Paliperidone Palmitate for Schizoaffective Disorder: A Review of the Clinical Evidence

Schizoaffective disorder has been a controversial diagnosis. It has long been recognized that many patients with psychotic symptoms do not neatly fit into the Kraepelinian diagnostic dichotomy of what we now label schizophrenia and bipolar disorder, but rather present with varying presentations of mood and psychotic symptoms. In 1933, Kasinin proposed the term “schizoaffective psychosis” to designate individuals prominently displaying both psychotic and mood symptoms, claiming that those so diagnosed would have a better prognosis [1].

The “affective” portion of the term “schizoaffective” itself remains something of an anachronistic misnomer, as aside from the psychotic symptomatology, there is also a primary disturbance in mood (a pervasive and sustained emotional state), not affect per se. Affect is defined as observable behaviors that express a current emotional state, which may fluctuate; in the past, other mood disorders were also inaccurately labeled “affective” disorders.

Early versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) included this entity using slightly different terminology, such as “schizophrenic reaction, schizoaffective type” in DSM-I and “schizophrenia, schizoaffective type” (either excited or depressed) in DSM-II, but in 1980 in DSM-III it was named “schizoaffective disorder,” and was the only diagnosis in that edition that did not employ specific diagnostic criteria. In DSM-III-R (1987) criteria were introduced, which required a period of psychosis meeting criteria for schizophrenia during which mood symptoms were present for “more than a brief” period of time, and also a period of psychotic symptoms without mood symptoms of at least two weeks, to distinguish schizoaffective disorder from a mood disorder with psychotic symptoms. DSM-IV (1994) further recognized two subtypes of schizoaffective disorder: “depressive type” and “bipolar type,” and DSM-IV-TR (2000) required that the mood symptoms must be present for “a substantial portion” of the course of the disorder, without further quantification.

This vagueness in the diagnostic criteria has been further compounded by the common difficulty in obtaining an accurate longitudinal description of the course of patients’ symptoms. It is commonly not possible to adequately establish accurate periods of time for which prominent mood symptoms have been present over the course of a patient’s history with and without delusions and hallucinations, and verify that such symptoms were not caused by the use of, or withdrawal from, substances of abuse, let alone formally decide on the definition of “substantial period.” Not surprisingly, therefore, kappa values for diagnostic agreement have been notably poor: Hiller et al. [2] reported a kappa of 0.08 using DSM-III-R criteria for schizoaffective disorder, and Maj et al. [3] reported a kappa of 0.22 using DSM-IV criteria, far below the more desirable range indicating at least moderate interrater agreement (0.4–0.6).

Appreciably better kappa values have been reported using International Classification of Diseases (ICD)-10 criteria, although that criteria set is quite similar to that of DSM-IV-TR. However, a study in Denmark of patients with hospital discharge diagnoses of schizoaffective disorder found that none met DSM-IV-TR criteria and only 10% met ICD-10 criteria [4]. Seeking to improve reliability, DSM-5 (2013) usefully added the specification that the symptoms of a major mood episode were present for the majority of the total duration of the active and residual portions of the illness, which is somewhat more specific, although whether this will appreciably improve diagnostic reliability and validity must await future study [5]. Exploring issues regarding the validity of the diagnosis, a detailed review by Kantrowitz and Citrome [6] examined possible differentiating characteristics that would distinguish schizoaffective disorder from schizophrenia and bipolar disorder, including prognosis, genetic linkage studies, neuropsychological testing and pharmacological response, finding at best very modest evidence, although some results of neurophysiological sensory testing pointed towards some possible discriminating characteristics. Likewise, a longitudinal study of first-admission patients with a diagnosis of schizoaffective disorder did not generate support for the validity of the diagnosis of schizoaffective disorder based on symptom course and outcomes [7].

In fairness, however, it should be noted that schizophrenia and bipolar disorder themselves do not admit of neatly separating genetic findings, with not only numerous proposed genetic linkages, but with some that appear to be common for both schizophrenia and psychotic bipolar disorder [8]. Moreover, there have been thoughtful proposals to formulate schizophrenia, schizoaffective disorder and bipolar disorder as representing more of a continuous spectrum, or viewed in a dimensional approach [9]. Clearly, this is still an enduring area of controversy; it remains a significant nosologic challenge for the field’s attempts to skillfully “carve Nature at its joints”.

Given these concerns, one must explain why we have the diagnostic category of schizoaffective disorder. Of most relevance is the fact that this diagnosis is very commonly used, with an estimated lifetime prevalence of 0.3% [10], that is, a third or more as common as the diagnosis of schizophrenia, and translating to about 750,000 adult Americans. It likely serves as a useful clinical marker for the clinician to consider the adjunctive use of mood stabilizers or antidepressants in a given patient, which indeed is commonly done, although there is little high-quality evidence available supporting the efficacy of these adjunctive treatments. Notably, in 2009, the Food and Drug Administration (FDA) approved paliperidone for the treatment of schizoaffective disorder, the first time that the agency recognized this as a valid diagnostic entity for a therapeutic indication [11]. Since that time, when new antipsychotic agents have been submitted for approval using studies that enroll both individuals with schizophrenia and schizoaffective disorder, the FDA has examined data for those two diagnostic groups separately. Recently, the FDA expanded the indication for paliperidone, to include relapse prevention of schizoaffective disorder using a long-acting injectable (LAI) formulation of paliperidone, paliperidone palmitate [12].

Paliperidone (trade name Invega^®; Janssen), the 9-hydroxy active metabolite of risperidone (trade name Risperdal^®; Janssen) responsible for most of the antipsychotic potency of risperidone, is an antipsychotic medication that was developed by Janssen Pharmaceuticals, and was approved by the FDA in 2006 for the indication of the treatment of schizophrenia [11]. It is available in an oral extended-release formulation (paliperidone ER) that employs two drug layers and an osmotically active core layer that pushes the drug out (“OROS,” a patented technology), allowing for slow, more even drug release supporting convenient once-daily dosing. Like other second-generation antipsychotics, it is believed that paliperidone’s antipsychotic mechanism of action is antagonism at dopamine D2 receptors and serotonin-2A receptors in the brain, the latter action also helping limit some extrapyramidal adverse effects. Paliperidone is also an antagonist at α₁ and α₂ adrenergic and H₁ histamine receptors, but, unlike most first-generation antipsychotics, not at muscarinic cholinergic receptors [13].

Activity at particular receptors informs expectations for specific adverse effects. Specifically, blocking dopamine D2 receptors does dampen down agitation and helps treat delusions and hallucinations, but, if too pronounced, may result in the extrapyramidal side effects of dystonic reactions, parkinsonism, and tardive dyskinesia, as well as akathisia (pronounced restlessness in the lower extremities), and may cause neuroleptic malignant syndrome. D2 receptor antagonism also increases serum prolactin levels, which may interfere with the menstrual cycle or cause lactation in women, and may cause breast swelling and interfere with sex drive and functioning in either sex, with long-term use potentially decreasing bone density. Blocking serotonin-2A receptors may help with anxiety, irritability, insomnia, and mitigate some extrapyramidal side effects. Alpha₁-adrenergic blocking medications such as prazosin and doxazosin have use in treating hypertension and benign prostatic hypertrophy, but are also prescribed off-label in treating posttraumatic stress disorder; they may be associated with adverse effects of postural hypotension and nasal congestion, as well as priapism and retrograde ejaculation [14, 15]. Alpha₂-blocking medications such as clonidine and guanfacine have been used to treat attention-deficit disorder symptoms, and may be associated with dry mouth, sedation, dizziness and constipation. Histamine H₁ antagonists treat allergies, but also can cause sedation and weight gain. As with many other antipsychotic medications, an increase in weight may be associated with glucose intolerance and the development of diabetes mellitus or a metabolic syndrome.

Knowledge of these other receptor effects is useful in treating individuals who often have co-occurring symptoms or disorders, or heightened sensitivities to particular adverse effects. Paliperidone does modestly increase the electrocardiogram QT interval, an issue for individuals particularly vulnerable to this effect, and can make certain medication combinations (such as with citalopram) problematic.

Paliperidone ER (available in 1.5, 3, 6 and 9 mg extended-release tablets) is the marketed oral formulation, and has a maximum serum concentration (C _max) approximately 24 h after a single dose. It can be taken with or without food, but it should be noted that it has 28% absolute oral bioavailability, with area under the plasma drug concentration–time curve (AUC) increased by 54% when administered with a standard high-fat/high-caloric meal. The recommended dose of the tablet is 6 mg/day (once-daily dosing), with a maximum recommended daily dose of 12 mg/day; pharmacokinetics are dose-proportional within the recommended dose range [11].

The long-acting parenteral form, paliperidone palmitate, is available in 39, 78, 117, 156 or 234 mg doses of injectable suspension (providing paliperidone doses equivalent to 25, 50, 75, 100 and 150 mg, respectively). Individuals should have had some previous exposure to either risperidone or paliperidone to rule out any severe intolerance, before beginning long-acting parenteral treatment. The recommended initial dosing to treat schizophrenia or schizoaffective disorder is administering 234 mg on the first day and 156 mg one week later, both in the deltoid muscle to facilitate more rapid absorption (and therefore not require a lead-in period of oral supplementation). Following this, an appropriate intramuscular dose should be administered monthly afterwards, in the deltoid or gluteal muscle, as preferred, of 39, 78, 156 or 234 mg (the 39 mg monthly dose was not studied in patients with schizoaffective disorder).

Paliperidone is metabolized by CYP2D6 and CYP3A4, but only to a limited extent, and is mainly excreted renally. Following a single oral dose, 59% was excreted unchanged in the urine, and most of the metabolites were also renally excreted. Because of limited hepatic metabolism, mild or moderate hepatic impairment has little effect on dosing recommendations, and extensive or poor metabolizer status for CYP2D6 is not particularly important, although the dose should be lowered for those with renal impairment. Dosage adjustment upwards of paliperidone may be required in the presence of strong CYP3A4/P-glycoprotein inducers (for example, carbamazepine, rifampin, St. John’s wort).

Paliperidone does not substantially inhibit the CYP450 hepatic enzymes, and is a weak inhibitor of P-glycoprotein but only at high concentrations; it is therefore also not likely to significantly affect the metabolism of other drugs.