Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia—A Systematic Review
Abstract
:1. Introduction
2. Materials and Method
2.1. Protocol and Registration
2.2. Search Process
2.3. Data Extraction
2.4. Study Inclusion and Exclusion Criteria
2.5. Risk of Bias Assessment
- 1.
- Control-comparison: Was there a control group or comparator to which adjunctive therapy was compared?
- 2.
- Ordering/assignment control: Was it assured that the interventions or intervention groups being compared were randomized or counterbalanced?
- 3.
- Pre/post-comparison: Was there a pre-measurement to which the post-measurement was compared?
- 4.
- Follow-up: Was there a follow-up measurement after weeks?
- 5.
- Registration: Was the study enrolled in an official study register?
- 6.
- Experimenter-blinding: Were the study conductors blinded with respect to the interventions or intervention groups being compared?
- 7.
- Analyst-blinding: Were the study evaluators blinded with respect to the interventions or intervention groups being compared?
- 8.
- Participant-blinding: Were the participants naive to whether they received an actual intervention or a control intervention?
3. Results
4. Discussion
4.1. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
4.2. Other Anti-Inflammatory Drugs
4.3. Antioxidants: N-acetylcysteine (NAC)
4.4. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonists
4.5. Estrogens
4.6. N-methyl-D-aspartate Receptor (NMDA) Antagonists
4.7. Serotonergic Drugs
4.8. Antihypertensive Drugs
4.9. Incretin Drugs
5. Clinical Significance—Future Directions
6. Limitations
7. Summary
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Study | N (Type of the Study) | Intervention/Number of RCT | Results |
---|---|---|---|
Non-steroid anti-inflammatory drugs | |||
Laan [22] | 70 (RCT) | Aspirin added to antipsychotic drugs for 3 months (1RCT) | Reduction of the severity of positive and negative symptoms and total PANSS scale 1.57 point; (95% CI 0.06 ÷ 3.07), p = 0.018. No influence on the efficiency of cognitive functions. |
Other anti-inflammatory drugs | |||
Sommer [23] | 61(RCT) | Simvastatin was added to antipsychotic drugs for 24 months in patients with schizophrenia spectrum disease diagnosed less than 3 years (1RCT) | No significant differences in the severity of psychopathological symptoms after 12 months, however, a significant reduction in the severity after 6 and 24 months (p = 0.02 and p = 0.04, respectively); no effect on the cognitive functions, performing daily activities of living, and the severity of depression symptoms. |
Shen [24] * | 339 (M) | RCTs with the use of different statins (6 RCTs) | Significant reduction of positive symptoms of the PANSS scale in the group receiving statins compared to the placebo: SMD = 0.31 (95% CI: 0.01 ÷ 0.62; p = 0.05, n = 168); reduction of negative symptoms of the PANSS scale: SMD = 0.31 (95% CI: 0.1 ÷ 0.53; p = 0.004, n = 339). In patients receiving simvastatin, the reduction of the total PANSS score: SMD = 0.42 (95% CI: −0.01 ÷ 0.84; p = 0.05, n = 89) and the severity of negative symptoms of the PANSS scale: SMD = 0.40 (95 % CI: 0.14 ÷ 0.67; p = 0.03, n = 220). |
Vincenzi [25] | 24 | Pravastatin added to antipsychotic drugs for 6 to 12 weeks | Significant reduction in positive symptoms of the PANSS scale at 6 weeks from baseline (p = 0.01), but it failed to remain after 12 weeks from baseline (p = 0.12). |
Ghanizadeh [26] | 36 | Lovastatin added to risperidone or placebo for 8 weeks | Reduction of the PANSS total score after 8 weeks of treatment in patients receiving risperidone and lovastatin, but without statistical significance. |
Tajik-Esmaeeli [27] | 33 | Simvastatin added to risperidone or placebo for 8 weeks | In patients receiving simvastatin, a significant reduction in negative symptom scores from baseline to week 8 (p = 0.003) and in total scores (p = 0.001). Results were not significant for positive symptoms or general psychopathology scores. |
Chaudhry [28] | 108 | Simvastatin added to antipsychotic medication for 12 weeks | Reduction in total symptoms of schizophrenia, especially in positive and general symptoms, rather than negative symptoms. |
Sayyah [29] | 40 | Atorvastatin added to risperidone or placebo for 6 weeks | No significant changes in schizophrenia symptoms. |
Deakin [30] | 98 | Simvastatin added to antipsychotic medication for up to 6 months | Combination of simvastatin with risperidone caused a significant reduction of the negative syndrome of schizophrenia while such an effect was not observed when simvastatin was added to other antipsychotic drugs. |
Antioxidants | |||
Berk [31] | 40 (RCT) | N-Acetylcysteine added to SGA for 24 weeks (1RCT) | Significant reductions of the score on the PANSS positive subscale [md −5.97 (95% CI: −10.44; −1.51), p = 0.009], PANSS negative subscale [md −1.83 (95% CI: −3.33; −0.32), p = 0.018] and PANSS general subscale [md −2.79 (95% CI: −5.38; −0.20), p = 0.035]. Improvement in akathisia intensity observed (p = 0.022). |
Farokhnia [32] | 42 (RCT) | N-Acetylcysteine added to risperidone for 8 weeks (1 RCT) | Improvement on the PANSS general subscale (p = 0.006) and on the PANSS general subscale (p < 0.001) in the intervention group. No side effects of NACC addition. |
Sepehrmanesh [33] | 42 (RCT) | N-Acetylcysteine added to first-generation antipsychotic for 12 weeks (1RCT) | Reduction in the positive (F = 5.47, p = 0.02) and negative (F = 0.20, df = 1) PANSS subscale scores. No significant difference in the frequency of adverse effects. |
PPARγ agonists | |||
Iranpour [34] | 40 (RCT) | Pioglitazone added to risperidone treatment for 8 weeks (1RCT) | Improvement in the severity of positive and negative symptoms (p < 0.001). |
Neuroprotective drugs | |||
Çakici [35] * | 368 (M) | Estrogens added to antipsychotic drugs for 28 days up to 8 weeks: 4 RCTs in women and 2RCTs in men | Significant reduction of positive and negative symptoms of schizophrenia on the PANSS scale (p < 0.0005) compared to the control group of both sexes; general improvement in functioning as measured by the Comprehensive Psychopathological Rating Scale (p < 0.0005); effect size value = 0.57. |
Kulkarni [36] | 36 | Estrogens added to antipsychotic treatment for 28 days | Significant improvement on the PANSS positive, negative, and general subscale (p < 0.001) was caused by estradiol (100 mdg-patch) in patients receiving antipsychotic medication versus the placebo group. Additionally, estrogen significantly enhanced treatment of acute, severe psychotic symptoms. |
Kulkarni [37] | 56 | Estradiol transdermal added to antipsychotic drugs for 28 days | Transdermal estradiol significantly reduced positive (p < 0.005) and general psychopathological symptoms of schizophrenia (p < 0.005) compared with women receiving only antipsychotic treatment. |
Kulkarni [38] | 53 | Estradiol 2 mg, orally added to antipsychotic drugs for 14 days | Significant improvement on the PANSS positive, negative, total, and general scales (p < 0.0047) in men receiving additionally, orally 2 mg of estradiol in comparison to the placebo group. |
Akhondzadeh [39] | 32 | Estradiol added to haloperidol for 8 weeks | Estradiol added to haloperidol decreased significantly the score of the PANSS positive, negative, and general psychopathological symptoms of schizophrenia (p < 0.001) versus the placebo group. |
Louzã [40] | 44 | Conjugated estradiol added to haloperidol for 28 days | Both the conjugated estrogen group and the placebo group showed a similar improvement on the BPRS total score scale (p < 0.001). |
Ghafari [41] | 32 | Conjugated estradiol added to antipsychotic treatment for 4 weeks | Significant decrease in positive (p = 0.003), negative (p < 0.001), general (p < 0.001), and total (p < 0.001) PANSS scores over 4 weeks in patients receiving a combination of medication versus the control group. |
Çakici [35] * | 205 (M) | Raloxifene added to antipsychotic drugs for 8 to 24 weeks (5 RTCs) | Improvement in the functioning of patients as measured by the Comprehensive Psychopathological Rating Scale: p < 0.002; Reduction of the severity of positive and negative symptoms on the PANSS scale (p = 0.027) positively correlated with the time of drug use; effect size value = 0.52. |
Kianimehr [42] | 23 | Raloxifene added to risperidone treatment for 8 weeks | Improvement of positive symptoms on the PANSS scale (p < 0.001) and not a significant change of negative and general psychopathology symptoms in women treated with medication versus the placebo. |
Khodaie-Ardakani [43] | 23 | Raloxifene added to risperidone treatment for 8 weeks | The raloxifene group showed significantly greater improvement on the negative subscale (p < 0.001), the general psychopathology subscale (p = 0.002), and total PANSS score (p < 0.001) in comparison to the placebo group. |
Kulkarni [44] | 26 | Raloxifene added to antipsychotic treatment for 12 weeks | Significant reduction in the PANSS general symptom scores for the raloxifene compared with the placebo (β = −3.72; 95%CI, −6.83 to −0.61; p = 0.02) groups. Results were not significant for positive and negative symptoms. |
Usall [45] | 33 | Raloxifene added to antipsychotic treatment for 24 weeks | Significant reduction of negative (p = 0.027), general symptoms (p = 0.003), and total symptomatology (p = 0.005) measured with the PANSS in women receiving treatment versus the placebo. |
Weiser [46] | 100 | Raloxifene added to antipsychotic treatment for 16 weeks | No reduction of the severity of positive and negative symptoms and total PANSS scale in severely ill decompensated women treated with a combination of drugs. |
NMDA antagonists | |||
Kishi [47] * | 448 (M) | Memantine added to antipsychotic drugs for 6–26 weeks (8 RCTs) | Statistically significant reduction of the severity of negative symptoms on the PANSS scale (p = 0.002), especially in younger adult patients, and improvement in the performance of the MMSE test (p < 0.0001); insignificant reduction of the severity of positive (p = 0.07) and general symptoms on the PANSS scale (p = 0.06) and the severity of depression symptoms (p = 0.326). |
Lucena [48] | 10 | Memantine added to clozapine for 12 weeks | Significant improvement (p < 0.01) in the total BPRS score, its subscales of positive (effect size [ES] = −1.38) and negative (ES = −3.33) symptoms, the CGI score (ES = 1.56), and the MMSE score was observed with memantine as compared with the placebo. |
Lieberman [49] | 70 | Memantine added to atypical antipsychotic drugs for 8 weeks | No significant differences in the severity of schizophrenia symptoms after 8 weeks in patients treated with a combination of drugs versus the placebo. Higher incidence of adverse effects than the placebo. |
Lee [50] | 26 | Memantine added to typical antipsychotic drugs for 12 weeks | Insignificant reduction of the severity of negative symptoms (p < 0.12); no improvement of cognitive functions and depressive symptoms. |
Rezaei [51] | 40 | Memantine added to risperidone for 8 weeks | A significantly greater improvement on the negative PANSS subscale, the total score (p < 0.001), and the general psychopathology subscale score (p = 0.002) than the placebo group; no significant difference in the reduction of positive symptoms score between the two groups (p = 0.757). |
Omranifard [52] | 32 | Memantine added to risperidone for 12 weeks | Improvement in the functioning of the intervention group patients was measured using the GAF and QLS scales (p < 0.001) versus the placebo. |
Fakhri [53] | 30 | Memantine added to olanzapine for 6 weeks | Significantly improved the positive and negative PANSS score in patients treated with a combination of drugs (p < 0.001) versus olanzapine alone; female patients showed significantly better response than males, especially in positive PANSS score. No significant changes in extrapyramidal symptoms. |
Veerman [54] | 26 | Memantine added to clozapine for 26 weeks | Improvement on the PANSS negative subscale score (effect size = 0.29); improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB (effect size = 0.30) in patients with adjunctive therapy versus the placebo. |
Mazinani [55] | 23 | Memantine added to risperidone for 12 weeks | Significant improvement of negative symptoms on the PANSS scale (p < 0.001) and cognitive functions; no significant differences between positive and psychopathologic symptoms in the intervention group of patients. |
Serotonergic drugs | |||
Zheng [56] * | 184 (M) | Ondansetron added to antipsychotic drugs for 12 weeks (5 RCTs) | Reduction of the severity of negative and general symptoms of schizophrenia (no effect on the severity of positive symptoms): standardized mean difference of the total PANSS score: −0.51. |
Akhondzadeh [57] | 30 | Ondansetron added to risperidone for 12 weeks | The ondansetron group had significantly greater improvement in the negative symptoms, general psychopathological symptoms, and PANSS total scores (p < 0.001). |
Chaudhry [28] | 36 | Ondansetron added to antipsychotic treatment for 12 weeks | Reduction of schizophrenia symptoms on PANSS total score versus antipsychotic treatment only, but without statistical significance. |
Kulkarni [58] | 42 | Ondansetron added to atypical antipsychotic drugs for 12 weeks | Ondansetron caused significant improvement both in the cognitive domain (p < 0.05) as measured by the Positive and Negative Syndrome Scale and on Total Positive and Negative Syndrome Scale (p = 0.06). |
Samadi [59] | 18 | Ondansetron added to risperidone for 12 weeks | Significantly larger improvement in the PANSS overall scale and subscales for negative symptoms and cognition (p < 0.001) in patients treated with adjunctive therapy, but without influence on depressive symptoms. |
Zhang [60] | 58 | Ondansetron added to haloperidol for 12 weeks | Significantly greater improvement on PANSS overall scale and subscales for negative symptoms, general psychopathology, and cognition (p < 0.05) in patients treated with adjunctive therapy. |
Other drugs | |||
Fan [61] | 43 (RCT) | Telmisartan added to clozapine or olanzapine at a dose for 12 weeks (1RCT) | Significant decrease in the PANSS total score compared to the placebo group (p = 0.038). No differences between groups in the score on the positive PANSS subscale: p = 0.105 (d = 0.39) and on the negative PANSS subscale: p = 0.422 (d = 0.18). |
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Dróżdż, W.; Wiciński, M.; Szota, A.M.; Szambelan, M.; Radajewska, I.; Popławski, I.; Wojciechowski, P. Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia—A Systematic Review. J. Clin. Med. 2023, 12, 4012. https://doi.org/10.3390/jcm12124012
Dróżdż W, Wiciński M, Szota AM, Szambelan M, Radajewska I, Popławski I, Wojciechowski P. Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia—A Systematic Review. Journal of Clinical Medicine. 2023; 12(12):4012. https://doi.org/10.3390/jcm12124012
Chicago/Turabian StyleDróżdż, Wiktor, Michał Wiciński, Anna Maria Szota, Monika Szambelan, Izabela Radajewska, Igor Popławski, and Paweł Wojciechowski. 2023. "Augmentation Therapies as Treatments for Coexisting Somatic Problems in Schizophrenia—A Systematic Review" Journal of Clinical Medicine 12, no. 12: 4012. https://doi.org/10.3390/jcm12124012