Pharmacological Management of Persistent Hostility and Aggression in Persons With Schizophrenia Spectrum Disorders: A Systematic Review
Abstract
Methods
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The olanzapine group was included in the study in order to provide a concurrent active control group to confirm that the study as executed was adequate to detect a drug effect in the event of negative findings for paliperidone ER compared with placebo (i.e., assay sensitivity to detect a “failed trial”). The study was not designed to support statistical comparison of the paliperidone ER and olanzapine arms52 (p. 150).
Results
1. Does evidence exist that any medication will reduce overt aggression or physical violence in patients With schizophrenia spectrum disorders?79,89
Corollary: Does evidence exist that one medication is more efficacious than another in reducing overt aggression or physical violence in patients with schizophrenia spectrum disorders? 45, 46, 57, 87, 89–102 (Table 1)
Study and Evidence Level | Journal | Study Type | Setting | N | Percent Complete | Medication and Dose | Duration | Outcome Measure | Concomitant Medications Permitted | Results | Class |
---|---|---|---|---|---|---|---|---|---|---|---|
Level III studies | |||||||||||
Spivak et al., 200390 | JCP | Open prosp | Inpatient | 44 | 84.1% | Cloz 150–500 mg/day versus HAL decanoate 150–300 mg/month | 6 months | 1. OAS | Benzos | Cloz assoc. w sig. greater ↓ OAS | III |
2. Plutchik IS | 2. Cloz assoc. w sig. greater ↓ IS | ||||||||||
Stabenau, 196491 | PsychQuart | RCT | Inpatient | 52 | 40/52=76.9% | Chlorp 100 - > 500 mg/day versus Thior 100 - > 500 mg/day | 3 weeks | MACL AC; WPRS Agg. item | NR | No sig. Diff. | III |
Swanson, 200846 | BJP | RCT | Out | 1445 | 653/1445=45.2% | Olan 7.5–30 mg/day versus Risp 1.5–6 mg/day versus Quet 200–800 mg/day versus Perph 8–32 mg/day versus Zip 40–160 mg/day | 6 months | MacArthur | All except antipsychotics | Perph assoc. w. sig. greater ↓ violence No other diff. | III |
Volavka et al., 200445 | J Clin PP | RCT | Inpatient | 157 | 58% | Cloz 200–800 mg/day versus Olan 10 –40 mg/day versus Risp 4–16 mg/day versus HAL10 –30 mg/day | 14 weeks | 1.Incidents of overt agg. | Lor; Diphenh;Chloral H | Cloz>others re. incidents; Cloz>HAL on OAS TAS | III |
2. OAS TAS | |||||||||||
Level IV studies | |||||||||||
Bitter, et al., 200592 | Eur Psych | Post hoc analysis of Prosp. naturalistic study | Out-patient | 5018a | 62.5% | Olan versus Cloz versus Risp versus HAL (doses NR). | 6 months | Yes/no exhibiting “verbal or physical hostility/aggression” | NR | Proportion of patients exhibiting “verbal or physical hostility/aggression” ↓ with all rxs | IV |
Buckley, et al., 1995 57b | B Am Acad PL | Pros observ | Inpatient | 30 [11 violent versus19 non violent] | Before and after Cloz (dose NR) | 12 months | S&R data compared in violent versus non-violent pts. | nr | Cloz=Larger decline in seclusion and restraint in “violent” subgroup | IV | |
Carney, 198493 | Pharm ther | Pros observ | Inpatient, then Out-patient | 23 | 20 | Before and after clopenthixol decanoate ∼200 mg/3 weeks | 11 months | 7 point agg. scale | Other antipsychotics; Benzos; procyclidine; benzhexol; TCAs | Sig. ↓in agg. score | IV |
Chiles et al., 199487c | HCP | Retro | Inpatient | 139 | 82.7%c | Before and after Cloz 200 –900 mg/day | 24 weeks | S&R data | NR | Cloz assoc. w ↓use of S&R | IV |
Dalal et al., 199994b | CBMH | Pros observ | Inpatient | 50 [20 violent] | Before and after Cloz, (m =465 mg/day) | 12–27 months | Violent bhv [nurses’ obser] | NR | At 12 m: 16/20 in violent subgroup “less severe violent behv” | IV | |
Kuoppasalmi et al., 199395 | Psych Fenn | Retro | Inpatient | 103 | N/A | Before and after Cloz 150–900 mg/day | 24 months | “Intensity” of agg bhv 0,1,2 | Other antipsychotics; Benzos | Sig ↓ in intensity of agg. behv. | IV |
Mallya et al., 199296 | JCP | Retro | Inpatient | 107 | N/A | Before and after Cloz (dose NR) | 13 months | S&R data | NR | Cloz assoc. w ↓S&R | IV |
Menditto et al., 199697 | Psych Serv | Prosp obs | Inpatient | 22 | 100% | Cloz 400–700 mg/day + ‘Social Learning’ versus typical antipsychotics + ‘Social Learning’ | 6 months | TSBC = # and freq of threats/assaults | Lithium; AEDs | Cloz assoc. w ↓threats or assaults | IV |
Spivak et al., 199798 | Clin NP | Prosp obs | Inpatient | 14 | 100% | Before and after Cloz (m=223 mg/day) | 18 weeks | 11. OAS | NR | 1. Cloz assoc. w ↓ agg. | IV |
2. Plutchik IS | 2. Cloz assoc. w ↓impuslivity | ||||||||||
Spivak et al., 199899 | Clin NP | retro | Inpatient | 60 | N/A | Cloz (dose NR) versus typical antipsychotics (dose NR) | 1 y | 1. OAS | NR | 1. Cloz assoc. w ↓ agg. versus typicals | IV |
2. Plutchik IS | 2. Cloz assoc. w ↓impuslivity versus typicals | ||||||||||
Swanson et al., 200489 | Schiz Bull | Prosp obs | Out-patient | 403 | 229/403=56.8% | Any atypical versus any typical (doses NR) | 2 years | Composite index from: | NR | Compliance with atypicals assoc. w<violence versus typicals | IV |
1. Macarthur | |||||||||||
2. Record review | |||||||||||
3. Arrest record | |||||||||||
Swanson et al., 2004100 | JCP | Prosp obs | Out-patient | 403 | NRd | Olan versus Risp (doses NR) | 3 years | Composite index from: | NR | Olan compliance for one year or more assoc. w<violence versus risperidone | IV |
1. Macarthur | |||||||||||
2. Record review | |||||||||||
3. Arrest record | |||||||||||
Wilson, 1992 101e | HCP | Retro | Inpatient | 37 | N/A | Before and after Cloz 300 –900 mg/day | 12 months | # violent episodes; S&R data | Other antipsychotics | Cloz assoc. w ↓ viol episodes (no stats. reported) | IV |
Wilson and Claussen, 1995102 | Psych Serv | Retro | Inpatient | 100f | N/A | Before and after Cloz 150 –900 mg/day | 25 months | # violent episodes | Other antipsychotics | Olan assoc. w ↓ viol episodes | IV |
2. Does evidence exist that any medication will reduce hostility in patients With schizophrenia spectrum disorders?34,48,49,51,52,54,55,103–113 ( Table 2)
Study and Evidence Level | Journal | Study Type | Setting | N | Percent Complete | Comparison | Duration | Outcome Measure | Concomitant Medications Permitted | Results | Class |
---|---|---|---|---|---|---|---|---|---|---|---|
Level II studies | |||||||||||
Borison et al., 1996103 | J Clin PP | RCT | Inpatient | 109 | 46% | Quet 75–750 mg/day versus placebo | 6 weeks | BPRS H/S Factor V | Chloral H; Benztr; Diphenh | No diff. at endpoint | II |
Canuso et al., 2009104 | AJP | RCT | Inpatient | 399 | 70% | PAL ER 9–12 mg/day versus quetiapine 600–800 mg/day versus placebo | 2 weeks | PANSS UH/E factor | Lorazepam; midazolam; amobarbital sodium; zaleplon; zolpidem; Benztr “or equivalent” | PAL assoc. w sig. greater ↓in UE/H versus placebo | II |
Canuso et al., 2010105 | J Aff D | Pooled anal of Davidson 07, Kane 07, Marder 07 | In- & out-patient | 193 (subset w “prominenet affective sxs” | 46% | PAL ER 3–12 mg/day versus placebo | 6 weeks | 1. PANSS HI | Benzos; AntiD | 1. PAL assoc. w sig. greater ↓in HI versus placebo | II |
2. PSP agg | 2. No results reported re. PSP | ||||||||||
Corrigan et al., 2004106 | Bio Psych | RCTa | Inpatient | 467 | 72.2% | Sone 1.5 versus 10 versus 60 mg/day versus Olan 15 mg/day versus placebo | 6 weeks | PANSS UH/E | Lor; Fluni; Chloral H; Benztr; benzhexol Hcl; Diphenh | 1. Olan assoc. w sig. greater ↓in UE/H versus placeboS | II |
2. Sone=no diff. versus placebo | |||||||||||
Czobor et al., 199534b | J Clin PP | RCT | Inpatient | 139 | NR | Risp 2–16 mg/day versus HAL 20 mg/day versus placebo | 8 weeks | PANSS HI | Benzos; Chloral H; AntiCh | 1. Risp assoc. w greater ↓in HI than HAL | II |
2. Risp assoc. w greater ↓in H versus placebo (trend) | |||||||||||
Kahn et al., 200751 | JCP | RCT | Inpatient and outpatient | 556 | 78% | Quet XR 400 mg/day versus Quet XR 600 mg/day versus Quet XR 800 mg/day versus Quet XR 400 mg/day versus Quet IR 400 mg/day versus placebo | 6 weeks | PANSS HF | AntiCh; Lor; Oxa; “sedatives and hypnotics” | All doses and forms of Quet assoc. w sig. greater ↓in HF versus placebo | II |
Kane et al., 200752 | Schiz Res | RCT | Inpatient | 628 | 66% | PAL ER 6 versus 9 versus 12 mg/day versus Olan 10 mg/day versus placebo | 6 weeks | 1. PANSS UH/E | Benzos; AntiD | 1. PAL assoc. w sig. greater ↓in UE/H versus placebo | II |
2. PSP agg | 2. No results reported re PSP | ||||||||||
Meltzer et al., 2008107 | JCP | Pooled reanalysisa | Inpatient | 1306 | 74% | PAL ER 3 versus 6 versus 9 versus 12 versus 15 mg/day versus Olan 10 mg/dN versus placebo | 6 weeks | PANSS UH/E | Benzos; AntiD | 1. PAL 6, 9, 12 0r 15 mg/day assoc. w sig. greater ↓in UE/H versus placebo | II |
Level III studies | |||||||||||
Chengappa et al., 2003108 | Clin Ther | RCTc | Inpatient | 257 | 52.9% | Quet 150–750 mg/day versus HAL 12 mg/day versus placebo | 6 weeks | BAS=agitation score derived from BPRS | Lor; Chloral H | 1. Quet assoc. w greater ↓in BAS versus placebo | III |
2. HAL assoc. w greater ↓in BAS versus placebo | |||||||||||
3. No sig. diff. in size of ↓in BAS between Quet+HAL | |||||||||||
Marder et al., 200755 | Bio Psych | RCT | Inpatient | 444 | 43% | PAL ER 6 versus 12 mg/day versus Olan 10 mg/day versus placebo | 6 weeks | PANSS UH/E | Benzos; AntiD; AntiCh; NSAIDs | 1. PAL 6 or 12 assoc. w sig. greater ↓in UE/H than placebo | IIId |
2. Olan assoc. w ↓in UE/H | |||||||||||
3. No results reported re PSP | |||||||||||
4. (no stats reported) | |||||||||||
Level IV studies | |||||||||||
Aleman and Kahn, 2001109 | Eur NP | Meta- anal | Inpatient | 2248Z | NR | Risp versus typical antipsychotics versus placebo | Varied | Varied | NR | 1. Risp assoc. w greater ↓H or agg. versus typical antipsychotics | IVe |
2. Risp assoc. w greater ↓H or agg. versus placebo | |||||||||||
Buckley, 200448 | Cur Med Res Op | Meta-anal | Inpatient | 624 | NR | Quet 150–750 mg/day versus placebo | 6 weeks | 1. BPRS HI | Chloral H; Lor; Other Benzos; Benztr; Diphenh | Quet assoc. w greater ↓HI and HF versus placebo | IVf |
2. BPRS HF | |||||||||||
Davidson et al., 200754 | Schiz Res | RCTa | Inpatient | 618 | 59% | PAL ER 3 versus 9 versus 15 mg/day versus Olan 10 mg/dE versus placebo | 6 weeks | PANSS UH/E | Benzos; AntiD; AntiCh; | 1. PAL assoc. w sig. greater ↓in UE/H than placebo | IVg |
Kane et al., 2011110 | JCP | RCT | NR | 386 | 54% | Asen (m=17.6 mg/d) versus placebo | 26 weeks | PANSS HF | Benzos; Partial benzo agonists; nonbenzo hypno tics; AntiD; mood stabilizers; “EPS medication” | 1. Asen assoc. w sig ↓HE | IV |
2. Impact of asenepine versus placebo=NR | |||||||||||
Marder and Meibach, 1994111 | AJP | RCT | Inpatient | 388 | 47% | Risp 2 versus 6 versus 10 versus 16 mg/day versus HAL 20 mg/day versus placebo | 8 weeks | PANSS HI | Lor; Chloral H; AntiP | 1. Risp versus placebo=NR | IV |
2. Risp 6 mg. Assoc. w sig. ↓ from baseline PANSS HI | |||||||||||
Simopoulos et al., 1974112 | Arch Gen Psych | RCT | Inpatient | 76 | 68.4% | DPH 375–625 mg/day versus placebo | 8 weeks | BPRS HI | NR | 1. DPH assoc. w less H at 4, not 8 weeks | IVh |
Singer and Lam, 1973113 | J Int Med Res | RCT | Inpatient | 33 | 91% | Cloz 200–600 mg/day versus placebo | 2 weeks | BPRS HI | NR | Cloz assoc. w greater ↓in H than placebo (no stats reported) | IV |
Volavka et al., 200549 | JCP | Post hoc anal. of pooled datai | Inpatient | 1476 | NR | 1. ARI versus placebo | 4 weeks | PANSS HI | Lor; Benztr | 1. Both ARI and HAL assoc. w sig. greater ↓in HI than placebo; | IV |
2. ARI versus HAL versus placebo | 2. No diff. between ARI and HAL |
Corollary: Does evidence exist that one medication is more efficacious than another in reducing hostility in patients with schizophrenia spectrum disorders? 44,47, 50, 108, 114–131 (Table 3)
Study and Evidence | Journal | Study Type | Setting | N | Percent Complete | Comparison | Duration | Outcome Measure | Concomitant Psychotropics Permitted | Results | Class |
---|---|---|---|---|---|---|---|---|---|---|---|
Class II Studiesa | |||||||||||
Czobor et al., 199534,b | J Clin PP | RCT | Inpatient | 139 | NR | Risp 2–16 mg/day versus HAL 20 mg/day versus placebo | 8 weeks | PANSS HI | Benzos; Chloral H; AntiCh | 1. Risp assoc. w sig. greater ↓in HI than HAL | II |
2. Risp assoc. w greater ↓in H versus placebo (trend) | |||||||||||
Min et al., 1993114 | Yon MJ | RCT | In- and outpatient | 35 | 91.4% | Risp 5–10 mg/day versus HAL 5–10 mg/d | 8 weeks | BPRS HF | Lor; oxazepam; Benztr | No diff. in impact on HF | II |
Niskanen et al., 1974115 | Psych Fenn | RCT | Inpatient | 48 | 100% | Cloz 75–1000 mg/day versus Chlorp 75–800 mg/d | 40 days | BPRS HF | NR | Cloz assoc. w sig. greater ↓HF versus Chlorp (NS) | II |
Seth et al., 1979116 | Cur Ther Res | RCT | Inpatient | 72 | 88.9% | Lox 20–90 mg/day versus Trif 5–45 mg/day | 12 weeks | BPRS HI | NR | Trif assoc. w sig greater ↓HI versus Lox. Both agents assoc. w sig. greater ↓HI versus baseline | II |
Vyas and Kalla, 1980117 | Cur Ther Res | RCT | Inpatient | 30 | 100% | Lox 30–90 mg/day versus Chlorp 300–900 mg/day | 6 months | BPRS HI | NR | Lox assoc. w sig. greater ↓HI versus Chlorp | II |
Class III studies | |||||||||||
Abuzzahab and Zimmerman, 1982118 | JCP | CT [not random] | Out-patient | 46 | 56.5% | HAL 5–40 mg/day versus Thioth 10–80 mg/day | 24 weeks | BPRS H/S | AntiP; “concomitant medications for patients’ well-being” | HAL assoc. with sig. greater ↓H/S versus Thioth | III |
Citrome et al., 200143 | Psych Serv | RCT | Inpatient | 167 | 58% | Cloz 200–800 mg/day versus Olan 10 –40 mg/day versus risperidone 4–16 mg/day versus HAL 10 –30 mg/d | 14 weeks | PANSS HI | Benztr; PROP; Lor; Diphenh; Chloral H | Cloz assoc. w sig. greater ↓HI versus Risp and HAL but not versus Olan | III |
Claghorn et al., 1987119 | J Clin PP | RCT | Inpatient | 151 | 58%c | Cloz 150–900 mg/day versus Chlorpr 300–1800 mg/day | ≥ 25 days | BPRS H/S | NR | Cloz assoc. w sig. greater ↓H/S versus Chlorp | III |
Gaebel et al., 200750 | JCP | RCT | In- and outpatient | 158 | 30.4%d | HAL 1–8 mg/day versus Risp 1–8 mg/day | 8 weeks inpt. + 10 months outpt | PANSS UH/E | All except other antipsychotics or mood stab. | No sig. diff. | III |
Høyberg et al., 1993120 | Acta Psych Scand | RCT | Inpatient | 107 | 73% | Risp 5–15 mg/day versus Perph 16–48 mg/day | 8 weeks | BPRS HF | Benzos; Orphenadrinee | Risp assoc. w sig. greater ↓HF versus Perph | III |
Kane et al., 2001121 | Arch Gen Psych | RCT | Out-patient | 71 | 51% | Cloz 200–800 mg/day versus HAL 4 –16 mg/day | 29 weeks | BPRS H/S | Lor; Benztr | Cloz assoc. w sig. greater ↓H/S versus HAL | III |
Marder et al., 200347 | AJP | RCT | Outpatient | 63 | 46% | HAL M=4.5 mg/day at 2y versus Risp M=5.7 mg/day at 2y (each arm w versus w/o ‘enhanced skills training’) | 2 years | 1. BPRS HF | AntiCh; PROP; others NR | Risp assoc. w greater ↓AH versus HALf; No sig. diff. on HF | III |
2. SCL–90-R AHf | |||||||||||
McEvoy et al., 1991122 | Arch Gen Psych | RCT | Inpatient | 47 | 68% | HAL (m=3.4 mg/d) versus HAL (m=11.6 mg/day) | 2 weeks | BPRS H/S | Lor; Biperiden; Diphenh | Higher dose HAL assoc. w sig. greater ↓H/S versus lower dose HAL. However, no sig. diff. on HI. | III |
Muller et al., 2002123 | J Clin PP | RCT | Inpatient | 319 | 74% | AMIS 100 versus 400 versus 800 versus 1200 mg/day versus HAL 16 mg/day | 4 weeks | BPRS H/S | Benzos; Chloral H | 1. AMIS 400 and 800 assoc. w greater ↓H/S versus AMIS 100 or HAL | III |
Peuskens et al. 1995124 | BJP | RCT | Inpatient | 1362 | 75% | Risp 1 versus 4 versus 8 versus 12 versus 16 mg/day versus HAL 10 mg/day | 8 weeks | BPRS “hostility cluster” | Lor; Oxa; Tem; biperiden; procyclidine | Risp 4, 8,12, or16 mg/day or HAL 10 mg/day assoc. w greater ↓H versus Risp 1 mg/d | III |
Wang, 2006125 | J Psych Res | RCT | Out-patient | 36 | 63.9% | Risp 2–6 mg/day versus Olan 5–15 mg/day | 12 weeks | PANSS UH/E | NR | Risp assoc. w sig ↓UE/H versus baseline, but not versus Olan | III |
Class IV studies | |||||||||||
Aleman and Kahn, 2001109g | Eur NP | Meta anal | Inpatient | 2248 | NR | Risp versus typical antipsychotics or placebo | Varied | Varied | NR | 1. Risp assoc. w greater ↓H or agg. versus typical antipsychotics | IV |
2. Risp assoc. w greater ↓H or agg. versus placebo | |||||||||||
Arango, 2003126 | AJP | RCT | Out-patient | 75 | 85.3% | Cloz 200–600 mg/day versus HAL 10–30 mg/day | 10 weeks | BPRS HI | Benztr | 1. Cloz assoc. w no sig. ↓HI | IV |
2. HAL assoc. w ↓ HI | |||||||||||
Conley et al., 200344 | J Clin PP | RCT (cross over) | Inpatient | 13 | 73.9% | Olan 50 mg/day versus Cloz 300–450 mg/day | 16 weeks | PANSS HF | Lor; Benztr | No sig. diff. | IVh |
Ebrahim et al., 1994127i | HCP | Retro observ. | Inpatient | 53 | 51% | Before and after switch to Cloz 87.5–850 mg/day | 6 months | 1. BPRS HI | Typical antipsychotics; enalopril; nifedipine | 1. Cloz assoc. w sig. ↓HI and ↓SandR | IV |
2. S&R data | |||||||||||
Herman, 1997128 | Aust NZ J MHN | Prosp observ | Inpatient | 11 | NR | Before and after switch to Cloz 375–600 mg/day | 5–16 months | BPRS HI | NR | Cloz assoc. w sig. ↓HI | IV |
Levinson et al., 1992129 | BJP | RCT | Inpatient | 61 | 67% | Fluph 10 to 30 mg/day (M=21 mg/day) | 29 daysj | BPRS HI | Chloral H; sodium amytal; Benztr | Fluph Assoc. w ↓HI | IV |
Mann et al., 1984130 | Pharm psych | Open | Inpatient | 14/ | 78.6% | Before and after AMIS mean 675 mg/day | 28 days | BPRS HI | Amitryptyline; lorazepam; biperiden | AMIS assoc. w sig. ↓ HI | IV |
Volavka et al., 1993131 | J Clin PP | Prosp observ | Inpatient | 223 | 82% | Before and after switch to Cloz (dose NR) | 1 years | BPRS HIk | NR | Cloz assoc. w ↓HI | IV |
Wilson, 1992101 | HCP | Retro | Inpatient | 37 | N/A | Before and after Cloz 300–900 mg/dayl | 1 years | 1. # violent episodes | Phenytoin; divalproex | ↓violent episodes and S&R episodes after switch to Cloz (sig. N/R) | IV |
2. # S&R episodes |
3. Does evidence exist that any adjunctive medication will reduce overt aggression or hostility in persons with schizophrenia spectrum disorders?70–72,88,132–142 (Table 4)
Study and Evidence Level | Journal | Study Type | Setting | N | Percent Complete | Comparison | Duration | Outcome Measure | Concomitant Medications Permitted | Results | Class |
---|---|---|---|---|---|---|---|---|---|---|---|
Class I studies | |||||||||||
Maoz et al., 2000132 | Eur Psychol | RCT | Inpatient | 42 | 81% | HAL 20–30 mg/d+PROP (m=159 mg/d) versus HAL+placebo | 8 weeks | 1. OAS | Benzos; biperiden | 1. Comb. rx assoc. w sig. ↓on State-trait PI anger | I |
2. Agg Behav Seq Para | 2. No diff on OAS, CGI-A, or MAI at 8w | ||||||||||
3. State-Trait PI anger | |||||||||||
4. MAI | |||||||||||
5. CGI-A | |||||||||||
Pugh et al., 1983133 | BJP | RCT | Inpatient | 41 | 93% | Neuroleptic+PROP 160–640 mg/day versus neuroleptic+placebo | 12 weeks | NOSIE IS | NR | Combo rx assoc. w sig. greater ↓NOSIE IS versus placebo | I |
Strous et al., 2009134 | Eur NP | RCT | NR | 18 with low activity COMT poly morph | 89% | Adjunct SAM-E 800 mg/d+antipsychotics versus placebo+antipsychotics | 8 weeks | 1. OAS | All except antipsychotics | Adj SAM-E assoc. w sig. ↓in OAS in this genetic subset | I |
2. Life Hx Agg | |||||||||||
Class II studies | |||||||||||
Farzin et al., 200572 | Iran JMS | RCT | Inpatient | 30 | NR | Perph 40 mg/d+Fam 60 mg/day versus perph+placebo | 6 weeks | PANSS “Aggressiveness risk score” | Biperiden | Combo rx assoc. w ↓agg. risk scores | II |
Omranifard et al., 2007135 | IJPBS | RCT | Inpatient | 32 | NR | Risp 6 mg/d+VPA max 20 mg/kg/day “if tolerated” versus Risp+placebo | 4 weeks | PANSS Impulse control item | Lor | Combo rx assoc. with ↓PANSS impulse control score | II |
Yorkston, et al., 1977136 | Lancet | RCT | Inpatient | 14 | NR | Typical antipsychotic+PROP “< 500 mg/d” versus typical antipsychotic+placebo | 12 weeks | Nurses’ rating of violence | NR | Adj PROP assoc. w sig. ↓ violence | II |
Class III studies | |||||||||||
Casey et al., 200370 | NeuroPP | RCT | Inpatient | 249 | 67% | Olan 15 mg/day versus Risp 6 mg/day versus Olan+VPA 15–30mg/kg/day versus olan+VPA | 28 days | PANSS “Suppl Anger Item”a | Chloral H; zolpidem; Lor; PROP; Benztr | Antipsych+VPA assoc. w sig. greater ↓in PANSS “suppl Anger Item” versus antipsych alone | III |
Caspi et al., 2001 137,b | Int Clin PP | RCT/crossover | Inpatient | 30 “at least 4 major agg. episodes within 2 months” | 76.6% | Antipsychotic agent+PIN 15 mg/day versus antipsychotic agent+placebo | 20 weeks | OAS | Diaz; CBZ; biperiden | Adj PIN assoc. w sig. ↓: | III |
1. # and severity of agg. Incidents twd. other persons | |||||||||||
2. # agg. and severity of agg. incid. twd. objects. | |||||||||||
Citrome et al., 2004138 | Psych Serv | RCT | Inpatient | 249 | 67% | Olan 15 mg/day versus Risp 6 mg/day versus olan+VPA 500–3500 mg/day versus Risp+VPA | 28 days | PANSS HI | Chloral H; zolpidem; Lor; PROP; Benztr | No diff. at endpoint | III |
Class IV studies | |||||||||||
Behdani, et al., 200871 | Eur NPP | RCT | Inpatient | 64 female | NR | Risp 6 mg/d+estradiol 0.05 mg/day versus Risp+placebo | 8 weeks | PANSS “Aggression supplemental scale”c | NR | Estradiol assoc. w sig. ↓PANSS “Aggression supplemental scale” | IV |
Gerlach et al., 197588 | Pharmako | RCT Crossover | Inpatient | 11 w TDd | NR | Lithium sulfate (0.8–1.2 meq/l) versus placebo | 42 days | “Rough evaluation” of agg. | NR | 9/11 exhibited ↓ agg. | IV |
Littrell, et al., 2004139 | JCP | prospeOpen | Out-patient | 10 | NR | Before and after Olan (dose NR) + VPA (plasma 50–100 μg/mL | 12 months | PANSS HI | None | Sig. ↓H | IV |
Suzana et al., 2009140 | Eur NPP | RCT | NR | NR | NR | HAL versus Risp versus Cloz versus HAL+VPA or CBZ versus Risp+VPA or CBZ (doses NR) | 4 weeks | PANSS HI | NR | 1. Cloz alone assoc. with sig greater ↓in H than Risp or HAL | IV |
2. Cloz+either adjunct assoc. with sig. greater ↓in H | |||||||||||
Wassef et al., 2001141 | J Clin PP | Prospec observ | Inpatient | 30 | 100% | HAL 20 mg/day w or w/o adjunctive VPA titrated to 80–100 μg/mL. | 22 days | BPRS HI | NR | No diff in H | IV |
Yoshimura et al., 2007142 | Pharmpsych | Pros observ | Inpatient | 12 | 100% | Before and after adjunctive VPA 400–800 mg/day added to Risp 2–6 mg/day | 4 weeks | PANSS HI | NR | Adj VPA assoc. w sig. ↓ H | IV |
Study and Evidence Level | Journal | Study Type | Setting | N/Selection Factor | Percent Complete | Comparison | Duration | Outcome Measure | Concomitant Medications Permitted | Results | Class |
---|---|---|---|---|---|---|---|---|---|---|---|
Class III studies | |||||||||||
Arango, et al., 2006143 | Eur Psych | Open prosp | Out-patient | 46 “previously violent pts.” | 89% | Oral Zuc (m=35 mg/day) versus depot Zuc (m=233 mg/2 w) | 1 year | Freq. viol acts scoring 2 or more on MOAS phys. agg. Subscale | Biperiden; Benzos | 1. Depot Zuc assoc. w longer delay to first viol. episode | III |
2. Depot Zuc assoc. w fewer viol. episodes in subgroup with previous freq. viol. | |||||||||||
Beck et al., 1997144 | JAAPL | Open/retros | Inpatient | 20 “violent treatment resistant” | N/A | Risp 6 mg/day versus typical antipsychotics | 1 year | TSBC Frequency of threats, assaults, serious property destruct | NR | No sig. diff. | III |
Caspi et al., 2001137a | Int Clin PP | RCT/crossover | Inpatient | 30 “at least 4 major agg. episodes… within 2 mos.” | 76.6% | Adjunct PIN 15 mg/day versus adj placebo | 20 weeks | OAS | Diaz; CBZ; biperiden | PIN assoc. w sig. ↓: | III |
1. # and severity of agg. Incidents twd. other persons | |||||||||||
2. # agg. and severity of agg. incid. twd. objects. | |||||||||||
Citrome et al., 2007145 | Int Clin PP | RCT b | Inpatient | 33 “who alos exhibited…poor impulse control, agg. Bhv. And/or hostility | 61% | Risp. 4 –6 mg/day versus Risp+Adj. VPA (50–100 μg/ml) | 8 weeks | OAS | Lor; Benztr | No sig. diff. on OAS, PANSS HI, BIS, or BDHI | III |
BDHI | |||||||||||
BIS | |||||||||||
PANSS HI | |||||||||||
Feldman, 1982146 | J Clin PP | Open prosp | Inpatient | 18 “hostile and aggressive” | 83.3% | Before and after Lox 50–150 mg/d | 10 days | BRPS H/S | AntiP | Lox assoc. w sig. ↓ BPRS H/S | III |
Krakowski, et al., 200640 | Arch Gen Psych | RCT | Inpatient | 110 “confirmed episode of phys. assault + persistence of agg.” | 63.6% | Cloz 200–800 mg/day versus Olan 10 –35 mg/day versus HAL 10 –30 mg/day | 12 weeks | MOAS | Lor; Chloral H; Mood stabilizers; AntiD; Diphenh; Benztr | 1. Cloz assoc. w sig. greater ↓ MOAS versus Olan. or HAL | III |
2. Olan assoc. w sig. greater ↓ MOAS versus HAL | |||||||||||
Krakowski, et al., 2008 147c | J Clin PP | RCT | Inpatient | 100 “Displayed persistent agg.” | Cloz 200–800 mg/day versus Olan 10 –30 mg/day versus HAL 10 –30 mg/d | 12 weeks | MOAS | Lor; Chloral H; Mood stabilizers; AntiD; Diphenh; Benztr | 1. Cloz assoc. w sig. greater ↓ MOAS versus Olan or HAL | III | |
2. Olan assoc. w sig. greater ↓ MOAS versus HAL | |||||||||||
Class IV studies | |||||||||||
Afaq, et al., 200286 | J Kor MA | retro | Inpatient | 60 “violent subjects” | N/A | HAL (m=21 mg/d), or Olan (m=19 mg/d), or Risp (m=8 mg/d); w versus w/o adjunct divalproex sodium, (dose NR) | ≤ 1 year | S&R | NR | No report of diff. in S&R | IV |
Allan et al., 1996148 | JCP | RCT | Inpatient | 34 “admitted b/c … agg behv” | 94% | Adj NAD 120 mg/day versus adj placebo | 3 weeks | BPRS H/S | NR | No report of BPRS H/S at endpoint | IV |
Alpert, et al., 1990149 | Psych P B | RCT | Inpatient | 32 “with measurable levels of agg.” | 93.8 | Adj NAD 80–120 mg/day versus placebo | 3 weeks | 1. BPRS H/S | Lithium | No report of BPRS H/S, NOSIE IS, or OAS at endpoint | IV |
2. NOSIE IS | |||||||||||
3. OAS | |||||||||||
Buckley, et al., 199557d | B Am Acad PL | Pros observ | Inpatient | 30 (11 violent versus 19 non- violent) | Before and after Cloz (dose NR) | 12 months | S&R data compared in violent versus non-violent pts. | NR | Cloz=Larger ↓ in seclusion and restraint in “violent” subgroup | IV | |
Dalal et al., 199994d | CBMH | Pros observ | Inpatient | 50 (20/50 violent) | Before and after Cloz(m=465 mg/day) | 12–27 months | Violent bhv [nurses’ obser] | NR | At 12 m: 16/20 in violent subgroup “less severe violent behv.” | IV | |
De Domenico, et al., 1999150 | IJPCP | retro | Inpatient | 16 “manifest agg. bhv.” | N/A | Before and after Cloz 150–400 mg/d | 12 months | 1. Agg acts per Wistedt Agg+Soc Dysfunc Scale 90 | Benzos | 1. Sig. ↓in agg. acts | IV |
2. S & R data | 2. ↓time in S&R | ||||||||||
3. need for chemical restraint | 3. ↓need for chemical restraint | ||||||||||
Gobbi et al., 2006151 | J Clin PP | Retro case-control | Inpatient | 45 at a max security hospital for agg. or impulsive patients (4% bipolar) | N/A | Before and after adjunct Top100–300 mg/day or VPA (350–700 μmol/L) or both | 24 weeks | 1. OAS | NR | 1. All rxs assoc. w ↓OAS scores | IV |
2. ACES | 2. VPA assoc. w ↓ACES | ||||||||||
3. Episodes of iso without seclusion | 3. Top assoc. w ↓ strict surveillance | ||||||||||
4. Episodes of therapeutic iso | 4. Neither rx impacted episodes of isolation | ||||||||||
5. Episodes of strict surveillance | |||||||||||
Grinshpoon, et al., 1998152 | Eur Psych | Open props | Inpatient | 10 “long term psychotic aggressive” | NR | Before and after Zuc decanoate 200–300 mg/4 w | 9 months | BPRS H/S | NR | Zuc d. assoc. w sig. ↓ H/S | IV |
Hakola and Laulumaa, 1982153 | Lancet | retro | Inpatient | 8 women w “violent episodic outbursts” | N/A | Before and after adjunctive CBZ 400–800 mg/day | 2 months – 11 years | violence | NR | ↓violence (no statistical measure reported) | IV |
Maier, 1992154 | B Am Acad PL | Pro observ | Inpatient | 25 (all agg. criminals) | 76% | Before and after Cloz 300–600 mg/day | 6–15 months | Release by court Transfer to less secure unit/hosp | Clon; PROP e | 52% either D/C’d or transfer to less secure hosp. | IV |
Morand, et al., 1983155 | Bio Psych | RCT/crossover | Inpatient | 12 “aggressive schizophrenics” | 100% | Adjunct tryptophan 4 g/day versus 8 g/day | 11 weeks f | 1. BPRS H/S | Antipsychotics | 1.Tryptophan 4 mg/d assoc. w 10% ↓ H/S | IV |
2. Ward checklist | 2. Either does assoc. w sig. ↓ ward incidents | ||||||||||
Okuma et al., 198936 | Acta Psych Scand | RCT | Inpatient+Out-patient | 162/subset of 94:”prominent violent or agg. Bhv.” | 91% | Antipsychotic+CBZ 200 –1200 mg/day versus antipsychotic+placebo | 4 weeks | BPRS HI | Sleeping pills; AntiP | 1. No sig. diff. on H in entire group of 162 | IV g |
2. Impact on agg. in agg. subset NR | |||||||||||
Rabinowitz, et al., 1996156 | Schiz Res | Retro | Inpatient | 47 pts with some one or more incid of agg over 6 mo | N/A | Before and after Cloz 100–600 mg/day | 9 months | 1. Agg incidents | NR | 1. Sig. ↓in agg. incidents [only in first 3 m) | IV |
2. S&R data | 2. ↓Restraint | ||||||||||
3. BPRS HI | 3. ↓BPRS HI | ||||||||||
Ratey et al., 1993157 | JCP | Retro | Inpatient | 5 “severely aggressive” | N/A | Before and after Cloz (dose NR) | ≤ 1 years | 1. Nurses’ prog. notes | Fluph; IMI; Lor; Clon; VPA; NAD; Benztr | 1. Trend: 31.8% ↓ in assaults | IV |
2. S&R data | 2. Trend:↓ S&R | ||||||||||
Ritrovato, et al., 1989158 | Clin Pharm | Prosp observ/crossoverh | In-patient | 7 “with aggressive behavior” | 28.6% | Thioth or Meso w and w/o adjucntive NADc | 76 days | OAS | Lor; Lithium; Benztr | No persistent diff. | IV |
Sorgi et al., 1986159 | AJP | retro | In-patient | 7 with “chronic assaultiveness” | N/A | Before and after adjunctive NAD 40–160mg/day or PROP 160mg/day | 4–20 weeks | 1. Level of restriction | NR | 1. ↓level of restriction | IV |
2. # agg. behaviors | 2. 4/7 exhibited “>70% ↓” in assaults i |
4. Does evidence exist that any medication will reduce overt aggression or hostility in persons with schizophrenia spectrum disorders preselected for clinically problematic aggression?36,40,57,86,93,143–159 ( Table 5)
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