Skip to main content
. 2019 Nov 27;9(6):336–348. doi: 10.9740/mhc.2019.11.336

TABLE 2.

Pharmacological agents discussed

Reference
 Type of Studies Reviewed
 Augmenters
 Outcomes
 Comment
Antipsychotics
 Barbui et al22 (2009) 21 Randomized studies (n = 1480): 6 studies were double-blind, placebo-controlled trials Amis, CPZ, Pipo, Risp, Sulp
  • •

    14 Randomized open studies significantly favored aug: SMD = −0.80; 95% CI: −1.14, −0.46

  • •

    6 RCT found no statistically significant positive effect: SMD = −0.12; 95% CI: −0.57, 0.32

 Mix of co-initiation (cloz + aug started at same time) and augmentation (Aug added) studies together. Authors concluded the evidence supporting the addition of an antipsychotic was weak.
 Taylor et al23 (2012) 14 Studies (n = 734): combination of open-label and double-blind studies Amis, Arip, CPZ, Hal, Pim, Risp, Sert, Sulp Aug with an antipsychotic conferred a small benefit over plac: effect size −0.239 (95% CI: −0.452, −0.026); P = .028 Focused only on symptom reduction, not response rates. Did not analyze open-label vs double-blind separately. Authors concluded augmentation with a second antipsychotic is modestly beneficial.
 Galling et al24 (2017) 20 Clozapine trials (n = 1112) compared randomized trials augmentation with a second antipsychotic vs continued antipsychotic monotherapy Ari, Flu, Pal, Pim, Risp, Sert, Sul, Zip
  • •

    Total symptom reduction—Aug superior to mono only in open-label and low-quality trials (P < .001)

  • •

    Double-blind and high-quality trials found no significant difference (P = .120 and .226, respectively)

  • •

    Study-defined response found no difference in low- or high-quality studies

 Evidence regarding symptom improvement lacking for augmentation of either clozapine or nonclozapine antipsychotics. Negative symptoms improved more with augmentation only with aripiprazole (8 studies, N = 532; SMD = −0.41; 95% CI: 20.79, 20.03; P = .036).
 Bartoli et al25 (2019) 12 Double-blind RCTs of adjunctive SGAs (n = 762) Amis, Arip, Risp, Sert, Sulp, Zip No difference between SGAs and placebo:
  • •

    Positive symptoms:

    •  o

      SMD = −0.21; P = .170, I2 = 68.0%, measure of heterogeneity

  • •

    Low-moderate effects

  • •

    Negative symptoms:

    •  o

      SMD = −0.38; P = .005, I2 = 62.7%

  • •

    Depressive symptoms:

    •  o

      SMD = −0.35; P = .003, I2 = 4.9%

 No demonstrable efficacy for positive symptoms. Small improvement for negative and depressive symptoms.
 Tiihonen et al26 (2019) Cohort study (n = 62 250) patients with schizophrenia: 29 different antipsychotic mono and poly Arip, LAI, Olan, Quet, Risp
  • •

    Lowest risk of psychiatric rehospitalization (poly vs mono with cloz)

  • •

    Poly-cloz + arip (HR, 0.86; 95% CI: 0.79, 0.94)

 Analyzing only first episode patients Poly-cloz + arip (0.78; 95% CI: 0.63, 0.96)
Anticonvulsants
 Tiihonen et al29 (2009) RCTs, 5 trials 10- to 24-wk duration (n = 161) Lamot
  • •

    Total score for psychosis:

    •  o

      SMD = 0.57; 95% CI: 0.25, 0.89; P < .001

    •  o

      OR 0.19; 95% CI: 0.09, 0.43

    •  o

      P < .001; NNT 4; 95% CI: 3, 6

  • •

    Positive symptoms: SMD = 0.34; 95% CI: 0.02, 0.65; P = .04

  • •

    Negative symptoms: SMD = 0.43; 95% CI: 0.11, 0.75; P = .008

 Authors suggest that 20% to 30% of clozapine-resistant patients may obtain clinical benefit from lamotrigine augmentation.
 Zheng et al32 (2017) 22 RCTs (n = 1227) for adjunctive antiepileptic agents:  Topiramate: 5  Lamotrigine: 8  Sodium valproate: 6  Magnesium valproate: 3 Lamot, MgVal, NaVal, Top, Significant superiority in total psychopathology over clozapine monotherapy:
  • •

    Topiramate P < .0001

  • •

    Lamotrigine P = .05

  • •

    Sodium valproate P = .002

 English and Chinese databases reviewed. After removal of outliers Lamotrigine lost significance. Topiramate had high dropout rate, NNH = 7. Only 3 of the 22 RCTs established that the clozapine plasma concentration was >350 ng/mL.
Antidepressants and mixed agents
 Sommer et al33 (2012) Double-blind RCTs: 29 studies reporting on 15 different aug (n = 1066) Amis, Arip, Cit, CX516, D-cycl, D-ser, Fluox, Gly, Hal, Lamot, Mir, Risp, Sar, Sulp, Top, Val
  • •

    Lamot and top were dependent on single studies with deviating findings

  • •

    Cit, sulp, and CX516 based on single studies

 Analyzed only individual drug combinations. Not limited to participants with cloz resistance. Authors concluded that pharmacological augmentation of cloz not demonstrated to be better than plac.
 Porcelli et al34 (2012) 62 Studies (n = 1556): only 8 RCTs (5 risp and 3 lamot, used for meta-analysis) Amis, Arip, Risp, Sulp, Zip Fluox, Fluv, Mirt, Lamot, Top, Li, CX516, D-cycl, D-ser, E-EPA, Gly, Maz, Mem, Mod, N-MG, ECT Evidence for augmentation with:
  • •

    Amis and arip

  • •

    Mirt

  • •

    E-EPA

 Meta-analyses did not support either the use of risp or lamot as cloz adjunct.
 Correll et al35 (2017) 9 Meta-analyses of 42 combination strategies 381 individual trials (n = 19 833) • 5 strategies that augmented cloz Amis, Arip, Hal, Pim, Risp, Sulp, Cit, Dul, Fluox, Mirt, E-EPA, Gly, Lamot, Top,
  • •

    No combination strategies with cloz outperformed controls

  • •

    Glycine efficacy for positive symptoms

 Effect sizes were inversely correlated with study quality (correlation coefficient, −0.06; 95% CI: 0.01, −0.12; P = .02).
 Siskind et al36 (2018) 46 Studies (n = 2182; 16 in Chinese database) of 25 interventions RCTs: • Cloz + aug vs Cloz + plac • Cloz + aug-1 vs Cloz + aug-2 Arip, Flu, Val, Mem
  • •

    Total symptoms:

    •  o

      Arip (SMD = 0.48; 95% CI: −0.89, −0.07)

    •  o

      Flu (SMD = 0.73; 95% CI: −0.97, −0.50)

    •  o

      Val (SMD = 2.36 95% CI: −3.96, −0.75)

  • •

    Negative symptoms:

    •  o

      Mem (SMD = −0.56; 95% CI: −0.93, −0.20)

 Not limited to the English language. All the Chinese studies were deemed to be of low quality. When low-quality studies were excluded arip and flu lost statistical significance. ECT, highly promising.
ECT
 Lally et al37 (2016) 5 Trials (n = 71): • 4 open label • 1 RCT Case series and case reports (52 patients) ECT
  • •

    5 trials proportion of response

  • •

    Cloz + ECT = 54% (95% CI: 21.8%, 83.6%)

  • •

    4 open label studies = 56% (95% CI: 19.4%, 87.2%)

  • •

    1 RCT = 48.7% (95% CI: 33.6%, 64.0%)

  • •

    Case series and case reports clinical response rate = 76%

 Data from retrospective chart reviews, case series, and case reports were added to the 5 trials resulting in a total of 192 subjects with a response to Cloz + ECT of 66% (95% CI: 57.5%, 74.3%). Mean number of ECT treatments = 11.3. 32% of cases (20 out of 62 patients) relapsed following cessation of ECT.
 Ahmed et al38 (2017) 23 Studies (n = 1179): • 9 studies Cloz augmented ECT (95 patients) • 14 studies other APs – aug ECT (1084 patients) ECT
  • •

    Non-cloz studies: SMD = 0.891

  • •

    Cloz studies: SMD = 1.504

 Nonclozapine APs: flup, cpz, risp, sulp, olanz, and lox.
 Wang et al39 (2018) 18 RCTs (n = 1769), 17 studies published in China and 1 study in the United States • Mean sample size = 88.5 ± 41.7 (range = 39–246, median = 79) subjects • Duration = 9.2 ± 2.6 (range = 4–12, median = 8) wk ECT
  • •

    Post-ECT assessment:

    •  o

      SMD = −0.88; 95% CI: −1.33, −0.44; I2 = 86%, P = .0001

    •  o

      Response NNT = 3

    •  o

      Remission NNT = 13

  • •

    End point assessment:

    •  o

      SMD = −1.44; 95% CI: −2.05, −0.84; I2 = 95%, P < .00001

    •  o

      Response NNT = 4

    •  o

      Remission NNT = 14

    •  o

      Memory impairment NNH = 4

    •  o

      Headache NNH = 8

 Significant separation occurring at wk 1–2.

Amis = amisulpride; Arip = aripiprazole; Aug = augmenter; Cit = citalopram; CPZ = chlorpromazine; Cloz = clozapine; CI = confidence interval; CX516 = glutamatergic agonist; D-cycl = D-cycloserine; D-ser = D-serine; Dul = duloxetine; ECT = electroconvulsive therapy; E-EPA = ethyl eicosapentaenoic acid; Fluox = fluoxetine; Flu = fluphenazine; Flup = flupenthixol; Fluv = fluvoxamine; Gly = glycine; Hal = haloperidol; I2 = measure of heterogeneity; Lamot = lamotrigine; LAI = long-acting injection; Li = lithium; Lox = loxapine; MgVal = magnesium valproate; Maz = mazindol; Mem = memantine; Mirt = mirtazapine; Mod = modafinil; Mono = monotherapy; N-MG = N-methylglycine; NaVal = sodium valproate; NNT = number needed to treat; NNH = number needed to harm; Olan = olanzapine; Pal = paliperidone; Pim = pimozide; Pipo = pipothiazine; Plac = placebo; Poly = polypharmacy; Quet = quetiapine; RCT = randomized controlled trial; Risp = risperidone; Sar = sarcosine; Sert = sertindole; SGAs = second-generation antipsychotics; SMD = standard mean difference; Sulp = sulpiride; Top = topiramate; Val = valproate; Zip = ziprasidone.