CNS Drugs Withdrawal Symptoms and Rebound Syndromes Associated with Switching and Discontinuing Atypical Antipsychotics Theoretical Background and Practical Recommendations Anja Cerovecki, Richard Musil, Ansgar Klimke, Florian Seemüller, Ekkehard Haen, Rebecca Schennach, Kai-Uwe Kühn, Hans-Peter Volz and Michael Riedel Corresponding author: Richard Musil, Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstr. 7, 80336 Munich, Germany.E-mail: Richard.musil@med.uni-muenchen.de Electronic Supplementary Material Table a Overview of switching trials reporting on a switch to amisulpride, trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Switching to Author Study type/Patients N Reason for switch Withdrawal/Rebound Treatment emergent adverse events (>5 %) Main outcomes/Comment Design Weight and BMI dropped significantly in switch-group vs. non-switch control group; lipid Different Open-label; levels improved in switch-group; Overweight or Crossatypical Amisulpride Lin et al.1 stable 46 Not explicitly mentioned prolactin levels increased in obesity taper antipsychotics inpatients switch-group; fasting glucose and HOMA-IR levels improved in switch-group; prevalence of metabolic syndrome decreased Patient compliance and psychopathology overall improved after switching; preswitch noncompliant patients Drug utilization Various reasons improved in EPMS scores, Conventional Not menAmisulpride Linden et al.2 study; 570 (e.g. insufficient Not mentioned Not explicitly mentioned psychopathology and antipsychotics tioned outpatients efficacy, EPMS) compliance, postswitch noncompliant patients worsened; psychopathology worsened in pre- and postswitch noncompliant patients AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) 7 patients dropped due to exacerbation of psychotic symptoms;2 patients dropped due to EPMS (not discussed as withdrawal or rebound phenomena) Duration of switch 4 weeks Not mentioned Table b Overview of switching trials reporting on a switch to aripiprazole, trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Risperidone Olanzapine, risperidone Amisulpride or risperidone Atypical antipsychotics Switching to Aripiprazole Aripiprazole Aripiprazole Aripiprazole Author Ryckmans et al.3 (BMS, Otsuka) Study type/Patients Randomized, open-label; outpatients Byerly et al.4 (BMS, Otsuka) Post-hoc sub analysis of open-label study; outpatients Lee et al.5 Open-label; stable female patients Kim et al.6 Open-label, stable in- and outpatients N 400 164, 105 7 61 Treatment emergent adverse events (>5 %) Main outcomes/Comment Design Duration of switch Four patients dropped due to worsening of symptoms (1 in titrated switch and 3 in fixeddose switch group) – not discussed as withdrawal syndromes TEAEs were insomnia, anxiety, headache and EPMS Rates of AEs and drop-outs were similar between titrateddose and fixed-dose strategies; PANSS, CGI, SWN-K and SAS scores improved significantly and did not differ between switching groups, weight dropped in both groups Titrated dose vs. fixeddose switching , descending taper 4 weeks Adverse events (hyperprolactinemi a) Not reported, but 11 patients had occurrence of psychosis as serious adverse event TEAEs encompassed insomnia, nausea, anxiety, psychosis, headache, somnolence, akathisia and upper respiratory infection (switched from olanzapine); insomnia, akathisia, nausea, lightheadedness, somnolence, agitation, anxiety and psychosis (switched from risperidone) Similar rates of adverse events regardless of switching strategy or prior medication, reduction in prolactin levels even during cross-over phases Three different switch strategie s (abrupt, descending taper and crosstaper) 14 days Hyperprolactinemi a Two patients experienced aggravation of auditory hallucinations and discontinued treatment with aripiprazole Not reported Hyperprolactinemia and related symptoms resolved in all patients, PANSS and CGI scores were stable in patients successfully switched Abrupt N/A Insufficient efficacy, adverse events or poor compliance One patient with exacerbation of symptoms after abrupt switch from LAIR resulting in completed suicide TEAE (> 5 %) were insomnia, agitation, weight loss, sedation, nausea, myalgia, obsessive-compulsive symptoms, fatigue (five drop outs) Cognitive functions significantly improved (verbal learning test, WST, TMT A), PANSS, SOFAS, DAI, SAS and AIMS scores improved, metabolic parameters and weight improved, tardive dyskinesia and hyperprolactinemia improved Crosstaper based on clinical judgement No data Reason for switch Withdrawal/Rebound Insufficient efficacy, adverse events Atypical antipsychotics Aripiprazole Other antipsychotics (atypical and typical) Aripiprazole Other antipsychotics Aripiprazole vs. Standard of care antipsychoti cs Conventional or atypical antipsychotics Risperidone, Sulpiride Risperidone, olanzapine, amisulpride, quetiapine, zuclopenthixol, clozapine Risperidone, olanzapine, amisulpride, quetiapine Aripiprazole Aripiprazole Aripiprazole Aripiprazole Kim et al.7 Ganguli et al.8 (BMS) Kim et al.9 Lin et al.10 Lu et al.11 Mir et al.12 Pae et al.13 Open-label pilot study; stable outpatients Open-label, outpatients Open-label; stable outpatients Observational study; outpatients Open-label; stable female patients Open-label, switching or add-on RCT, openlabel, partial nonresponders 15 33 292 45 23 27 77 Weight gain BMI ≥ 26, PANSS 60-90 Five patients were restarted on previous medication (olanzapine or clozapine) due to actual or fear of symptom exacerbation Not reported CGI and PANSS scores significantly improved in patients successfully switched, metabolic parameters and weight did not change significantly No significant symptom improvement (PANSS, CGI); weight, waist circumference and LDL levels decreased, all were successfully switched Descending taper 2 weeks or more Crosstitration 2 weeks or more Not reported Not reported Not reported 12.4 % of patients experienced symptom worsening TEAEs in aripiprazole group were insomnia, nausea, headache, anxiety Overall psychopathology improved in patients switched to aripiprazole, prolactin-related TEAE were lower in patients switched to aripiprazole compared to standard of care antipsychotics Descending taper 2 weeks Insufficient efficacy, adverse events 42.9 % terminated switching in early phase of cross tapering likely related to rebound phenomena TEAE included insomnia, anxiety, EPMS, akathisia and headache Type of preswitch antipsychotic (FGAs had lowest success rate) and duration of illness determined successful switching, most patients switched due to metabolic side effects Abrupt vs. Descendingtaper No data Not reported 2 drop-outs due to AEs (sleep disturbance, excessive anxiety); other AEs were reduced duration of sleep, tension, nausea, akathisia, tremor Prolactin levels and menstrual cycle normalized; PANSS and CGI scores did not change significantly Plateau crosstaper Mean 7.9 weeks Not mentioned Prolactin levels significantly decreased, libido improved, erectile and ejaculatory difficulties and menstrual dysfunctions improved; 54.5 % received aripiprazole as add-on strategy; psychopathology and side effects improved Crosstaper, some abrupt No data Severity of side effects did not change significantly Overall symptoms improved, Baseline severity predicted symptom worsening at weeks 1, 2 and 4; lesser disease severity at baseline predicted worsening after switching to aripiprazole, taper switch was better tolerated than abrupt switch 3 different strategies: abrupt, descending taper or plateau descending Up to 6 weeks Symptomatic hyperprolatinemia Insufficient efficacy, adverse events Insufficeint efficacy, adverse events Not mentioned Patients with abrupt switch showed increase of symptoms at week 1 taper Conventional and atypical antipsychotics Other atypical antipsychotics Olanzapine, quetiapine, risperidone Risperidone, olanzapine and other antipsychotics Aripiprazole Aripiprazole Aripiprazole Aripiprazole Sarin et al.14 Randomized. open-label, outpatients Spurling et al.15 Retrospective chart review on outpatients (schizophrenia and other diagnoses) Stroup et al.16 Takeuchi et al.17 RCT, stable patients, double-blind Randomized, open-label TEAE included fatigue, insomnia, somnolence, headache, nausea, vomiting and diarrhea, tremor, rigidity, constipation PANSS scores, EPMS, prolactin levels and weight improved Descending taper 7 days Various Various 136 Insufficient efficacy, adverse events 24 Metabolic adverse events Not reported Not reported Total cholesterol, LDL and weight significantly decreased, patients switching from olanzapine benefited most Metabolic risk factors (BMI ≥ 27), non-HDL cholesterol ≥ 130 mg/dl Switching to aripiprazole was associated with higher rate of treatment discontinuation (16.8 % vs. 7.5 %), eight switchers and five stayers were hospitalized due to psychiatric reasons TEAEs in switch group were insomnia (stayers had more sleepiness, hypersomnia, nausea, dry mouth, increased appetite and akinesia) Switchers lost more weight and had higher non-HDL cholesterol reduction compared to stayers; rates of efficacy failure were similar between groups Crosstaper 3 weeks TEAEs included insomnia and akathisia CGI, EPMS, SWN did not differ between switching strategies, both were well tolerated, metabolic parameters improved significantly (weight, total cholesterol, triglycerides, prolactin) Plateau descending taper vs. Descending taper Up to 12 weeks 109 (switch) vs. 106 (mainta ined on current antipsy chotic) 53 Comparison of 2 switching strategies Not reported None (discussed as being related to slow switching strategy) AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) Table c Overview of switching trials reporting on a switch to olanzapine, trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Clozapine Switching to Olanzapine Author Study type/Patients Dossenbach et al.18 (Eli-Lilly) Open-label, chronic treatmentresistant patients Reason for switch Withdrawal/Rebound Treatment emergent adverse events (>5 %) Main outcomes/Comment Design Duration of switch 48 Adverse events, insufficient efficacy One patient was hospitalized due to psychosis (not discussed as rebound phenomenon) 2 drop-outs due to insufficient efficacy, one due to adverse events; TEAEs included psychosis, liver function test abnormality PANSS, BPRS and SAS scores dropped significantly Descending taper switch No data Dyskinesia 7 patients required hospitalization, slow taper was not protective Plateau cross taper Sev. weeks Crosstaper No data No data N Clozapine Olanzapine Henderson et al.19 Open-label; outpatients 19 Pats. request for switch, insufficient efficacy, adverse events Clozapine Olanzapine Littrel et al.20 Open-label; outpatients 20 Adverse events, but clozapine responders Not reported Adverse events, insufficient efficacy Two patients dropped due to insufficient efficacy and two due to adverse events (worsening of psychosis, suicide attempt) (not discussed as rebound phenomena) Risperidone Risperidone Risperidone Olanzapine Olanzapine Olanzapine Dossenbach et al.21 (Eli-Lilly) Open-label Faries et al.22 (Eli-Lilly) Post-hoc analysis of open-label randomized trial; mainly outpatients Kim et al. 23 Female patients 34 43 Insufficient efficacy, adverse events 20 Menstrual disturbance, galactorrhea or sexual dysfunction Not reported Not reported BPRS scores overall worsened; pats. successfully switched were treated with clozapine for shorter period of time and lower dose; new adverse events: sedation, constipation Equal efficacy of olanzapine and clozapine in 90 %, rates of adverse events dropped TEAEs comprised abnormal liver function tests, weight gain PANSS total and subscores decreased significantly, olanzapine was well tolerated, ESRS scores dropped Switch after discontinuation and wash-out over 4 days Weight gain Switchers from risperidone to olanzapine and non-switchers did not differ significantly in BPRS scores, QoL scores and absolute weight, weight increased Mostly abrupt N/A Not reported Serum prolactin levels decreased; PANSS, AIMS and SAS decreased, improvements in menstrual functioning Crosstaper 2 weeks Risperidone Haloperidol Conventional depot antipsychotics (Haloperidol, Fluphenazine) Conventional antipsychotics or risperidone Olanzapine Olanzapine Olanzapine Olanzapine Takahashi et al.24 Costa e Silva et al.25 Godleski et al.26 (Eli-Lilly) Kinon et al. Open-label; first episode patients Open-label; inand outpatients Open-label, RCT; outpatients 27 Open-label, randomized; outpatients, clinically stable 58 94 26 (13 vs. 13) 209 Insufficient efficacy Not reported 7 Patients discontinued due to adverse events; 46.6 % of patients had significant weight gain (>7 %), other TEAEs were excessive appetite, headache, somnolence, dry mouth, insomnia, constipation, blurred vision, dizziness and nausea EPMS 30.9 % symptom exacerbation, seizures, headache, anxiety, dizziness, insomnia discussed as attributable to haloperidol/anticholinerg ic discontinuation; akathisia, dyskinesia, movement disorder discussed as potential rebound phenomena TEAEs were somnolence, increased appetite, weight gain, headache, anxiety, dizziness, insomnia, EPMS Symptoms and EPMS significantly improved (PANSS; CGI; SAS, BAS, AIMS); 90.5 % of patients were successfully switched Direct switch N/A Not reported Improvement in PANSS general and negative scores, CGI and GAF scores in switch group to oral olanzapine, weight gain in olanzapine group, no other difference in adverse events Plateau cross taper (chosen as quite safe strategy) No data TEAEs included shortened sleep, difficulty falling asleep, increased perspiration, interrupted sleep, early waking, drowsiness Comparison of abrupt or gradual discontinuation and double-blind comparison of immediate initiation or up-titration Gradual discontinuation and initiation of full dose showed best efficacy and tolerability; significant decrease in prolactin levels in all groups; No differences in antiparkinsonian medication or use of benzodiazepines Four switching strategies Up to 3 weeks No optimal cuntioning Not reported Efficacy of olanzapine switching strategies Sleep disturbances (abrupt discontinuation and stepwise initiation); drowsiness (abrupt discontinuation and immediate initiation); worsening of symptoms (highest while abrupt discontinuation and stepwise initiation), discussed as potential withdrawal syndromes 29.3 % were responders, symptomatology significantly decreased (BPRS); ESRS and BAS scores dropped; prolactin levels dropped significantly; relative absence of positive symptoms at baseline predicted good response Crosstaper 2 weeks Conventional antipsychotics or risperidone Other antipsychotic compounds (mono- and polypharmacy) Long-acting injectable antipsychotics Predominantly typical antipsychotics Haloperidol, Olanzapine, Clozapine, Risperidone Conventional antipsychotics (mainly haloperidol, chlorpromazine, perphenazine) Olanzapine Olanzapine Kinon et al.28 (Eli-Lilly) Kluge et al.29 Open-label, randomized; stable patients Open-label Labelle et al.30 Open-label; stable outpatients Olanzapine Lee et al.31 Open-label; randomized; inpatients and outpatients Olanzapine Lindenmayer et al.32 Open-label; inpatients Lu et al.33 Observational trial; in- and outpatients Olanzapine Olanzapine 54 198 25 Hyperprolactinemi a Not reported (hallucinations occurred in 11 % in both patients switched to olanzapine or remaining on current medication) TEAE in both groups did not differ significantly, TEAEs in patients switched to olanzapine were hallucinations, rhinitis, somnolence Serum prolactin levels decreased in patients switched to olanzapine compared to patients remaining on previous medication; improvements in sexual functioning in both genders, weight increased and SAS scores improved in patients switched to olanzapine Crosstaper 2 weeks Insufficient efficacy or insufficient tolerability Psychotic decompensation (1 patient; paranoid reaction (1 patient); hallucinations (6 patients); authors discussed TEAE as related to olanzapine Restlessness, insomnia (1 patient); anxiety, agitation (1 patient); sleep disorder (9 patients); nervousness (7 patients), dizziness (5 patients)]; authors discussed TEAE as related to olanzapine Immediate initiation of 10 mg olanzapine; 89 % of patients improved in CGI or were unchanged; subjective wellbeing improved significantly; EPMS scores decreased; Abrupt switch N/A Feasibility of switching from long-acting substances to olanzapine Exacerbation of psychosis (2 pat.); No differences in parkinsonism, dystonia and dyskinesia between completers and noncompleters Increased anxiety (2 pat.); depressed mood (1 pat.); insomnia (2 pat.) Significant improvements on CGI, PANSS-scores and parkinsonism; weight gain was reported in 8 patients Immediate initiation of 10 mg olanzapine on day of scheduled injection No data TEAEs were similar in both switching groups Improvement in symptoms and EPMS (SAS, BAS), weight increased, no difference in switching strategies Abrupt switch vs. Starttaper switch 2 weeks Not reported Only PANSS cognitive factor significantly improved; Nonsignificant decrease in EPMS, sign. increase in weight Crosstitration 2 weeks Not reported 93.3 % of completers (n=954) responded to olanzapine; AIMS scores dropped, mean weight increased; QoL increased (fastest during first 8 weeks) At discretion of treating psychiatrist No data 108 Various reasons 45 Insufficient efficacy 1267 Insufficient efficacy Not reported Not reported Not reported Focus on switches from and to Olanzapin or non-olanzapine antipsychotics Olanzapine Novick et al.34 (Eli-Lilly) Observational study; outpatients 10972 Several reasons Not reported Patients switching from olanzapine were more likely to display EPMS and loss of libido; patients switching to olanzapine had higher weight gain Patients switching from olanzapine were less likely to respond than patients switching to olanzapine which had overall better outcome Not reported Not reported In both groups improvement in parkinsonism, in olanzapine 6 patients developed Non-significant trend of treated patients improvement of Olanzapine TD; Cholinergic rebound increased sedation and dyskinetic movements; Open-label, Conventional (or discussed in risperidone postural Cross4 symptomatology improved in Ritchie et al.35 randomized; 66 EPMS antipsychotics Risperidone arm as possibly related hypotension/dizziness in taper weeks both groups with no differences; elderly patients ) to gastrointestinal olanzapine arm, weight QoL improved in patients symptoms increased in both arms switched to olanzapine more than in patients switched to risperidone AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) Table d Overview of switching trials reporting on a switch to quetiapine, trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Main outcomes/Comment Design Duration of switch Not reported Not reported Small decrease in weight, no alterations in symptoms (PANSS) or new adverse events Crosstaper switch over 4 weeks 4 weeks None, but generally discussed Not reported Improvement in EPMS (BAS, SAS) and symptoms (PANSS) in pats. switched to quetiapine Crosstaper 1 month s Insufficient efficacy, adverse events Not reported TEAE were somnolence, constipation and dizziness, asthenia, anxiety, insomnia, dry mouth, weight gain (from Ris/Hal) Improvement in symptoms (PANSS) and EPMS (SAS, BAS) Crosstaper switch 7 days 74 25 patients with hyperprolactinemi a 8 patients dropped due to exacerbation of psychotic symptoms during eight weeks of treatment Not reported Serum prolactin levels dropped significantly in patients successfully switched, PANSS levels remained stable in these patients; successful switching was associated with lower positive symptoms before switch Crosstaper 2 weeks 497 To show noninferiority of switching to quetiapine XR compared to maintaining quetiapine IR One patient switched to Quetiapine XR experienced aggression and psychotic disorder AE rates were similar in both groups, no TEAE occurred with frequency ≥5% Efficacy remained without significant adverse events; noninferiority was shown in perprotocol population abrupt N/A Insufficient efficacy, adverse events (e.g. EPMS, weight gain) Not reported, serious AEs (akathisia and EPMS, psychosis, exacerbation of psychosis) – were related to Que XR; 8 % EPMS related AEs (tremor, akathisia) TEAE were somnolence, sedation, dizziness, dry mouth, constipation, headache, insomnia; AEs leading to discontinuation were sedation, dizziness, psychotic disorder (4 %), schizophrenia (0.8 %) Improvement in symptoms, improvement in BAS and SAS scores, less anticholinergic medication, improvement in prolactin levels Crosstitration 1-4 days Author Olanzapine Quetiapine Gupta et al.36 (AstraZeneca) Open-label; stable patients 16 Weight gain, BMI > 25 kg/m2 Several antipsychotics Quetiapine Cortese et al.37 Open-label, randomized 22 EPMS 164 Haloperidol, olanzapine, risperidone Conventional antipsychotics Quetiapine IR Conventional antipsychotics, Olanzapine, Risperidone or other atypical antipsychotics Quetiapine Quetiapine Quetiapine XR Quetiapine XR Larmo et al.38 Nakajima et al.39 Möller et al.40 (Astrazeneca) Ganesan et al.41 (AstraZeneca) Study type/Patients Treatment emergent adverse events (>5 %) Switching to Open-label Open-label; female patients Double-blind, randomized; stable outpatients Open-label; Inand outpatients N 135, 79, 122, 73 Reason for switch Withdrawal/Rebound AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) Table e Overview of switching trials reporting on a switch to risperidone, trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Olanzapine Olanzapine Clozapine Switching to Risperidone Risperidone Risperidone Author Ganguli et al.42 (Janssen) Meyer et al.43 Still et al.44 Study type/Patients Open-label; randomized; rater-blinded; outpatients Rater-blinded, open-label, retrospective; stable out- or inpatients Open-label; treatmentresistant inpatients N 123 123 10 Reason for switch Withdrawal/Rebound Insufficient efficacy, BMI > 26 kg/m2 or glucose dysregulation Nausea, vomiting, agitation, movement disorders attributed as potential withdrawal symptoms (low incidence); Incidence of aggravated psychosis highest in abrupt group (13 % vs. 0 % and 5 % in gradual 1 and 2), similar with anxiety symptoms, mean reduction in standing diastolic RR, possibly related to cholinergic rebound Insufficient efficacy, abnormal metabolic status Not reported Insufficient efficacy, adverse events Adverse events (cognitive impairment, irritability) were attributed to risperidone, withdrawal symptoms were noticed (2 pat.); 5 patients showed exacerbation of psychosis Treatment emergent adverse events (>5 %) TEAE comprised insomnia, anxiety, sedation, somnolence, headache, aggravated psychosis 10 patients withdrew due to adverse events TEAEs were decreased concentration, impaired memory and irritability, akathisia, confusion Main outcomes/Comment Design Duration of switch Improvement in symptoms; Significantly more patients in abrupt (25 %) and gradual 1 (28 %) group discontinued early compared to strategy gradual 2 (12 %), hypnotic/sedative drugs were more often prescribed in first two groups 3 switching strategies: abrupt, gradual 1 (1 week) or gradual 2 (2 weeks) Up to 2 weeks Prevalence of metabolic syndrome decreased; PANSS scores dropped significantly only in patients without metabolic syndrome 3 different switching strategie s: abrupt discontinuation, gradual taper over 1 or 2 weeks Up to 2 weeks Crosstaper switch 10 days tapering clozapine from 565 mg No patient improved, switch from clozapine to risperidone in treatment-resistant pat. Not recommended by authors Various antipsychotics (mainly conventional) Typical antipsychotics Risperidone Kirov et al.45 Risperidone 46 Malla et al. Open-label; inand outpatients Retrospective open-label; outpatients 41 Investigation of specific switching strategy; insufficient efficacy or adverse events 31 Insufficient efficacy or due to adverse events (mainly EPMS) Four patients had recurrence of EPMS after switching, a more gradual taper of previous anticholinergic medication was suggested as being helpful by the authors Not reported TEAEs included insomnia, headache, dizziness and dystonia, 1 patient dropped due to dizziness, 1 due to orthostatic hypotension and 3 due to ejaculatory dysfunction 64 % of patients were switched successfully (completions of study and no worsening of any rating scale); overall symptoms improved and side effects got better (SAS); more gradual taper of previous medication would have been better for certain patients Abrupt with uptitration of risperidone and gradual taper of anticholinergic medication Immed iate Not reported Symptomatology improved; EPMS overall improved; mean hospital admissions and days in hospital dropped No data No data Symptomatology decreased 3 significantly (predominantly different negative symptoms); use of switching Risperidone antiparkinsonian drugs strategie (monothera decreased, rate of patients with s: py or in Residual polypharmacy decreased; lower Up to Conventional Nakanishi et Stable in- and Discussed, but none Discussed, but none ascendin combination 54 symptoms, pre-switch antipsychotic dosage 8 antipsychotics al.47 outpatients reported reported g or with other adverse events was associated with successful weeks descendi compounds switch to risperidone ng cross ) monotherapy; more gradual taper, switching may have resulted in abrupt higher frequencies of successful switch switching to monotherapy AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) Table f Overview of switching trials reporting on a switch to paliperidone palmitate or risperidone long-acting injectable (RLAI), trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Switching to Oral risperidone Paliperidon e palmitate Author Study type/Patients N Reason for switch Withdrawal/Rebound Treatment emergent adverse events (>5 %) Main outcomes/Comment Design Duration of switch Sliwa et al.48 Post-hoc analysis of double-blind placebocontrolled trial 216 Insufficient efficacy Not reported TEAEs comprised insomnia, anxiety and headache PANSS, CGI and PSP scores improved Abrupt N/A Different antipsychotics Risperidone long-acting injectable (RLAI) Hawley et al.49 (Janssen) Conventional antipsychotics Long-acting Risperidone 50 Oral atypical antipsychotics (mainly risperidone) Risperidone long-acting injectable (RLAI) Van Os et al. Kim et al. 51 Open-label; stable in- and outpatients Open-label Open-label; stable patients 182 Insufficient efficacy, adverse events, poor compliance 725 Fokus on 46 stable patients 36 Switching study with focus on cognitive functions Not discussed (potentially cases of relapse, insomnia, anxiety, movement disorders) TEAEs were headache, relapse (mostly within first 3 weeks), insomnia, disease exacerbation, anxiety, movementdisorders (2 %) (akathisia, tremor) Significant improvement in EPMS, modest weight gain Not reported TEAEs were anxiety, insomnia, hyperkinesia, depression and psychosis Symptomatology improved even in stable patients, EPMS decreased (ESRS) Not reported 2 pat. dropped out due to adverse events (dystonia, skin rash), one due to insufficient efficacy; TEAE were weight gain, amenorrhea, headache, fatigue, akathisia, galactorrhea, pain at injection side, tardive dyskinesia Cognitive functions improved significantly (digit span test, verbal learning test, WST, TMT B); PANSS, SOFAS and SAS scores improved significantly. Weight and Prolactin increased. Different switching strategies depending on oral formulation or depot interval First conversation to oral risperidone No data No data Up to 3 weeks 31.5 days in mean Oral or depot conventional antipsychotics Risperidone long-acting injectable (RLAI) Conventional depot antipsychotics Risperidone long-acting injectable (RLAI) Marinis et al.52 Lai et al.53 Sub analysis of open-label trial; stable patients Open-label, stable in- and outpatients 100 (oral); 565 (depot) 25 Inadequate efficacy, adverse events, noncompliance and other Not reported Not reported, but 5.3 % disease exacerbation or relapse and other psychiatric symptoms TEAEs were anxiety, insomnia, weight increase, EPMS, depression (switching from oral), weight increase, disease exacerbation (depot) Overall PANSS total and subscales, GAF, QoL improved No data No data Exacerbation of EPMS in 13.6 % not discussed as rebound phenomena TEAEs were menstrual irregularity, dizziness, somnolence, talkativeness PANSS and ESRS scores significantly improved (apart from PANSS positive scores); cholesterol and triglyceride levels decreased, none significant increase in weight Abrupt N/A AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) Table g Overview of switching trials reporting on a switch to ziprasidone, trials investigating a switch from only one compound are followed by trials investigating switches from several compounds; trials are further stratified in alphabetical order of authors Switching from Aripiprazole Quetiapine Haloperidol, olanzapine, risperidone Switching to Ziprasidone Ziprasidone Ziprasidone Study type/Patients Author Kim et al. 54 Karayal et al.55 (Pfizer) Alptekin et al.56 (Pfizer) Prospective, open-label study; outpatients Open-label; outpatients Open-label, stable outpatients N 19 241 99, 82, 104 Reason for switch Insufficient efficacy, adverse events Insufficient efficacy, adverse events Insufficient efficacy or adverse events Withdrawal/Rebound Treatment emergent adverse events (>5 %) Main outcomes/Comment Design Duration of switch Not reported; one dropout due to insufficient efficacy One drop-out due to agitation; TEAEs were sedation, poor appetite, weight loss, insomnia, agitation and dystonia, 1 patient developed tardive dyskinesia PANSS negative scores, SOFAS, CDSS and BDI scores improved significantly, PANSS positive and total scores decreased in completers; weight (- 3kg), BMI and waist/hip circumferences decreased, fasting glucose decreased, prolactin increased Crosstaper 4 weeks TEAEs were somnolence, insomnia, sedation, headache, dizziness, nausea, akathisia, decreased appetite Decrease in weight, improvement in lipid profiles and decrease of PANSS, CGI, CDSS scores, 45 % of patients discontinued due to various reasons – authors discussed high rates as attributable to cross-over titration and exposure to high doses of two compounds Crosstaper 2 weeks 15.8 % of patients dropped due to AEs, more patients switching from olanzapine discontinued; TEAE comprised somnolence, dizziness, insomnia, headache, nausea and anxiety Immediate discontinuation was preferred; significant improvements in BPRS, PANSS and CGI scores in all three groups and in AIMS, SAS and BAS scores switching from haloperidol or risperidone, weight reduction in patients switching from olanzapine or risperidone Three different switch strategies: abrupt, descending taper and plateau descending taper 1 week 23 patients discontinued due to schizophrenia or psychotic disorder; insomnia after switch from quetiapine was attributed to ziprasidone Not reported Conventional antipsychotics, risperidone or olanzapine Olanzapine, risperidone and other conventional or atypical antipsychotics Conventional or atypical antipsychotics Conventional antipsychotics Ziprasidone Ziprasidone Ziprasidone Ziprasidone Harvey et al.57 (Pfizer) Stable outpatients, no history of treatment resistance Montes et al.58 (Pfizer) Prospective observational study; stable outpatients Rossi et al.59 (Pfizer) Stip et al. 60 Open-label, chronic schizophrenic patients Open-label, chronic or sub chronic patients Not reported Mean total learning scores, long-delay recall improved and recognition discrimination improved in all three groups, effects on attention, vigilance, executive function and verbal fluency improved in only some of the tests and switching groups; there was no deterioration in any domain after switching; overall PANSS total scores improved in all three groups Crosstaper or abrupt switch 7 days Crosstaper or abrupt switch Up to 4 weeks 270 Insufficient efficacy, adverse events Not reported 84 Glucose intolerance, diabetes, dyslipidemia, weight gain EPMS occurred in five patients: akathisia, oculogyric crisis, tremor and rigidity, none discussed as withdrawal or rebound phenomenon TEAEs encompassed dizziness, tremor (3 %) Overall weight (- 5.1 kg), BMI, glucose, total cholesterol, LDL and triglycerides levels decreased (greatest in patients switched from olanzapine); psychopathology improved Psychiatric symptoms in 22.8 % of patients reported, not discussed as withdrawal or rebound phenomena 10.9 % drop-outs due to adverse events; TEAEs were heart rhythm disorders, gastrointestinal discomforts, central or peripheral nervous system events Overall PANSS total scores, GAF, CGI, SWN scores and Trail-making test improved; SAS scores, sexual dysfunction, total cholesterol, LDL and triglycerides improved, weight decreased Crosstaper 1 week Occurrence of withdrawal-induced dyskinesia in abrupt or fast taper strategies were discussed TEAEs were evenly distributed across groups, two treatmentrelated drop-outs (insufficient efficacy and adverse event) BPRS scores did not differ at endpoint in any two switching groups, but were greatest reduced in slow taper group at week one, fast taper was superior in EPMS reduction compared to slow taper, but inferior to abrupt switch in BAS scores 3 switching strategies: abrupt, fast and slow taper 7 days 312 54 Insufficient efficacy, adverse events Insufficient efficacy, adverse events Different switchstrategies: abrupt; TEAEs comprised Improvement in EPMS, weight Conventional descenWeiden et Insufficient Insomnia after switch insomnia, somnolence, and prolactin levels; antipsychotics, Open-label; 108, ding Ziprasidone al.57, 57, 61 efficacy, adverse from olanzapine, anxiety, nausea, improvement in cognitive olanzapine, outpatients 104, 58 taper (Pfizer) events attributed to ziprasidone dizziness, headache, functions risperidone (immedia asthenia te or delayed dose reduction ) AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation Up to 2 weeks antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch) Table h Overview of case reports reporting on withdrawal/rebound phenomena; trials are further stratified in alphabetical order of authors Switching to Author Study type/Patients N Reason for switch Withdrawal/Rebound Treatment emergent adverse events (>5 %) Main outcomes/Comment Design Duration of switch Clozapine Olanzapine DelassusGuenault et al.62 Refractory schizophrenia 2 Insufficient efficacy Diaphoresis, hypersialorrhea, brochial obstruction, agitation, anxiety, enuresis Not further reported Slow clozapine discontinuation over 3 weeks with concurrent anticholinergic treatment Descending taper 3 weeks Typical antipsychotic Atypical antipsychotic Cook et al.63 Stable outpatients 43 Various Not reported Not reported Improvement in positive symptoms, quality of life, resource requirement No data No data Chen et al.64 Chronic schizophrenic inpatients Descendingtaper switch 8 weeks taper of risperi done Gradual crosstaper Up to four weeks abrupt N/A abrupt N/A No data No data Switching from Case Reports Risperidone Zuclopenthixole or risperidone Aripiprazole Aripiprazole 9 Sexual dysfunction due to risperidone Not reported Not reported Improvement in sexual function, decrease in prolactin levels, improvement in symptoms 5 Symptomatic hyperprolactinemi a (amenorrhea or galactorrhea) and psychotic exacerbation Not reported No serious AEs during or after switching were observed Hyperprolactinemia and psychotic symptoms improved (PANSS) Not reported Kuloglu et al.65 Female schizophrenic inpatients 1 Oral dyskinesia No cholinergic rebound or side effects were noted Aripiprazole Paliperidone Lai66 Female schizophrenic patient Risperidone Paliperidone Teng and Lane67 Outpatient 1 Chronic hepatitis Exacerbated catatonia was discussed after abrupt switching 3 weeks after switch NMS developed Risperidone Paliperidone Wei et al.68 Female schizophrenic patient 1 Side effects Not reported Tardive dyskinesia Taper of aripiprazole did not alter oral dyskinesia, after switch to paliperidone, oral dyskinesia subsided within 1 month; psychotic symptoms remained stable NMS subsided after intensive care treatment; psychotic symptoms were managed thereafter with aripiprazole. Switch from risperidone to paliperidone should be done in adequate dosing First case of reported TD associated with paliperidone treatment. Dyskinesias subsided after switch to clozapine AE: Adverse events; AIMS: Abnormal Involuntary Movement Scale; BAS: Barnes Akathisia Scale; BDI: Beck Depression Inventory; BMI: body mass index; BPRS: Brief Psychotic Rating Scale; CDSS: Calgary Depression Scale for Schizophrenia; CGI: Clinical Global Impression; DAI: Drug Attitude Inventory; EPMS: Extra-pyramidal motor symptoms; ESRS: Extra-pyramidal Symptom Rating Scale; FGA: first generation antipsychotic; GAF: Global Assessment of Functioning; HOMA-IR: Homeostasis model assessment insulin resistance; LAIR: long-acting injectable risperidone; LDL: low density lipoprotein; NMS: Neuroleptic malignant syndrome; PANSS: Positive And Negative Symptome Scale; PSP: Personal and Social Performance Scale; QoL: Quality of Life; SAS: Simpson Angus Scale; SGA: second generation antipsychotic; SOFAS: Social and Occupational Assessment of Functioning; SWN-K: Subjective-Wellbeing under Neuroleptic treatment, short version; TD: Tardive dyskinesia; TEAE: Treatment-emergent adverse event; TMT: Trail Making Test; WST: Wisconsin Card Sorting Test; N/A: not applicable (in the case of abrupt switch there is no duration of the switch Reference List (1) Lin CC, Bai YM, Wang YC et al. 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