For patients meeting full criteria for schizoaffective disorder, clinicians often chose long-term treatment with both an antipsychotic and either an antidepressant or a mood stabilizer. Medication choice and dosing can be guided to some extent by the predominant symptom clusters.1 However, rigorous studies of treatment efficacy in schizoaffective disorder have been limited by the low diagnostic reliability of schizoaffective disorder, historical inappropriate use of the diagnosis, and blending of patients to a broader category of “schizophrenia spectrum” for research studies;2 thus, no current consensus treatment guidelines exist. Given these limitations, the treatment discussion in the following text is organized by pharmacologic category, using data from available clinical trials in the mood disorder and psychosis literature as well as the authors' clinical practice.
The term “schizoaffective disorder” should be applied rigorously and not simply used as a label for a patient with both mood and psychotic symptoms. For patients meeting full diagnostic criteria for schizoaffective disorder, long-term treatment with both an antipsychotic and either an antidepressant or mood stabilizer will generally be necessary. For patients with schizophrenia, identifying comorbid syndromes or prominent symptom clusters (eg, depression, agitation) despite treatment with antipsychotics will guide further add-on pharmacotherapy. In such cases, documentation should clearly indicate treatment for schizophrenia and the indicated symptom cluster or comorbidity. In the clinic, the treatment of patients with an admixture of psychosis and mood symptoms will often result in the same treatment, regardless of conceptualization.
Antipsychotic treatment remains the mainstay of pharmacotherapy for illnesses on the schizophrenia spectrum, including schizoaffective disorder, both depressive and bipolar subtypes. Paliperidone and the long-acting injectable paliperidone palmitate are the only two agents approved by the US Food and Drug Administration (FDA) for schizoaffective disorder. However, given the aforementioned difficulty in rigorous study of schizoaffective disorder as a distinct entity, trials comparing antipsychotic medications for this condition are extremely limited, and there is no reason to suspect that paliperidone is uniquely efficacious for schizoaffective disorder.
Given the inherent mood component of the presentation of people with schizoaffective disorder, the literature on antipsychotic treatment in bipolar disorder and major depressive disorder with psychotic features might provide a roadmap to antipsychotics that may have a greater efficacy for this clinical picture.
Current antipsychotic treatment recommendations for bipolar disorder (based on available evidence from placebo-controlled trials) highlight various antipsychotics depending on stage of bipolar illness.3,4 For acute mania, aripiprazole, asenapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone have demonstrated some effect. For acute bipolar depression, olanzapine, lurasidone, and quetiapine have been shown to be the antipsychotics with greatest efficacy, in addition to the combination of olanzapine and the antidepressant fluoxetine.5 Literature on psychotic depression has demonstrated some evidence of improved outcomes with combinations of olanzapine plus fluoxetine, olanzapine plus sertraline, and quetiapine plus venlafaxine.6–8 As further discussed below, use of an antidepressant (in combination with an antipsychotic) should typically be limited to patients with the depressive subtype of schizoaffective disorder or patients with schizophrenia with significant depressive symptoms.
For maintenance treatment and prevention of future mood episodes in bipolar disorder, aripiprazole, olanzapine, long-acting risperidone, and quetiapine have been the most studied.3–5 Although antipsychotics are often discontinued during periods of greater clinical stability during treatment of bipolar disorder, this is less often the case in treatment of schizoaffective disorder.
Clozapine has been used empirically in treatment of bipolar disorder and schizoaffective disorder,9 and it is currently the most effective antipsychotic on the market. The International Suicide Prevention Trial (InterSePT) demonstrated a significant reduction in suicidal behavior for patients diagnosed with schizophrenia and schizoaffective disorder,10 and clozapine has also demonstrated anti-aggressive properties.11 Clozapine should also be considered for patients with first-episode psychosis who have failed to respond to treatment in the first several months.12
In conclusion, given the lack of rigorous trials examining explicit treatment of schizoaffective disorder, clinicians may do well to optimize first-line antipsychotic treatment for schizoaffective disorder guided by the presenting clinical picture (depressive or bipolar subtype, cross-sectional examination for burden of mood symptoms) and using data from trials of antipsychotics in the mood disorder literature that may also demonstrate greater efficacy in treating symptoms trans-diagnostically. Patients with suicidality and aggression may benefit from clozapine.
Metabolic side effects place people with schizophrenia spectrum disorder at high risk of cardiovascular and cardiometabolic complications. Prior to starting antipsychotic treatment, baseline weight, waist circumference, blood pressure, fasting glucose, fasting lipids, and hemoglobin A1C should be obtained, and this measuring should be repeated at least annually.13 Weight should be obtained and tracked at every appointment, particularly at the beginning of treatment.
For patients with schizoaffective disorder, depressive type, a trial of combination antipsychotic and antidepressant therapy is a reasonable therapeutic starting point. As numerous international organizations recommend a combination of an antipsychotic and antidepressant as first-line treatment for depression with psychosis, it is rational to use this approach in treatment of schizoaffective disorder, depressive type.14 As mentioned above, three antipsychotic-antidepressant combinations have been studied and shown to have efficacy in treatment of psychotic depression: olanzapine plus fluoxetine, olanzapine plus sertraline, and quetiapine plus venlafaxine.6–8 Although these combinations are far from exhaustive, they may provide a good starting point for patients with schizoaffective disorder, depressive type.
Adding an antidepressant to antipsychotic drug therapy has been studied in patients with schizophrenia, demonstrating small-to-medium effect on total and negative symptom reduction15,16 and a reduction in risk of psychiatric hospitalization.17 Zisook et al.18,19 have studied citalopram in patients with schizophrenia and schizoaffective disorder with subthreshold depressive symptoms, finding a lessening of depressive symptoms and a reduction in suicidal ideation. Citalopram, or other antidepressants, may be considered for patients with schizophrenia and comorbid major depression or dysthymia.
For patients with schizoaffective disorder, bipolar type, antidepressant therapy is generally not indicated. Trials have not demonstrated that antidepressant therapy adds significant long-term protection from recurrence of depressive episodes in maintenance treatment of bipolar disorder,20 nor is it demonstrably more effective than mood stabilizers. It may also worsen agitation, anger, and dysphoria when used for treatment of acute bipolar depression.3
Mood stabilizers may be an important component of treatment for people with schizoaffective disorder, bipolar type. Mood stabilizers may also be considered for people with schizophrenia and a clinical presentation with high agitation or aggression. For medications that allow for therapeutic blood level monitoring, levels should be obtained to ensure appropriate dosage; there should be no role for subtherapeutic medication dosing, as this practice exposes patients to medication side effects without confirmed therapeutic benefit.
Lithium is approved for treatment of acute mania and maintenance therapy in bipolar disorder, including prevention of recurrent episodes of depression and mania. Among patients with bipolar disorder and major depressive disorder, treatment with lithium has been demonstrated to substantially reduce the risk of completed suicide.21 Although impact on suicidality has not been studied specifically in schizoaffective disorder, it is reasonable to consider lithium as a first-line mood stabilizer in this population for patients with suicidal ideation, in addition to consideration of clozapine for antipsychotic therapy with anti-suicidal properties. Lithium has also been recommended as an augmenting agent for unipolar major depression and may be worth considering for patients with a depressive subtype of schizoaffective disorder or schizophrenia with comorbid major depressive disorder or dysthymia.
As is the case for using lithium for other conditions, precautions should be taken and monitoring regularly performed. Prior to treatment, weight, blood urea nitrogen/creatinine, thyroid-stimulating hormone (TSH), and a pregnancy test should be obtained, along with an electrocardiogram if the patient has a history of cardiac disease.22 Blood levels aiming for 0.6 to 0.8 mEq/L for maintenance treatment should be obtained every 6 months if new side effects emerge or if toxicity is expected. TSH, creatinine, and metabolic laboratory results should be checked at least yearly,23 and weight should be measured at each appointment.
Valproate has been demonstrated to be effective in treatment of acute mania in bipolar disorder, and some small trials have suggested evidence for valproate as being effective for treatment of acute bipolar depression.24 Although it is commonly used as maintenance treatment, this remains an off-label use lacking regulatory approval.3 For long-term prevention of episode recurrence in bipolar disorder, valproate has been shown to be less effective than lithium in multiple trials.3 Clinically, valproate is most often considered for patients with a violent or agitated component to their presentation; however, this use has yet to be corroborated by rigorous studies.25 The addition of valproate in acutely exacerbated patients with schizophrenia may reduce hostility during the first week26 but does not lead to better symptom control otherwise.27
If using valproate for the treatment of schizoaffective disorder, levels should be obtained 4 days after initiation and after each change in dose, with target therapeutic level of >55 ng/L.22 Liver function tests, complete blood count, and ammonia levels should be obtained at least every 6 months during treatment, weight obtained at each visit, and metabolic laboratory results obtained at least yearly. Of note, valproate interacts with numerous other drugs, so a full medication interaction check should be performed every time valproate is added to a regimen or a new drug is added to a regimen containing valproate. Valproate raises lamotrigine levels (increasing the risk for rash) and may increase levels of other protein-bound drugs including warfarin. Only under exceptional circumstances should valproate be prescribed for women of child-bearing age given the significant risk of neural tube defects in pregnancy.28,29
Lamotrigine may have a role in acute bipolar depression; however, it only carries FDA approval for maintenance treatment in bipolar disorder and prevention of recurrent depression. It has not been shown to be effective for treatment of acute mania or prevention of recurrence of mania.3 Lamotrigine requires a slow up-titration to minimize risk of Stevens-Johnson syndrome; thus, it may only be appropriate for patients with schizoaffective disorder who remain fairly stable on an antipsychotic and would benefit from prevention of depressive episodes in the future. Trials of treatment of unipolar depression with adjunct lamotrigine have not demonstrated a consistent significant effect.30
Within the bipolar literature, evidence for carbamazepine and other anticonvulsants is limited and inconsistent. For treatment of schizoaffective disorder, therefore, we recommend starting with lithium, valproic acid, or lamotrigine depending on clinical presentation.
Given the limited literature on treatment for schizoaffective disorder and the poor diagnostic concordance between studies, we have turned to literature on the schizophrenia spectrum and the bipolar spectrum disorders to consider treatment options that may be more efficacious in schizoaffective disorder. Clinicians should (1) determine that a schizophrenia spectrum disorder is present, (2) determine if a patient meets full criteria for schizoaffective disorder and identify the subtype, (3) initiate antipsychotic therapy, and (4) determine if a mood stabilizer or antidepressant is warranted given the clinical picture. See Figure 1 for a summary.
Treatment decision-making for patients presenting with psychosis, depending on the presence of schizoaffective disorder or schizophrenia.
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- Selle V, Schalkwijk S, Vázquez GH, Baldessarini RJ. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry.2014;47(2):43–52. doi:10.1055/s-0033-1363258 [CrossRef] PMID:24549862
- Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand.2010;121(3):190–200. doi:10.1111/j.1600-0447.2009.01464.x [CrossRef] PMID:19694628
- Meyers BS, Flint AJ, Rothschild AJ, et al.; STOP-PD Group. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch Gen Psychiatry.2009;66(8):838–847. doi:10.1001/archgenpsychiatry.2009.79 [CrossRef] PMID:19652123
- Rothschild AJ, Williamson DJ, Tohen MF, et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol. 2004;24(4):365–373. doi:10.1097/01.jcp.0000130557.08996.7a [CrossRef] PMID:15232326
- Hummel B, Dittmann S, Forsthoff A, Matzner N, Amann B, Grunze H. Clozapine as add-on medication in the maintenance treatment of bipolar and schizoaffective disorders. A case series. Neuropsychobiology. 2002;45(suppl 1):37–42. doi:10.1159/000049260 [CrossRef] PMID:11893876
- Meltzer HY, Alphs L, Green AI, et al. International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82–91. doi:10.1001/archpsyc.60.1.82PMID:12511175 [CrossRef]
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- Agid O, Remington G, Kapur S, Arenovich T, Zipursky RB. Early use of clozapine for poorly responding first-episode psychosis. J Clin Psychopharmacol. 2007;27(4):369–373. doi:10.1097/jcp.0b013e3180d0a6d4 [CrossRef] PMID:17632221
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