THE '-DONES'

RISPERIDONE

The first modern atypical antipsychotic, risperidone, was approved for the treatment of schizophrenia in 1993. It is currently approved for both the acute and maintenance treatment of schizophrenia (in adults and adolescents aged 13-17 years), the acute phase of bipolar I disorder (mania or mixed episode) either as monotherapy or adjunct treatment with lithium or valproate, and irritability associated with autistic disorder (Table 1). This drug is absorbed consistently after ingestion, with an oral bioavailability of 70.0% and a peak plasma concentration within 1-2 hours (Table 4). With respect to dosing strategies in adults with schizophrenia, a typical initial dose is 1.0-2.0 mg/day, with a target dose of 4.0-6.0 mg/day and a maximum dose of 16.0 mg/ day (Table 1). Adolescents should be started at 0.5 mg/day and titrated to a daily dose of 3.0 mg/day. Dosing adjustments should not occur at intervals less than 24 hours and at increments of 1.02.0 mg for adults and 0.5-1.0 mg for adolescents. There are no current guidelines for to the long-term use of risperidone (beyond 8 weeks) in adolescents with schizophrenia. However, a recent open-label, multicenter study demonstrated risperidone maintenance treatment was efficacious and well tolerated over 6 to 12 months in adolescents with schizophrenia.

In adults with bipolar mania, initiation doses are typically higher and utilize a loading strategy (2.0-3.0 mg/day with a maximum dose of 6.0 mg/day; Table 1). In pediatric populations, a starting dose of 0.5 mg/day with a target of 2.5 mg/ day and maximum dose of 6.0 mg/day is recommended. As these recommendations were based on short-term, 3-week trials of antimanic efficacy, there are no current guidelines or approvals for the use of risperidone as maintenance therapy for bipolar mania.

Lastly, in regard to the treatment of irritability and aggression associated with autism (5-18 years of age), lower initiation doses of 0.25 mg/day (patients < 20.0 kg) and 0.5 mg/day (patients > 20.0 kg) are recommended (Table 1). The titration strategy is slow, with a minimum of four days at the starting dose, with increases in increments of 0.25-0.5 mg at 14-day intervals. Average efficacious doses range between 0.5 mg/day and 2.5 mg/ day, with a maximum daily dose of 3 mg/day.

For all treatment indications, the dosing of risperidone (or any atypical antipsychotic) should be individualized and should demonstrate a careful balance between symptom alleviation and patient tolerability. Once clinical efficacy has been maintained, physicians must always consider a gradual taper or further titration of the dosage to optimize this balance between symptom efficacy and safety. Based upon clinical trials and clinical experience, it therefore appears that higher doses of risperidone are required for the treatment of psychotic or manic symptoms, while lower doses can be used to curb irritation in children with autism. This antipsychotic attenuation is most likely due to higher (> 65.0%) D2 receptor occupancy and antagonism in the mesolimbic pathway at higher doses, while at lower doses, there is little receptor occupancy and therefore less antipsychotic effect. This is a property common to all SGAs.

Although not approved for the treatment of depression or anxiety, there exists a fair amount of evidence supporting the efficacy of risperidone in these psychiatric illnesses. The doses are often lower, suggesting that D2 receptor antagonism is not the responsible mechanism. The efficacy of risperidone in the treatment of MDD was first described in case reports, and there are currently five randomized, placebo-controlled trials suggesting low-dose risperidone as successful augmentation therapy in treatment resistant depression. The oldest of these studies in 2006 demonstrated that low-dose risperidone augmentation (0.25-2.0 mg/ day) to citalopram (40.0-60.0 mg/day) in patients with treatment resistant depression improved both the relapse rate (56.1% vs. 64.1%) and median time to relapse (97 days vs. 56 days). In this study, patients were treated with 4-6 weeks of citalopram monotherapy, followed by 4-6 weeks of open-label risperidone augmentation, and finally a 24-week double-blind continuation phase. A smaller but similarly designed trial also found a trending, but non-significant decrease in the relapse rate (56.0% vs. 65.0%) with low-dose risperidone augmentation . In 2007, a six-week trial of risperidone augmentation (1.0-2.0 mg/day) demonstrated a statistically significant reduction in depressive symptoms, an increase in both response rate and remission, and improvements in Hamilton rating scale for depression (HAM-D) scores. A randomized crossover study in 2008 also suggested that low-dose risperidone (0.5-2.0 mg/day) was especially efficacious in the treatment of suicidality. Finally, the most recent of these five studies (2009) provided further evidence for the use of low-dose risperidone (0.5-3.0 mg/day) as a therapeutic option for treatment resistant depression, demonstrating both faster responses and improved quality of life in a short-term, 4-week augmentation trial. Mechanistically, 5-HT2a antagonism (similar to that seen with the antidepressants nefazodone and trazodone) may explain this antidepressant efficacy.

Other, less well-controlled investigations have also demonstrated such antidepressive efficacy of low-dose risperidone. For example, a recent study demonstrated significant improvements in both depressive and psychotic symptoms when risperidone (2.0 mg/day) was used as an adjunct (to citalopram or venlafaxine XR) for the short-term treatment of MDD with psychotic features. In addition, there was similar efficacy with either quetiapine (300.0 mg/day) or olanzapine (15.0 mg/day) adjunctive therapy. However, larger controlled trials are needed to compare the long-term efficacy and tolerability of risperidone in the treatment of MDD, both with and without psychotic features. Finally, a small, open-label study suggested risperidone augmentation to sertraline improved symptoms in patients with sertraline-resistant depression and promoted increased levels of brain derived neurotrophic factor (BDNF). It is plausible that increased levels of BDNF, a known mediator of neuronal growth, differentiation, and synaptogenesis, alleviates depressive symptoms through improved neuronal connections and/or neurotransmission. Abnormalities in BDNF signaling have also been linked to the etiologies of both schizophrenia and mood disorders , further suggesting that the use of pharmacologic agents which modify BDNF signaling (i.e. low-dose risperidone) may prove helpful in these disorders.

In regard to the treatment of anxiety disorders, early investigations suggested low-dose adjunctive risperidone (0.5-1.5 mg/day) might be a useful tool in the management of generalized anxiety disorder (GAD) patients. Although this double-blind, placebo-controlled study demonstrated significant improvements in Hamilton Rating Scale for Anxiety (HAM-A) scores after 5 weeks of adjunctive treatment, the higher response rates in the treatment group failed to achieve statistical significance. In addition, a brief (8 week) open-label study suggested augmentation with low-dose risperidone (0.25-3.0 mg/day) might be a useful option for the treatment of panic disorder (PD), GAD, or social anxiety disorder (SAD), as assessed by a significant reduction in anxiety symptoms. This study however had no control or placebo group. A double-blind, prospective, placebo-controlled, randomized 4 week study however demonstrated similarly improved outcomes in the treatment of GAD with either adjunctive risperidone or placebo . In addition, a more recent placebo-controlled trial found 8 weeks of risperidone monotherapy (0.5-4.0 mg/day) was not effective for the treatment of bipolar patients with comorbid PD or GAD. Overall, the currently available data suggests that risperidone may have greater antidepressant than anxiolytic properties.

These studies shed light on a common theme in this review: the complex pharmacodynamics of risperidone (and by extension all SGAs) allows these agents to function at differing doses to treat varied symptoms and syndromes. In this case, risperidone can be used at higher doses to treat psychotic and/or manic symptoms, primarily through its D2 antagonism in the mesolimbic pathway . At lower doses (< 3.0 mg/day), it appears useful for the treatment of depressive symptoms (and to a lesser extent, anxiety), albeit as augmentation strategies. Although risperidone demonstrates a high binding affinity for the D2 receptor (Table 5), at lower doses, there is presumably lower D2 blockade. It is therefore believed that this antidepressant efficacy is mediated via antagonism of the 5-HT2a receptor, for which risperidone has an even higher affinity (Table 5). As previously discussed, 5-HT2a receptor antagonism and the subsequent increased release of dopamine and norepinephrine in the nigrostriatal pathway decreases the risk for EPS. In the mesocortical pathway, this increase in dopamine is suggested to not only alleviate the negative symptoms of schizophrenia, but also promote improved concentration, attention, and executive functioning . These 'cognitive' symptoms are also common in depressive and anxiety disorders and therefore this selective promotion of dopaminergic activity may be responsible for the aforementioned antidepressant effects. In addition, it is believed that antagonism at the a2-adrenergic receptor (for which risperidone has a high affinity; Table 5) contributes to antidepressant efficacy of this drug via enhancement of terminal norepinephrine release. Risperidone also has some affinity for the 5-HT7 receptor (Table 5), and antagonism at this site has been shown to mediate antidepressant-like effect in animal models of MDD and in humans may improve cognition and circadian function.

Based upon the pharamacodynamic profile of risperidone, it should also be noted that patients should be monitored for dizziness, sedation, and hypotension, due to the high affinity and antagonism for a1-adrenergic receptors (Table 5). This a1 antagonism may also theoretically reduce nightmares, similar to the use of prazosin for the treatment of nightmares in patients with post-traumatic stress disorder (PTSD). Risperidone's moderate affinity for, and antagonism to, the histamine H1 receptor (Table 5) should also prompt clinicians to monitor for sedation and increased cardiometabolic side effects. Despite a high affinity for 5-HT2a receptors in the tuberoinfundibular pathway, risperidone has a higher risk of hyperprolactinemia than other SGAs. It has been proposed that poor penetration of the blood-brain barrier of both risperidone and its metabolite (9-hydroxyrisperidone) might contribute to this drug's high propensity to cause hyperprolactinemia (and the subsequent amenorrhea, galactorrhea, and sexual side effects). Lastly, physicians should also be aware of the potential SGA class-effect risks including: metabolic syndrome (diabetes, hyperglycemia, dyslipidemia, and weight gain), leukopenia, neutropenia, agranulocytosis, neuroleptic malignant syndrome (NMS), suicidal behavior, cerebrovascular adverse reactions (in elderly populations with dementia), priapism, body temperature dysregulation, venous thromboembolism, rebound psychosis upon withdrawal, seizure induction, increased sensitivity in patients with Parkinson's disease/dementia with Lewy bodies, and prolongation of the QT interval . These class-effect risks are given for all SGAs, but the specific risks for each SGA may very immensely. For example, the newer SGAs tend to have less metabolic risks but carry the same class warning.

Lastly, as risperidone is a known substrate of cytochrome P450 (CYP)2D6 (Table 4), concomitant use of enzyme inducers (carbamazepine, phenytoin, rifampin, and phenobarbital) should necessitate an approximate doubling of the patient's usual dose . Co-administration of CYP2D6 inhibitors (fluoxetine, paroxetine, and quinidine) should be accompanied by a reduction of risperidone to approximately half of the usual dose (not to exceed 8.0 mg/day).

PALIPERIDONE

Paliperidone, the active metabolite or risperidone, appeared on the market in the US in 2006, and is currently approved for the treatment of psychosis related to schizophrenia (in both adults and adolescents) and as either monotherapy or adjunct treatment to mood stabilizers for schizoaffective disorder in adults(Table 1). It has an oral bioavailability of 28.0% (42.0% with food) and a peak plasma concentration of 24 hours (Table 4). Regarding dosing strategies, an average initial dose in adults with schizophrenia or schizoaffective disorder is 6.0 mg/day (no initial dose titration is needed) with a maximum dose of 12.0 mg/day (Table 1). If dose titration is required, increments of 3.0 mg/day at intervals of greater than 5 days is recommended. Similar to risperidone, lower doses are recommended in the treatment of adolescents (1217 years) with schizophrenia, with a 3.0 mg/day starting dose and a maximum of 6.0 mg/day .

In regard to the off-label use of paliperidone augmentation in treatment resistant depression, only a single case report is currently available. This case report describes a 54-year old female who received 3.0 mg/day of paliperidone in addition to venlafaxine-XR 37.5 mg/day (previously treated with venlafaxine 225.0 mg/day 3 weeks prior to augmentation). Within six days, there was reported improvement of depressive symptoms (mood, sleep, energy level) and a 40.0% decreased in her HAM-D score, and within 2 weeks, the patient achieved full remission (maintained for 4 months). A MEDLINE search suggests no findings for the use of paliperidone in the treatment of anxiety disorders.

As an active metabolite of risperidone, paliperidone displays a similar pharmacodynamic profile to that of its parent product (Table 5), and also shares its mechanism for its antipsychotic properties at therapeutic doses. Although there is an extremely limited evidence base (one case report), the similar binding affinities to and antagonism for D2/5-HT2a receptors suggests paliperidone might have an ability to treat depressive symptoms when used as a low-dose, augmentation strategy. In addition, its affinity for the histamine H1 and a1-adrenergic receptors are responsible for the side effects of sedation and orthostasis, similar to risperidone. Lastly, a comparative database analysis (of six double-blind, randomized, placebo-controlled, short term clinical trials) suggested that paliperidone ER dosed at 6.0-12.0 mg/day was more efficacious than risperidone 2.0-4.0 mg/day, and equally efficacious as risperidone 4.0-6.0 mg/day. Interestingly, a placebo-adjusted adverse effect analysis revealed no difference in weight gain between these two medications. However, a case report in 2014 demonstrated a lower risk for weight gain and better appetite control after switching from risperidone (5.0 mg/ day) to paliperidone (9.0 mg/day) in a patient with schizoaffective disorder. Until additional randomized, head-to-head trials are published, the precise risk of metabolic adverse effects of paliperidone as compared to risperidone remain unknown.

ZIPRASIDONE

Ziprasidone appeared on the market in 2001 and is currently approved for both the acute and maintenance treatment of schizophrenia in adults, acute agitation in patients with schizophrenia, acute manic or mixed episodes of bipolar I disorder in adults (as monotherapy), and as maintenance therapy in bipolar I disorder (as adjunctive therapy to lithium or valproate) (Table 1). Pharmacokinetically, ziprasidone clearly requires administration with food in order to maximize absorption and bioavailability (60.0% with food), and reaches peak plasma concentration in 6-8 hours (Table 4). This drug requires a bi-daily dosing schedule given its shorter half-life and lower absorption. For the treatment of schizophrenia in adults, ziprasidone should be initiated at 20.0 mg twice daily, with subsequent dosage increases up to 80.0 mg twice daily (Table 1). Dosing adjustments should occur in increments of 20.0 mg twice daily at intervals no less than 2 days, with a maximum dose of 80.0 mg twice daily. As with any SGA, patients should be observed prior to dosage increases, so as ensure the use of the lowest effective dose.

Although there is a paucity of evidence addressing the dosing strategy for the maintenance therapy of schizophrenia, a 44-week, randomized, double-blind, multicenter extension study demonstrated similar efficacy with either ziprasidone (80.0160.0 mg/day) or risperidone (6.0-10.0 mg/day) in the treatment of patients with schizophrenia and schizoaffective disorder. Although more subjects on ziprasidone failed to complete the study, there were fewer adverse effects (weight gain, EPS, and hyperprolactinemia) than the risperidone arm. In addition, a more recent report on the extension phase (3-73 month follow-up) of three multicenter, phase III studies, found ziprasidone to be well tolerated, with only mild to moderate adverse effects. Lastly, the use of ziprasidone in schizophrenia is currently only approved for adults, and a recent placebo-controlled, long-term open extension study found no difference in efficacy between ziprasidone and placebo in the treatment of schizophrenia in adolescents (13-17 years).