The issue of combination of antipsychotic drugs has not gained accepted insight, and almost all clinical treatment guidelines recommend single drug therapy, but in order to improve the efficacy of treatment of schizophrenia and to improve residual positive symptoms, negative symptoms, cognitive impairment, depressive symptoms, hostile-aggressive symptoms or other symptoms such as obsessions and anxiety in schizophrenia, the combination of drugs is accepted by many patients in clinical practice.
The results of a survey of 5,898 schizophrenia inpatients and outpatients in 41 psychiatric hospitals or psychiatric departments of general hospitals in 10 provinces and cities in China showed that the proportion of combined use of more than 2 antipsychotics was as high as 26.1%. Although combination therapy is not recommended as a conventional first-line treatment, the results of some clinical studies have shown that drug combination therapy can benefit many patients, and multiple antipsychotic combinations or combinations of antipsychotics and other drugs have received attention.
I. Combination therapy with 2 antipsychotics
Shiloh et al. combined treatment with 600 mg/d sulpiride in schizophrenic patients with partially effective treatment with clozapine alone and a Brief Psychiatric Rating Scale (BPRS) score >42. Treatment showed a 15% greater decrease in total BPRS score, a 10% decrease in negative symptom score, and a 12% decrease in positive symptom score in patients treated with the combination of sulpiride than in the placebo group by the end of the 10th week. Kreinin et al. selected 20 patients who were non-resistant to clozapine with slight improvement in psychiatric symptoms and randomized them to the combination of sulpiride 400 mg/d or placebo. The results showed a significant improvement in negative symptoms in the combination group.
Josiassen et al. randomized patients with disease duration >20 years who were not treated with at least 2 antipsychotics and also not or partially effective with clozapine into clozapine combined with risperidone versus clozapine combined with placebo groups, and showed that the total BPRS score and positive symptom factor score were reduced more significantly in the combined risperidone group. The authors concluded that clozapine has broad receptor activity but weak D2 receptor antagonism, whereas risperidone has strong D2 receptor antagonism and may enhance the therapeutic effect of clozapine.
Lerner et al. used a combination of olanzapine and risperidone in patients with schizophrenia and schizoaffective psychosis who had received two to four 1st-generation antipsychotics or had poor results with clozapine, and showed improvement in positive symptoms in almost all patients without significant adverse effects. The results of this preliminary study support the combination of olanzapine and risperidone.
In recent years, the combination of aripiprazole has been reported to treat antipsychotic-induced hyperprolactinemia. shim et al. showed that 88.5% of patients on the combination could have their prolactin levels reduced to the normal range.
Combination therapy of antipsychotics and other drugs
1. Anticonvulsants: Casey et al. randomly assigned 242 acute phase severe patients treated with risperidone or olanzapine to combination placebo or bivalirudin therapy. The results showed faster improvement in the first 2 weeks in the bivalirudin group than in the placebo group. The rate of improvement in the 2 groups was equal at the end of week 4. Therefore, it is proposed that the early improvement may be related to the shortened discharge time with bivalvulinic acid.
2. antidepressants: Kirli and Caliskan found that sertraline was effective in the treatment of post-psychotic depression. matthews et al. reported that fluoxetine and olanzapine combined in the treatment of psychotic depression had an efficiency of 66. 7% for depressive symptoms and 59.3% for psychotic symptoms.
Many studies have shown that antidepressants are effective in treating negative symptoms of schizophrenia. Fluvoxamine is effective in the treatment of schizophrenia with obsessive-compulsive symptoms. Citalopram combined with first-generation antipsychotics is more effective than placebo in patients with aggressive schizophrenia.
3, benzodiazepine: Wolkowitz and Pickarr review: studies evaluating the combination of benzodiazepine and antipsychotic drugs showed that 7 of 16 studies were effective for symptom factors such as anxiety, agitation, psychosis or overall impairment. 5 of 13 studies for psychotic symptoms showed effectiveness. The authors concluded that benzodiazepines may enhance the efficacy of antipsychotics. Benzodiazepines have also been reported to be effective in the treatment of antipsychotic-induced acute dystonia.
4. β-blockers: β-blockers are usually used to treat drug-induced inability to sit still. A two-variable crossover study of 30 male schizophrenic patients in a custodial unit showed that indololol 5 mg three times daily treatment resulted in a significant reduction in patient aggression scores.
5, cognitive enhancers: impaired cognitive function is one of the features of schizophrenia, and studies have found that the combination of cholinesterase inhibitors and antipsychotics used for the treatment of Alzheimer’s disease is effective, and that high doses of donepezil improve cognitive function better than placebo.
6, glutamatergic drugs: glycine in combination with antipsychotics is more effective on negative symptoms, and the negative symptom reduction rate is 15%~40%. The effect on positive symptoms is not significant.
7, lithium: lithium alone has limited effect in the treatment of schizophrenia, while the combination of lithium and antipsychotics can enhance the efficacy of antipsychotics, especially in improving negative symptoms lithium has a synergistic effect.
The current clinical evidence for antipsychotic combination therapy is insufficient, but this does not mean that combination therapy will not lead to optimal treatment outcomes for patients with schizophrenia. Combination therapy should be selected for patients who are not responding well to monotherapy or who have difficulty with treatment. Clinicians should have knowledge of combination therapy drug side effects and drug interactions, understand the possible adverse effects of combination therapy in terms of treatment costs and treatment compliance, and choose combination drug therapy when the patient’s condition warrants it.
(Mei Qiyi. Drug combination therapy for schizophrenia[J]. Chinese Journal of Psychiatry, 2014, 47(3): 175-176.)
Single medication is the mainstream of schizophrenia medication treatment
For various reasons, the current clinical pharmacological treatment of schizophrenia in China often favors the use of multiple drug combinations, which is not in line with the principle of single-drug therapy recommended in schizophrenia treatment guidelines around the world.
The 2004 American Psychiatric Association (APA) guidelines for the treatment of schizophrenia (2nd edition) clearly suggest that single medication is recommended for both acute and stable treatment, and that combination medication is recommended for specific clinical conditions, such as benzodiazepines for catatonia, anxiety, and agitation, and antidepressants for combined depression and obsessive-compulsive symptoms. When depression and obsessive-compulsive symptoms are combined, recurrent, severe hostility and aggression can be combined with mood stabilizers, but these combinations all require monitoring for adverse effects and drug interactions.
The 2009 supplemental guidelines of the American Psychiatric Association suggest that in some recent studies (e.g., clinical trial studies of the effects of antipsychotic interventions), first-generation antipsychotics have produced clinical efficacy that is no less than second-generation drugs, even suggesting that the division of antipsychotics into first- and second-generation drugs is less meaningful from the perspective of efficacy.
The Canadian 2005 guidelines suggest that the principle of treating schizophrenia should be individualized, that simple medical advice can help improve patient compliance, and clearly suggest that there is no evidence to support that combining 2 or more antipsychotics improves efficacy.
In the 2012 guideline, the World Federation of Biological Psychiatry systematically reviewed the literature evidence from medline/pubmed and the cochrane library in recent years and classified the clinical evidence into 6 levels, suggesting that in the acute treatment phase of schizophrenia, although the combined use of benzodiazepines may reduce insomnia and behavioral disturbances in patients. However, long-term benzodiazepine use may increase the morbidity and mortality of patients.
Similarly, in the guidelines for the long-term treatment of schizophrenia published in 2013, it was suggested that single medication should be used whenever possible. In the 2014 National Institute for the Advancement of Health and Care’s “Treatment and Management of Psychosis and Schizophrenia in Adults”, the principle of a single antipsychotic for the treatment of schizophrenia is still proposed.
Therefore, based on the safety and efficacy of antipsychotics in schizophrenia, single antipsychotic treatment is currently the preferred choice for patients with acute episodes, especially first-episode schizophrenia.
Although a few studies in recent years have been investigating the combined use of antipsychotics with different mechanisms of action for the treatment of different symptoms of schizophrenia, or relatively refractory schizophrenia, more studies still focus on discussing the efficacy and adverse effects of different drugs in the acute treatment and maintenance phases of schizophrenia. Studies on combination therapy are more often concerned with anxiety, depression, cognitive function, substance abuse, and sleep disorders in patients with schizophrenia; or the combination of antipsychotics with other treatments such as psychotherapy, electroconvulsive therapy, and repetitive transcranial magnetic stimulation; therefore, the combination of medications should be mastered for its indications, and attention should also be paid to the increase in adverse events that may result during the combination of antipsychotics.
Since there is little difference in the efficiency of first- and second-generation antipsychotics for the treatment of positive symptoms in schizophrenia, combining drugs for positive symptoms does not improve the efficacy; there are still no satisfactory drugs for the treatment of negative symptoms in schizophrenia, and studies are ongoing to determine whether the combination of glutamatergic drugs with antipsychotics is effective in improving negative symptoms in patients. In studies of relapse prevention, meta-analyses have shown that second-generation antipsychotics are superior to first-generation antipsychotics.