for patients, and 3) and long term outcomes of patients. Patients and methods This study was approved for all research procedures by the Ethics Committee in Human Research of the Khon Kaen University (EC code: HE521089). From 1 June 1999 to 1 June 2009, a total of 750 SLE patients were registered in the database at Srinagarind hospital, Faculty of Medicine, Khon Kaen University, Thailand. The database was coded in the
P. Paholpak et al. / Journal of Psychosomatic Research 73 (2012) 448–451
ICD-10 format. As ACR has previously proposed, mental disorders which have occurred from a direct consequence of SLE can be considered under two categories: “mental disorder due to general medical condition” in the Statistical Manual of Mental Disorders 4th edition (DSM-IV) [17] and “organic mental disorder” category in the International Statistical Classification of Diseases 10th Revision (ICD-10) [18] nomenclatures. The database was scrutinized using the ICD code as above and a total of 76 inpatients and outpatients records were found. All records were included in this study. The clinical information of each visit of every patient was collected, and then all of the psychiatric episodes were carefully reviewed. Since the main objective was to study real NP episodes, the criteria ensured that all of psychotic episodes did not occur as a result of other metabolic or medication-induced conditions. The majority of steroid-induced psychosis usually occurred within 5–14 days [19] after initiating and increasing corticosteroid dosage, and these episodes were likely to respond after the dose had been tapered within a week. Therefore, psychotic episodes which occurred within 5–14 days after initiating and increasing steroid therapy, and the psychotic episodes which responded to dose tapering within 7 days were excluded due to a high possibility that the episodes were actually steroid induced psychosis [20,21]. Overall, a total of 40 records were excluded for the following reasons: 1) 12 records were incomplete, 2) 10 records did not meet at least four of ACR 1997 criteria for SLE [2], and 3) 18 episodes were likely to be steroid-induced psychosis. None of patients have had a preexisting primary psychotic disorder. From the 36 remaining records, 17 patients had not had complete follow up by the end of June 2009. In order to detect any psychotic episode during loss of follow up, one psychiatrist performed the Mini International Neuropsychiatric Interview, Thai version 5 (MINI Thai version 5), module L (psychotic disorders) [22], via phone calls with all patients and knowledgeable caregivers. Thus, it was very unlikely that any psychotic episode would have been missed. Patient data were retrospectively reviewed from medical records. Demographic data collected were the age of onset of SLE, clinical manifestations of SLE, laboratory findings of SLE during each psychotic episode, characteristics of psychotic episode, duration, treatments and outcomes of each episode. Hematologic involvement was defined by having the autoimmune hemolytic anemia (AIHA) blood picture with a positive direct Coomb's test. Renal involvement was defined by evidence of protein in the urine of more than 0.5 g/day, or presenting of red blood cells, or confirmation via renal biopsy. Central nervous system (CNS) involvement was defined by diagnosis of other neurological disorders than psychosis. In the investigations, the most significant result of the repeated evaluations done during each psychotic episode like complete blood count and serum complement level, that could explain the temporal relationship with the NP symptoms, was used. A complete resolution of positive symptoms and a return of function reported by caregivers were considered as remission. Results Patients All of the patients were Thai. Thirty five patients had a total of thirty six psychotic episodes. There were 29 psychotic episodes and 7 psychotic depressive episodes; only 1 patient in the psychosis group had a recurrence of psychosis. Average ages were 29.97 (SD ± 12.77) and 26.14 (SD ± 7.96) years for psychosis and psychotic depression group, respectively. Most of the patients were female with only three males (11%) in the psychosis group.
SLE manifestations, characteristic of psychotic episodes and psychotic depression episodes In the psychosis group, an average delay of psychosis from SLE onset was 35.9 months (SD ± 52). In 9 patients (32.1%), psychosis appeared in first visit of SLE. Twenty-two (75.8%) patients were being treated with corticosteroids at an average dose of 27.7 mg/day (SD ± 23.4). For the psychotic depressive group, 2 episodes (29%) appeared in first visit of SLE. All patients (100%) were being treated with
449
corticosteroids at an average dose of 45 mg/day (SD ± 21.4). The average delay from lupus onset was 40.1 months (SD ± 44.6). From the total subjects of both groups, active organs involvement occurred in 24 episodes (67%). Active organ involvement included renal (39%), hematologic (36%), skin rashes (22%), central nervous system (19%), arthritis (8%), vasculitis (5%), and cardiac (3%). Central nervous system involvement, other than psychosis, was comprised of 4 cerebral ischemia, 2 seizures and 3 encephalopathies. Twenty nine patients (80.6%) were being treated with corticosteroids at an average dose of 31.1 mg/day (SD ± 23.8). All of demographic data and SLE manifestations that occurred during psychotic episodes are summarized in Table 1. Psychotic elements of both groups included persecutory delusion (50%), bizarre delusion (44.4%), third person auditory hallucinations (44.4%), complex visual hallucinations (36.1%), auditory and visual hallucinations (17%), and controlled delusions (17%). From the 7 depressive psychotic episodes, guilty delusion occurred 3 times (43%). According to DSM-IV criteria, the average severity of depression was moderate by 5.5(SD ± 1.4). The characteristics of psychosis in each group are detailed in Table 2.
Investigation During psychotic episodes, the average blood levels of both C3 and C4 were normal in both groups. ANA was positive in 33 patients (92%), antiphospholipid antibody was positive in 3 patients, but we were unable to perform anti-ribosomal P antibody testing. Neuroimaging (CT or MRI) was done in 21 episodes (72%) during psychosis, and abnormal findings were described in 15 of the 21 patients (72%). Seven of the fifteen (47%) patients had mild to moderate brain atrophy while other abnormalities included 4 ischemic processes at frontal lobe and basal ganglia, 1 leptomeninges involvement and 4 white matter hyperintensities. Lumbar puncture was performed in 15 patients, and elevated protein levels (above 45 mg/dL) were found in 6 samples. EEG was performed on 3 patients and all three demonstrated encephalopathy by exhibiting a diffused slow wave, while 2 of them had co-existing epileptic activity.
Neuropsychiatric treatment and outcome All 36 psychotic episodes required hospitalization and both immunotherapy and symptomatic treatments were also required. Patients were treated with methylprednisolone 1 g daily for 3 days (58.3%) or cyclophosphamide 500 mg every 2 weeks (8%) or with both (19.4 %). All of psychotic episodes required antipsychotic treatment; haloperidol, risperidone, and quetiapine were used in 23, 4 and 2 episodes. All episodes were fully remitted with an average haloperidol dose and duration of treatments of 5.9 (SD±7.7) mg/day and 71 (SD±61) days. Depressive psychotic patients required both antidepressant and antipsychotic treatment. A combination of fluoxetine and haloperidol was used in six (85%) patients with an average dose of 30 mg/day and 5 mg/day. The mean duration of treatment in depressive psychosis was 410 days (SD±379 days) due to the prolonged use of antidepressant. Another patient (15%) was successfully treated with a combination of paroxetine and risperidone. One death occurred from suicide by a drug resistant patient in the psychosis group. One (2.9%) of thirty four remaining patients had a recurrence of psychosis after 4 years of remission while other psychotic episodes remitted completely during the mean follow up of 44 (SD ± 29.7) months.
Table 1 Demographic data and clinical manifestations of lupus during psychotic episodes. Demographic data
Age (years) Appear in first visit of SLE Previous episode of lupus psychosis Delay of psychotic presentation (months) Organ involvement Any organ involvement Renal Vasculitis Pulmonary Cardiac Serositis Hematologic CNS (other than psychosis) Skin rash, vasculitis Arthritis Medications Corticosteroid Average corticosteroid (mg/day)
Psychosis episodes
Depressive psychotic episodes
(N = 29)
(N = 7)
29.97 ± 12.77 9 (32.1%) 1 35.9 ± 52
26.14 ± 7.96 2 (28.6%) 0 40.1 ± 44.6
20 (69%) 11 (37.9%) 1 (3.4%) 0 (0%) 1 (3.4%) 0 (0%) 12 (41.4%) 6 (20.7%) 6 (20.7%) 2 (6.9%)
4 (57.1%) 3 (42.9%) 1 (14.3%) 0 (0%) 0 (0%) 0 (0%) 1 (14.3%) 1 (14.3%) 2 (28.6%) 1 (14.3%)
22 (75.8%) 27.7 ± 23.4
7 (100%) 45 ± 21.40
450
P. Paholpak et al. / Journal of Psychosomatic Research 73 (2012) 448–451
Table 2 Common symptoms in psychosis and depressive psychotic groups. Characteristic of NP episodes
Hallucination Auditory (third person) Visual (complex) Both auditory and visual Other Delusion Bizarre Persecutory Control Other
Psychosis episodes
Depressive psychotic episode
(N = 29)
(N = 7)
13 (45%) 12 (42%) 6 (21%) 1 Tactile (4%)
3 (43%) 1 (14%) 0 0
16 (55%) 14 (48%) 4 (14%) 3 TB (10%), 1 TI (3.5%), 1 TW (3.5%)
0 4 (57%) 2 (29%) 3 Guilty delusions (43%)
TB = thought broadcasting, TI = thought insertion, TW = thought withdrawal.
Discussion This case series reports a total of 36 psychotic episodes, a prevalence of 4.8%, which included 29 episodes of psychosis and 7 of depressive psychotic episodes. Patients with depressive psychosis tended to receive higher doses of corticosteroids than the pure psychosis group, but without statistical significance (p > 0.05). The mean severity of depressive symptoms in depressive psychosis was moderate. Most of the psychotic episodes remitted completely, except for the one death from suicide. In the long duration of the follow up, only one recurrence occurred. It was found that lupus psychosis resembled psychosis in the primary psychotic disorders e.g. schizophrenia and steroid induced psychosis. All of these patients presented with bizarre delusions along with either visual or auditory hallucinations [12,13]. Third person auditory hallucination, persecutory delusion and bizarre delusion were the three most common psychotic symptoms in this case series; and they are also very common in schizophrenia. Since one-third of psychotic episodes appeared in the first diagnosis of SLE and all of them had positive ANA (unpublished data); this encourages psychiatrists to screen for ANA in the first visit of psychotic female patients. However, it is not recommended to use phenotypes of psychosis to distinguish between lupus psychosis and psychosis from other causes. Our prevalence was relatively low compared to other studies; this might have arisen from differing methods of inclusion and exclusion criteria utilized among studies. Although we tried to exclude psychosis from the other causes, we could not totally exclude steroid-induced psychosis, which in some cases could occur later than 2 weeks after initiating and increasing the dose. The Brazil [12], UK [13], US [23] and this case series found that psychotic episodes usually occurred with florid activity of lupus. From the laboratory aspect, renal and hematologic involvements were predominant and lymphopenia was found in nearly half of psychotic episodes (unpublished observations). This differs from the previous UK study in which malar rash and hematologic manifestations were the two most common lupus exacerbations while renal involvement was less evident [13]. This difference could not be explained, however, from our observation, that ethnicity might have played role in neuropsychiatric manifestations. From the neurologic investigation, coexistence of nonspecific cerebral atrophy appeared in a majority of patients but ischemic or inflammatory lesions which required further treatment were not uncommon. Encephalopathy, epileptic activity and lesions at the frontal lobe or basal ganglia might explain psychosis with bizarre delusion in this series as well [24,25]. In conclusion, it is suggested that neuroimaging and electroencephalogram should be performed in every lupus psychotic episode in order to detect any missable underlying causes. Based on evidence from case series [26–28], treatment of lupus psychosis used either methylprednisolone, or cyclophosphamide, or both. In the experiences of this study, although all patients were treated
by immunotherapy, they required psychotropic treatment for rapid control of behavioral disturbances [29]. Psychosis alone required antipsychotic therapy for 2–3 months. In our series, haloperidol was used in most cases but risperidone, aripiprazole, olanzapine and quetiapine also have been reported with satisfactory results [23,30,31]. All depressive psychotic episodes were successfully treated with a combination of antidepressant and antipsychotic for a longer period of treatment than in pure psychosis. In this group, 3 patients, however, experienced prolonged 6–8 months of auditory hallucinations before the psychotic component gradually subsided. In 2 cases, psychiatrists decided to prolong antidepressants for more than 1 year to normalize their affects. As a result, this may imply a trend of showing a longer period of psychotic symptoms in depressive psychotic patients. Although psychosis caused one death from suicide, the final outcomes of other psychotic episodes were very favorable. This was unlike the UK and Brazil reports wherein the cohorts had a higher rate (31%) of corticosteroid-related recurrence [12] and 40% of chronic psychosis after 1 year [13]. It was not possible to explain the differences of psychosis outcomes among studies since knowledge of predictors and factors influencing lupus psychosis is still lacking. A recent large prospective study found that the autoantibody ribosomal P proteins (anti-P) were associated with a 3.92 fold risk of having psychosis in future [3]. Only a limited number of laboratories could perform these protein investigations and they have not been studied as a predictor of recurrence and duration of psychosis. Therefore, in terms of clinical implications, this usefulness of this autoantibody is being explored for its use in daily practice [32–34]. The number of patients in our cohort might be small but large when compared to other lupus psychosis cohorts. To the best of our knowledge, no previous publications have considered depressive psychosis and the duration of psychotropic medication. The limitations of this study were that it was a retrospective study. The results of this study seem to suggest that the numbers of patients with psychosis might be underestimated. Mild psychotic episodes, which did not cause severe distress to caregivers and did not lead patients to medical attention, might have been missed. Most of records in the database also did not contain psychological stressors and cognitive evaluations. Thus, it was not possible to report associations with stressors or cognitive impairment during psychosis. These limitations and the lack of this being a controlled trial should warrant interested researchers to conduct further studies in larger prospective design with more precise measurements and controlled management in order to develop a more comprehensive understanding of lupus psychosis. Disclosure statement This study had been supported by grants from the Faculty of Medicine, Khon Kaen University. All authors have declared no conflicts of interest. Acknowledgments The authors would like to thank Mr. Fred Burton Setzler and Professor James Will for editing this article. References [1] The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599-608 [Epub 1999/04/22]. [2] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40: 1725 [Epub 1997/10/27]. [3] Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Clarke A, et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis 2011;70:1726-32 [Epub 2011/09/07]. [4] Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-Romo D, Stallworth CL, et al. Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology 2002;58:1214-20 [Epub 2002/04/24].
P. Paholpak et al. / Journal of Psychosomatic Research 73 (2012) 448–451 [5] Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology 2001;57: 496-500 [Epub 2001/08/15]. [6] Hanly JG, McCurdy G, Fougere L, Douglas JA, Thompson K. Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance. J Rheumatol 2004;31:2156-62Epub 2004/11/02. [7] Jarpa E, Babul M, Calderón J, González M, Martínez ME, Bravo-Zehnder, et al. Common mental disorders and psychological distress in systemic lupus erythematosus are not associated with disease activity. Lupus 2011;20(1):58-66 [Epub 2010 /11/17]. [8] Kasitanon N, Louthrenoo W, Piyasirisilp S, Sukitawu W, Wichainun R. Neuropsychiatric manifestations in Thai patients with systemic lupus erythematosus. Asian Pac J Allergy Immunol 2002;20:179-85 [Epub 2003/02/18]. [9] Mok CC, Lau CS, Wong RW. Neuropsychiatric manifestations and their clinical associations in southern Chinese patients with systemic lupus erythematosus. J Rheumatol 2001;28:766-71 [Epub 2001/05/01]. [10] Mok CC, To CH, Mak A. Neuropsychiatric damage in Southern Chinese patients with systemic lupus erythematosus. Medicine 2006;85:221-8 [Epub 2006/07/25]. [11] Stojanovich L, Zandman-Goddard G, Pavlovich S, Sikanich N. Psychiatric manifestations in systemic lupus erythematosus. Autoimmun Rev 2007;6:421-6. [12] Appenzeller S, Cendes F, Costallat LT. Acute psychosis in systemic lupus erythematosus. Rheumatol Int 2008;28:237-43 [Epub 2007/07/20]. [13] Pego-Reigosa JM, Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation of the disease. Rheumatology (Oxford) 2008;47:1498-502 [Epub 2008/07/29]. [14] Chiewthanakul P, Sawanyawisuth K, Foocharoen C, Tiamkao S. Clinical features and predictive factors in neuropsychiatric lupus. Asian Pac J Allergy Immunol 2012;30:55-60 [Epub 2012/04/25]. [15] Bodani M, Kopelman MD. A psychiatric perspective on the therapy of psychosis in systemic lupus erythematosus. Lupus 2003;12:947-9 [Epub 2004/01/13]. [16] Bertsias GK, Ioannidis JP, Aringer M, Bollen E, Bombardieri S, Bruce IN, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010;69:2074-82Epub 2010/08/21. [17] American Psychiatric A, American Psychiatric Association. Task Force on D-I. Diagnostic and statistical manual of mental disorders: DSM-IV. Washington, DC: American Psychiatric Association; 1994. [18] Diseases WHOCCfCo. International Conference for the Tenth Revision of the International Classification of D. International statistical classification of diseases and related health problems, 10th revision: ICD-10. Geneva: World Health Organization; 1992. [19] Hall RC, Popkin MK, Stickney SK, Gardner ER. Presentation of the steroid psychoses. J Nerv Ment Dis 1979;167:229-36 [Epub 1979/04/01]. [20] Ayd FJ. Lexicon of psychiatry, neurology, and the neurosciences. Baltimore: Williams & Wilkins; 1995.
451
[21] Hermosillo-Romo D, Brey RL. Diagnosis and management of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Best Pract Res Clin Rheumatol 2002;16:229-44 [Epub 2002/06/04]. [22] Kittirattanapaiboon P, Mahatnirunkul S, Kongsuk T, Choovong K, Booncharoen H, Kwansanit P, Charatsingha A. Validity and Reliability of Mini International Neuropsychiatric Interview: M.I.N.I.: 5.0.0 Thai Version. J Mental Health Thai 2005;13: 125-35. [23] Muscal E, Nadeem T, Li X, Mian A, Harris TB. Evaluation and treatment of acute psychosis in children with Systemic Lupus Erythematosus (SLE): consultation-liaison service experiences at a tertiary-care pediatric institution. Psychosomatics 2010;51:508-14 [Epub 2010/11/06]. [24] Kaplan HI, Sadock BJ. Kaplan & Sadock's comprehensive textbook of psychiatry., 2. Philadelphia [u.a.]: Lippincott Williams & Wilkins; 2009. [25] Kaplan HI, Sadock BJ. Kaplan & Sadock's comprehensive textbook of psychiatry, 1. Philadelphia [u.a.]: Lippincott Williams & Wilkins; 2009. [26] Boumpas DT, Yamada H, Patronas NJ, Scott D, Klippel JH, Balow JE. Pulse cyclophosphamide for severe neuropsychiatric lupus. Q J Med 1991;81:975-84 [Epub 1991/12/01]. [27] Neuwelt CM, Lacks S, Kaye BR, Ellman JB, Borenstein DG. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med 1995;98:32-41 [Epub 1995/01/01]. [28] Ramos PC, Mendez MJ, Ames PR, Khamashta MA, Hughes GR. Pulse cyclophosphamide in the treatment of neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol 1996;14:295-9 [Epub 1996/05/01]. [29] Mok CC, Lau CS, Wong RW. Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open-label study. Am J Med 2003;115:59-62 [Epub 2003/07/18]. [30] Muscal E, Bang L, Mian A, Harris TB. Use of aripiprazole in adolescents with a history of lupus-associated psychosis and refractory psychiatric manifestations. J Psychiatr Pract 2011;17:212-6 [Epub 2011/05/19]. [31] Pinto JP, Morais SL, Hallak JE, Dursun SM. Effectiveness of olanzapine for systemic lupus erythematosus-related psychosis. Prim Care Companion. J Clin Psychiatry 2006;8:377-8 [Epub 2007/01/25]. [32] de Macedo PA, Borba EF, Viana Vdos S, Leon EP, Testagrossa Lde A, Barros RT, et al. Antibodies to ribosomal P proteins in lupus nephritis: a surrogate marker for a better renal survival? Autoimmun Rev 2011;10:126-30 [Epub 2010/09/14]. [33] Doria A, Zen M, Canova M, Bettio S, Bassi N, Nalotto L, et al. SLE diagnosis and treatment: when early is early. Autoimmun Rev 2010;10:55-60 [Epub 2010/09/04]. [34] Rekvig OP, Putterman C, Casu C, Gao HX, Ghirardello A, Mortensen ES, et al. Autoantibodies in lupus: culprits or passive bystanders? Autoimmun Rev 2012;11: 596-603 [Epub 2011/11/02].