Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.27
More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).
Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),28 the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.
More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).
Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.29
Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.
Table 2
Agents studied as adjuncts to antipsychotics
| Acetylsalicylic acid and nonsteroidal anti-inflammatory agents |
| Anticonvulsants and lithium |
| Antidepressants |
| Antiglucocorticoids |
| Agents used to treat attention-deficit/hyperactivity disorder |
| Beta blockers |
| Cholinesterase inhibitors and other agents used to treat Alzheimer’s disease |
| Experimental agents that act on glutamate receptors |
| GABAA receptor drugs |
| Neurosteroids and hormones |
| Omega-3 fatty acids |
| Opioid system agents |
| Peptides |
| Purinergic agents |
| Serotonin 5-HT1A receptor agonists |
| Serotonin 5-HT3 receptor antagonists |
| Wakefulness promoting agents |
Therapeutic neuromodulation
More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),30 prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis31 of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.
Fewer controlled trials are available for electroconvulsive therapy,32,33 but its use with clozapine appears encouraging.34
Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.
Complementary and alternative therapies. Patients and their families may ask about complementary and alternative therapies, particularly when conventional approaches have not been successful. A meta-analysis of 6 studies (n=828)35 that reviewed adjunctive use of ginkgo in patients with chronic schizophrenia found statistically significant moderate improvement in total and negative symptoms. Negative reports also are available, including a 5-month study of adjunctive megavitamins that did not demonstrate any benefits.36 In a review of 13 RCTs of acupuncture for schizophrenia, Lee et al found the overall methodological quality was too low to draw firm conclusions.37
Table 3
Cognitive-behavioral therapy for schizophrenia
| Study | Design | Patients | Results |
|---|---|---|---|
| Pinto et al, 1999a | 6-month, randomized controlled | 37 treatment-resistant schizophrenia patients were randomized to CBT plus social skills training or supportive therapy | Both groups showed statistically significant improvement on the BPRS, SAPS, and SANS; however, patients in the CBT group had lower BPRS and SAPS scores. No difference on SANS scores |
| Barretto et al, 2009b | 21-week, controlled (nonrandom-ized) | Patients refractory to clozapine were placed in a CBT or befriending control group | The CBT group showed significant improvement in PANSS total score and general psychopathology subscale score, as well as an improvement of QLS; improvement persisted at 6-month follow-up |
| BPRS: Brief Psychiatric Rating Scale; CBT: cognitive-behavioral therapy; PANSS: Positive and Negative Syndrome Scale; QLS: Quality of Life Scale; SANS: Scale for the Assessment of Negative Symptoms; SAPS: Scale for the Assessment of Positive Symptoms | |||
| Source: References a. Pinto A, La Pia S, Mennella R, et al. Cognitive-behavioral therapy and clozapine for clients with treatment-refractory schizophrenia. Psychiatr Serv. 1999;50(7):901-904. b. Barretto EM, Kayo M, Avrichir BS, et al. A preliminary controlled trial of cognitive behavioral therapy in clozapine-resistant schizophrenia. J Nerv Ment Dis. 2009;197(11):865-868. | |||
Clinical recommendations
Before declaring a patient with schizophrenia as treatment-resistant, ensure that an adequate trial of medication did take place. This includes consideration of adequate dosing and pharmacokinetic issues. Awareness of potential substance use and/or partial adherence or nonadherence also is critical because these factors can impact treatment response.
When prescribing for a treatment-resistant schizophrenia patient, identify specific target symptoms to better inform medication selection—especially for symptoms that the patient feels are important. For example, consider an antidepressant for patients who have negative or depressive symptoms. Also take into account other patient-centered concerns, such as tolerability issues that may have interfered with adherence and response in the past.