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1 , CASE REPORT ARIPIPRAZOLE IN PSYCHOTIC DEPRESSION: FOUR CASE REPORTS Kuppuswami Shivakumar, Amna Mir, Victoria D.M. McAllister, Veronica O Keane, Katherine J. Aitchison Summary Object: Aripiprazole is an antipsychotic with partial agonism activity at D 2 and 5-HT 1A receptors, not currently licensed for the treatment of psychotic depression (Burris et al and Jordan et al. 2002). This case series reports outcomes of using aripiprazole in the treatment of patients with psychotic depression. Methods: Four individuals with psychotic depression treated with a combination of an antidepressant and an antipsychotic with inadequate therapeutic response or intolerance were switched to aripiprazole. Clinical ratings included Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Scale for Severity/ Improvement (CGI-S/I), Global Assessment of Functioning Scale - Symptoms/ Disability (GAF-S/D), Antipsychotic Non- Neurological Side-Effects Rating Scale (ANNSERS, Yusufi et al. 2005), Quality of Life (QoL, Heinrichs et al. 1984) and Preference of Medication Scale (POM, a 1-5 scale, 1 = greatest preference). Results: Case 1: Switching was conducted without cross-tapering, and was uneventful. At one-year follow-up (on aripiprazole 10 mg and citalopram 40 mg), there was improvement on GAF-S (70 to 80), ANNSERS (16 to 5) and POM (1). Case 2: Cross-taper with amisulpride resulted in an improvement by 12 weeks in GAF-S (60 to 70), and ANNSERS (41 to 18). From week 26, depressive symptoms recurred. His medication (aripiprazole from 30 mg to 20 mg, citalopram 30 mg to 40 mg) was adjusted, which resulted in some improvement. However at one year, the patient was still reporting depressive symptoms along with paranoid ideation. At this point he was treated by introducing 200 mg of amisulpride. Case 3: Cross-taper with risperidone (4 mg) over 12 weeks was well tolerated and resulted by 1 year in a PANSS change from 71 to 40, CGI-S change from 3 to 1, and a POM score of 1. Case 4: Aripiprazole (10 mg to 15 mg over 2 weeks), cross-tapering with risperidone (2 mg), resulted in an improvement in his total side effects (ANNSERS from 13 to 9) as well as sexual side effects only by week 26. Conclusions: This case series suggests that further study of aripiprazole in the treatment of psychotic depression is indicated. Key words: Aripiprazole Psychosis Depression Dopamine Serotonin Agonist Declaration of interest: This study was funded by Bristol-Myers Squibb Pharmaceuticals Limited (see Acknowledgements). Dr Katherine J Aitchison is on the UK Core Steering Group for Abilify (Aripiprazole), and has received consultancy fees from Bristol-Myers Squibb Pharmaceuticals Limited. Kuppuswami Shivakumar, Amna Mir, Victoria D M McAllister, COAST Team (Croydon Early Onset Psychosis Service), Westways Resource Centre, 49 St James s Road, Croydon, UK Veronica O Keane, Perinatal Psychiatry Section of the Division of Psychological Medicine, King s College, London, UK Katherine J Aitchison, MRC Social, Genetic and Developmental Psychiatry Centre and Clinical Neuropharmacology Section of the Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, Internal Box PO 80, De Crespigny Park, London, SE5 8AF, UK Corresponding Author Katherine J Aitchison, MRC Social, Genetic and Developmental Psychiatry Centre and Clinical Neuropharmacology Section of the Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, Internal Box PO 80, De Crespigny Park, London, SE5 8AF, UK. [email protected] Introduction There is mounting evidence to support the theory that depression with psychotic symptoms is not only the most difficult type of depression to treat, but is also associated with significantly greater morbidity and mortality than non-psychotic depression. The American Psychiatric Association guidelines recommend that major depression with psychotic features should be treated with an antipsychotic as well as an antidepressant (American Psychiatric Association 1993). Aripiprazole is a second generation antipsychotic that has partial agonism activity at D 2 and 5-HT 1A receptors. Clinical trials have demonstrated efficacy of RECEIVED MARCH 2006, ACCEPTED DECEMBER Giovanni Fioriti Editore s.r.l.

2 Aripiprazole in Psychotic Depression: Four Case Reports aripiprazole in the treatment of schizophrenia. However, aripiprazole does not currently hold a licence for the treatment of psychotic depression. Here we report four cases of psychotic depression treated with aripiprazole. Methods Subjects were recruited as a part of a study aiming to investigate changes in sexual dysfunction on switching to aripiprazole. They were recruited from the COAST Team (Croydon Early Intervention in Psychosis Service), and Croydon Community Mental Health Teams. The inclusion criteria were: subjects (male or female) in the age range 18 to 65 years, with a psychotic illness living in the community, who had failed to respond adequately to another antipsychotic (either inadequate therapeutic response or intolerance).there were no restrictions in terms of ethnicity. Open label switch to aripiprazole was offered to eligible subjects. The starting dose at the commencement of the study was 10 mg, but was reduced to 5 mg once the 5 mg tablets became available in the UK (January 2005). Clinical ratings performed included: Positive and Negative Syndrome Scale (PANSS: scale where 30 is absent), Clinical global impression scales (CGI-Severity of illness: 1 7 scale where 1 is normal; CGI- Improvement: 1-7 scale where 1 is very much improved), Global Assessment of Functioning Scale- Symptoms and Disability (GAF-S and GAF-D respectively: 1 90 scale where 1 is very low functioning), Antipsychotic Non-Neurological Side-Effects Rating Scale, (ANNSERS: scale where 0 is absence of any side effect; Yusufi et al. 2005), general satisfaction items regarding overall sexual functioning from the Sexual Functioning Questionnaire (SFQ: 0 10 scale where 10 is completely satisfied; Smith et al. 2002), and Quality of Life Scale (QoL: scale where 0 is poorest QoL; Heinrichs et al. 1984). Compliance was also measured (1 7 scale where 7 is very good compliance; Kemp et al. 1995) and a five point preference of medication questionnaire (PoM: 1-5 scale where 1 is the greatest preference, Tandon et al. 2006). Serial hormonal measurements including prolactin were also performed. The time points for all clinical ratings and serum levels were: baseline, and 1, 2, 6, 12, 26 and 52 weeks thereafter except for the Quality of Life Scale, which was applied only at baseline, week 26 and week 52. Case Series Case 1 Ms. W, a 37-year-old single mother, with a strong family history of psychiatric disorder first presented to psychiatric services in 2001 with a 2-week history of severe depressive symptoms with psychotic features. She was admitted, and a diagnosis of severe depressive symptoms with psychotic features was made. She was treated with olanzapine 12.5 mg/day and citalopram 10 mg/day, to which she showed some improvement. However, after 15 months of treatment, the reappearance of severe depressive symptoms with psychotic features and suicidal ideation led to an increase in the dose of olanzapine to 15 mg/day and citalopram to 40 mg/day. This produced a substantial increase in weight gain (13 kg in 6 months) with sexual dysfunction (decreased libido, galactorrhoea, and oligomenorrhoea) and increased prolactin level (4879 mu/l). Switching to amisulpride did not alleviate the side effects. Ms. W was switched to aripiprazole 10 mg/day in September 2004 and amisulpride was stopped without a cross-taper of the two medications (Figure 1). Her antidepressant dose (Citalopram 40 mg) remained the same. She reported some sleep difficulties in the first week and zopiclone 7.5 mg on an as required basis was prescribed for a week. By week 6, the side effects she was experiencing reduced from 16 to 4 on ANNSERS (total score), and the PANSS depression item score improved from 2 to 1. Her other psychopathology remained stable. Her preference of medication increased to much better (1). At one year follow-up, she remained well (Total PANSS = 32, PANSS depression item = 1, CGI-I = 1, GAF-D = 85) and the medication combination (aripiprazole 10 mg/day and citalopram 40 mg/day) was well tolerated (ANNSERS total score reduced from 16 to 5, with reduction in prolactin to 272 mu/l). Moreover, the sexual side effects that were reported at baseline had resolved. Her preference of medication was still much better as compared to her old antipsychotic and she was fully compliant (score on compliance measure = 7) with her treatment. Case 2 Mr. T, a 38-year-old married housing officer with a child is on long-term disability living allowance due to ill-health. He was diagnosed with recurrent depressive disorder with psychotic symptoms at 17 years, following a minor head injury. For the next 20 years, he remained severely depressed and socially impaired, despite different pharmacotherapeutic strategies. On referral to our team, he was on amisulpride 400 mg/day, citalopram 40 mg/day, lithium 1000 mg/day and reboxetine 8mg/day. Owing to ongoing depressive symptoms (PANSS depression item score = 3 (mild severity) with auditory hallucinations and sexual dysfunction, a switch to aripiprazole 10 mg/ day was initiated (Figure 2), gradually increasing to 30 mg/day over 14 weeks, with a cross-taper from amisulpride over 10 weeks. He remained on the same dose of lithium, reboxetine and citalopram. From 6 weeks after switching, he began to show improvement in his symptomatology. By week 12, the Positive and Negative Symptoms Scale (PANSS) score reduced from 43 to 35, with a 38.5% reduction in the negative subscale and the PANSS depression item reduced from 3 to 1, accompanied by an improvement in the CGI-I (3 to 1) and GAF-S (60 to 70). The adverse effects ratings also decreased over the 12-week period: ANNSERS (41 to 18), and Sexual Functioning Questionnaire (19 to 6). The patient reported some depressive symptoms at the 19-week review point (PANSS = 54, with score for depression item in PANSS = 6). His citalopram was increased from 20 mg to

3 Kuppuswami Shivakumar et al. $PLVXOSULGH Figure 1. Antipsychotics prescribed for Ms. W over period of observation $PLVXOSULGH &XUUHQW Figure 2. Antipsychotics prescribed for Mr. T over period of observation 334

4 Aripiprazole in Psychotic Depression: Four Case Reports 5LVSHULGRQH Figure 3. Antipsychotics prescribed for Mr. C over period of observation mg. This resulted in improvement of symptoms within a week (PANSS = 33). This improvement was maintained at 26-week follow up (PANSS = 36, GAF- S = 70, GAF-D = 75, CGI-I = 1, PoM = 1, ANNSERS = 17). Mr. T also reported significant improvement in social functioning, reflected in the Quality of Life rating (18 to 87 at 26 weeks). After 7 months of being on aripiprazole, he started to report some deterioration in his mood with reoccurrence of some psychotic symptoms. Within a month, his mood and psychotic symptoms had worsened. At that time Mr. T was having some relationship difficulties with his wife. His daughter also had some symptoms of low mood symptoms similar to Mr T which was of concern to him. He was also stressed about starting of a new voluntary job. This contributed to the exacerbation of the symptoms. His antidepressant was increased (from 30 mg/day of citalopram to 40 mg/ day), which resulted in some improvement, but he still had some depressive symptoms and paranoid ideation. Simultaneously, his aripiprazole was reduced to 20 mg/ day, as it was thought that the aripiprazole might have been contributing to an exacerbation of his psychotic symptoms. At one year follow up, no improvement in his symptoms was noted (PANSS = 66, PANSS depression item = 5, GAF-D = 51). As a result, amisulpride 200 mg/day was added to his treatment regime (Aripiprazole 20 mg, citalopram 40 mg, reboxetine 8 mg, lithium 1000 mg). This resulted in improvement of both his depressive and psychotic symptoms. Case 3 Mr. C, a 27-year-old single chef, unemployed since the onset of his illness, with no family history of psychiatric illness, had a 12-month history of progressively worsening severe depressive symptoms with delusions. He was initially treated with risperidone 4 mg and citalopram 40 mg, to which he responded poorly (PANSS score of 71, predominantly negative symptoms; PANSS depression item = 3). He also had side effects, including prolactin elevation (1244 mu/l), weight gain and sexual side effects. He was started on aripiprazole 10 mg/day, with a gradual cross-taper of risperidone over 12 weeks, increasing to 20 mg/day of aripiprazole after week 12. His antidepressant dose remained the same. At one year, he remained on aripiprazole 20 mg/day (Figure 3) and citalopram 40 mg/day, and this regime was clinically well tolerated. He remains well with reduction in total PANSS score to 40 and PANSS depression item score to 1 (absent) after 1 year, with an improvement also on other measures by one year follow up: CGI-S (3 to 1), CGI-I (1), GAF-D (41 to 80), QoL (69 to 86), ANNSERS (from 21 to 4), Compliance (7) and POM (1). 335

5 Kuppuswami Shivakumar et al. 5LVSHULGRQH &XUUHQW Figure 4. Antipsychotics prescribed for Mr. P over period of observation Case 4 Mr. P, a 27-year-old male with a history of severe depressive symptoms with psychotic features, presented with low mood, suicidal ideation and psychotic symptoms characterised by thought disorder, auditory hallucinations and delusions in August He was initially treated with fluoxetine and then also with olanzapine, to which he responded poorly. The olanzapine was switched to risperidone 3 mg, and symptoms were controlled. However, three months later, he developed extra pyramidal side effects (tremor), and the risperidone was reduced to 2 mg. In early 2004, he developed severe sexual side effects (delayed erection, retrograde ejaculation and loss of libido) and weight gain. He was on risperidone 2 mg and clonazepam 1 mg at that time. Aripiprazole 10 mg was commenced in July 2004, increasing up to 15 mg over 2 weeks, cross-tapering with the risperidone. His clonazepam was stopped after 2 weeks of being on aripiprazole. This resulted in an improvement in his side effects and psychopathology by week 26. The total side effect score on the ANNSERS reduced from 13 to 9 by one year, including improvement in all four measures of sexual dysfunction on this scale. His psychopathology remained stable (PANSS = 33, PANSS depression item = 1, GAF-D = 75) after two years and four months on aripiprazole 15 mg in this case (Figure 4). He was fully compliant with the medication (7) and preferred this medication regime much better on preference of medication scale (1). Interestingly, this has been achieved as monotherapy, in the absence of an antidepressant. Discussion Our data suggest that aripiprazole has efficacy either alone or in combination treatment in psychotic depression. Three out of four cases of psychotic depression found aripiprazole to be effective in reducing both their psychotic and depressive symptoms. Moreover, they experienced less adverse effects than on their previous treatment regime. However, one patient relapsed after 7 months of being on aripiprazole. Of note, the maximum dose of aripiprazole used in this case (30 mg) was higher than that in the other cases. It is possible that his remaining on 30 mg for a total of 5 months contributed to the destabilisation at month 7, and that had his aripiprazole been reduced to 15 mg at week 26, that this could have been avoided. However, this case also had the longest duration of illness, and a history of a head injury and psychosocial stressors, all of which could have contributed to increased likelihood of relapse. The partial agonism of aripiprazole at both serotonin 5HT 1A and dopamine D 2 receptors is consistent with our findings. Further studies and clinical 336

6 Aripiprazole in Psychotic Depression: Four Case Reports trials of aripiprazole in the treatment of psychotic depression are indicated. Acknowledgements This study was funded by Bristol-Myers Squibb Pharmaceuticals Limited (Investigator Sponsored Study, Principal Investigator: Dr KJ Aitchison). However, none of the grant was used for antipsychotic prescriptions. We thank Dr Holloway (Clinical Director, Croydon Integrated Adult Mental Health Services), and the COAST and local Community Mental Health team staff and service users for their assistance with and participation in this study. References Heinrich DN, Hanton TE, Carpenter WT (1984). The quality of life scale: An instrument for rating the schizophrenic deficit syndrome. Schizophr Bulletin 10, American Psychiatric Association (1993). Practice guideline for major depressive disorder in adults. Am J Psychiatry 150, Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB (2002). Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D2 Receptors. Psychopharmacol 302, Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA (2002). The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT 1A receptor. Eur J Psychopharmacol 441, Kemp R, Hayward P, Applewhaite G, Everitt B, David A (1995). Compliance therapy on psychotic patients: randomized controlled trial. BMJ 312, Smith S, O Keane V, Murray R (2002). Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 181, Tandon R, Marcus R N, Stock E G, Riera L C, Kostic D, Pans M, McQuade R D, Nyilas M, Iwamoto T, Crandall D T (2006). A prospective, multicentre, randomized, parallelgroup, open-label study of aripiprazole in the management of patients with schizophrenia or schizoaffective disorder in general psychiatric practice: Broad effectiveness trial with aripiprazole (BETA). Schiz Res 84, 1, Yusufi BZ, Mukherjee S, Aitchison K, Dunn G, Page E, Barnes TRE (2005). Reliability of the Antipsychotic Non- Neurological Side-Effects Rating Scale (ANNSERS). J Psychopharmacol 19 suppl, A