Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation

Introduction: Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER) oral formulation and a long-acting injectable paliperidone palmitate (PP) formulation. Paliperidone has demonstrated efficacy in the reduction of acute schizophrenia symptoms and clinical benefits were maintained also in the long-term treatments. Paliperidone ER and PP are generally well tolerated with a predictable adverse event profile.

Areas covered: Data from studies evaluating safety and tolerability in the acute and maintenance treatment of schizophrenia with paliperidone are reviewed. The reported treatment-emergent adverse events of these formulations are discussed.

Expert opinion: In the treatment of schizophrenia and schizoaffective disorders the safety profile has a central role because it can enhance patient compliance. In fact treatment-emergent adverse events are one of the main causes of discontinuation in these patients. In particular the main limitation in the administration of paliperidone could be represented by the onset of hyperprolactinemia (especially in women) and of mild parkinsonism. Paliperidone has a high impact on current long-term drug strategies, especially given the new 3 month long-acting injectable formulation of PP.     

Oral and Palmitate Paliperidone Long-Acting Injectable Formulations’ Use in Schizophrenia Spectrum Disorders: A Retrospective Cohort Study from the First Episode Psychosis Intervention Program (CRUPEP)

BackgroundLong-acting injectable antipsychotics (LAIs) may be a suitable therapeutic option for those patients in earlier stages of psychosis to avoid relapses and disease progression. Despite that, there is a lack of evidence in the literature regarding the use of LAIs in this profile of patients.MethodsThis is a retrospective cohort analysis to assess the efficacy, tolerability, and pattern of use of palmitate paliperidone long-acting injectable (PPLAI) formulations (1- and 3-month doses) compared to oral paliperidone/risperidone in patients with a nonaffective first episode of psychosis (FEP) over 12 months of follow-up. Relevant sociodemographic and clinical information were assessed, as well as main clinical scales: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, and Clinical Global Impression Scale Improvement and Severity measures.ResultsThe study included 48 patients, 16 per arm, who were aged 20–50 years and had an FEP. Significant improvements were registered for all treatment groups. Despite that, patients receiving PPLAI 1- and 3-month formulations obtained greater improvements than those in the oral group in the main domains assessed (P < .001). We found no statistically significant differences in hospitalizations between groups. Side effects were presented in 24% of patients. A trend towards reducing antipsychotic doses was observed in 43.8% of patients to achieve the minimum effective dose and avoid the occurrence of side effects.ConclusionsTo our knowledge, this is the first study assessing the use of palmitate paliperidone long-acting formulations versus oral risperidone or paliperidone in FEP. Treatment with PPLAI formulations seems to be an effective therapeutic choice at earlier stages of the disease.     

Pharmacological strategies for the management of comorbid depression and schizophrenia

ABSTRACT

Introduction: Depressive symptoms may occur in any phase of schizophrenia and can have far-reaching consequences.

Areas covered: The author focuses on recent reviews and meta-analyses dealing with the prevalence, importance, etiopathogenesis, and pharmacotherapy of comorbid depression and schizophrenia. Depressive symptoms in acute episodes may improve in parallel with psychosis due to antipsychotic treatment. Therefore, the first step is to evaluate the current antipsychotic treatment of psychotic symptoms and consider changing the dosage. A second step is switching antipsychotic medications, since there are indications that some medications are slightly more effective in reducing depressive symptoms than others. For persistent depressive episodes, additional therapeutic interventions are indicated. Most guidelines recommend the administration of antidepressants as an add-on treatment with a limited evidence level. Immunotherapeutic strategies could be successful, at least in some schizophrenia patients.

Expert opinion: In the near future, precision psychiatry should enable clinicians to recognize specific biotypes with unique biosignatures that will guide accurate and prompt clinical management for individual patients.     

Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance

Introduction: Bipolar disorder is characterized by a complex set of symptoms, including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of patients with bipolar disorder is mandatory to prevent symptom relapse and episode recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence combinations of mood stabilizers and antipsychotics are widely utilized in patients showing no or partial response to, as well as intolerance to, monotherapies. This may offer a therapeutic advantage, however, the possibility of an increased incidence of side effects should be considered.

Areas covered: This paper reviews the current treatment guidelines for the treatment of bipolar disorder and examines the rationale behind the use of aripiprazole in combination with mood stabilizers for acute and long-term treatment of bipolar disorder.

Expert opinion: The combination of aripiprazole and mood stabilizers seems to offer an effective and relatively well-tolerated option for the treatment of acute mania and for the maintenance treatment of patients with bipolar I disorder. The combination presents a lower risk of metabolic side effects compared with other combination therapies, but increases the risk of extrapyramidal side effects with long-term treatment. The aripiprazole–valproate combination seems to be particularly promising in the treatment of patients with comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to confirm these observations and to provide a useful insight for improving the use of drug combinations in bipolar patients.     

Cognitive and mood side effects of lower urinary tract medication

ABSTRACT

Introduction: Muscarinic receptor antagonists, 5α-reductase inhibitors and α₁-adrenoceptor antagonists are frequently used drug classes for the treatment of lower urinary tract symptoms including those of overactive bladder syndrome and benign prostatic enlargement/benign prostatic obstruction.

Areas covered: The authors review the evidence for adverse effects of these drug classes on cognitive function, mood and other functions of the central nervous system and discuss such effects against the evidence for mechanistic plausibility.

Expert opinion: Muscarinic antagonists carry a risk for impaired cognition and other brain functions that differs quantitatively between compounds, being highest with oral formulations of oxybutynin. 5□-Reductase inhibitors can cause depressive symptoms even at low doses and starting several months after discontinuation of treatment. The evidence for α₁-adrenoceptor antagonists and specifically tamsulosin to cause dementia is controversial and lacks mechanistic plausibility. We recommend that physicians treating patients with lower urinary tract symptoms carefully monitor mental status prior to prescribing and periodically thereafter.     

A review of the clinical efficacy,safety and tolerability of the antidepressants vilazodone,levomilnacipran and vortioxetine

Introduction: As a leading cause of disability, major depressive disorder (MDD) is characterized by reduced quality of life and altered functioning. Current pharmaceutical treatment options are limited in their success by modest effects and adverse events that often lead to discontinuation. One current trend in antidepressant development is to combine inhibition of the serotonin transporter with other pharmacological targets, including the norepinephrine transporter or different serotonin receptors.

Areas covered: In a span of < 3 years, the FDA approved three new antidepressants for the treatment of MDD: vilazodone in January 2011, levomilnacipran in July 2013 and vortioxetine in September 2013. This article reviews the efficacy, safety and tolerability of these three drugs mainly from the Phase III trial data.

Expert opinion: All three drugs are effective in the treatment of MDD, but data comparing them to other antidepressants is currently lacking. Vilazodone was proposed to produce a more rapid onset and have fewer sexual side effects but neither effect has been conclusively shown. Levomilnacipran appears to be effective in improving functional impairment, including both social and work functioning. Vortioxetine is currently the only drug of the three with proven efficacy in elderly patients. It also appears to have cognitive enhancing properties which are largely independent of improved depressive symptoms. Overall, these drugs represent a promising step forward in antidepressant drug development.     

Paliperidone extended-release in patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics

Objective: This study explores relevant outcomes with flexibly dosed paliperidone extended-release (ER) in a real-world design.

Research design and methods: Patients were recruited from 23 countries. Adults with non-acute schizophrenia (n = 1812), previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER and prospectively treated for 6 months.

Main outcome measures: Primary efficacy outcome for patients switching for the main reason of lack of efficacy was ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for main reasons other than lack of efficacy, primary outcome was non-inferiority in efficacy compared with the previous medication.

Results: Among the lack-of-efficacy group, 61% achieved a ≥ 20% improvement in PANSS total scores from baseline to endpoint. For switchers from other than the lack-of-efficacy group, efficacy maintenance after switching to paliperidone ER was confirmed. Clinically relevant and statistically significant symptomatic improvements occurred for each patient group based on main reason for switching.

Conclusion: Paliperidone ER was well tolerated and associated with a meaningful clinical response in patients who switched from other oral antipsychotics, with insomnia and anxiety as most frequent side-effects.     

The Influence of Acute SSRI Administration on White Matter Microstructure in Patients Suffering From Major Depressive Disorder and Healthy Controls

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder. These antidepressants exert their effects by blocking the serotonin transporter (SERT), leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain’s WM microstructure are lacking.MethodsIn this interventional longitudinal study, 81 participants were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging on 2 separate days, receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated within the FMRIB software library and analyzed using tract-based spatial statistics.ResultsThe repeated-measures ANOVA model revealed significant decreases after SSRI administration in mean diffusivity, axial diffusivity, and radial diffusivity regardless of the group (P < .05, family-wise error [FWE] corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, and external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found, and no changes in fractional anisotropy were present.ConclusionsOur investigation provides the first evidence, to our knowledge, that fast WM microstructure adaptations within 1 hour after i.v. SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy. This study was registered at clinicaltrials.gov with the identifier {"type":"clinical-trial","attrs":{"text":"NCT02711215","term_id":"NCT02711215"}}NCT02711215.     

Managing comorbid obesity and depression through clinical pharmacotherapies

Introduction: Obesity and mood disorders co-occur more often than expected by chance alone. As no randomized, controlled pharmacotherapy trials have been conducted in obese patients with an active mood disorder, it is unclear how to use medication to treat this patient group.

Areas covered: We briefly overview the relationship between obesity and mood disorders; the effects of psychotropic medications commonly used in mood disorders on body weight; the psychiatric effects of available anti-obesity medications; and highlight the few treatment studies of medications in obese patients with mood disorders or depressive symptoms. As binge eating and psychotropic-induced weight gain are common correlates of obese patients with mood disorders, we also provide brief overviews of the pharmacotherapy of these conditions.

Expert opinion: When treating a patient with a mood disorder and obesity, both conditions need to be a focus of clinical attention. Psychotropic medications that have minimal weight gain effects should be used if possible. Weight-loss agents can probably be used in some mood disorder patients, but must be done so cautiously and with a full understanding of their potential psychiatric effects and interactions with psychotropic medications. Knowledge of the pharmacotherapy of binge eating and psychotropic-induced weight gain is also crucial.     

Pain management in opioid maintenance treatment

ABSTRACT

Introduction: Opioid addiction is a worldwide disease with a significant impact. A multitude of physical and mental comorbidities are associated with opioid addiction, pain being one of the most relevant. Insufficient pain management may lead to a disruption in medical treatment, self-medication, and subsequent harm to patients.

Areas covered: In this review, the authors provide a general overview of opioid addiction. A literature search for pain management and opioid maintenance treatment was conducted. Different settings of acute or chronic pain and situations specific to patients addicted to opioids are described. Pain management therapy in addiction is also addressed with an emphasis on treatment strategies such as the optimization of methadone and buprenorphine medication, additional opioid analgesia, and multimodal pain management.

Expert opinion: Opioid addiction is a growing global health concern, and maintenance therapy remains an effective and lifesaving treatment option. However, there remains uncertainty on the appropriate pain management for this patient group. The backbone of pain management in opiate-addicted patients remains maintenance therapy while adjunctive treatment such as regional analgesia, non-opioid analgesia, antidepressants, steps to improve sleep, acceptance and commitment therapy, biofeedback, and hypnosis should be considered. Additional opioid medication is possible as well.     

Evaluating lurasidone as a treatment option for bipolar disorder

ABSTRACT

Introduction: Lurasidone has been approved in the United States as a monotherapy and adjunct for acute bipolar I depression, as well as an antipsychotic for patients with schizophrenia.

Areas covered: Herein, the authors review the pharmacodynamics and pharmacokinetics of lurasidone as well and the major randomized clinical trials. The authors also provide their expert opinion.

Expert opinion: Lurasidone has not been studied in patients with mania or bipolar psychosis. It has been studied, both as a monotherapy and adjunctive treatment to lithium or valproate, in acute depression and in prevention of recurrence of any mood episode in patients with bipolar disorder initially treated for bipolar depression or mania. It is approved in the United States for acute bipolar I depression. It has clinically meaningful treatment effect sizes for improvement in depression compared to placebo (0.51 monotherapy, 0.34 adjunct). The number needed to treat (NNT) for response with monotherapy was 5 (for both lower and higher dose groups), and for remission was 6 and 7 (for lower dose and higher dose groups, respectively); the NNT for adjunctive therapy was 7. It has not demonstrated efficacy in relapse prevention when added to a mood stabilizer but is safe in combination with other medications.     

Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Abstract

Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8?weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.

Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8?weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8?weeks of treatment with each agent, and safety.

Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n?=?30); baseline characteristics were similar between groups. After 16?weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p?=?.014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8?weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.

Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.

Trial registration: ClinicalTrials.gov identifier: NCT03231709.     

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone

ABSTRACT

Introduction: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections.

Areas covered: Fourteen PP1M articles and one PP3M article were identified. Using the paliperidone concentration/dose (C/D) ratio as a measure of clearance provided a weighted mean of 7.7 ng/ml per mg/day among 69 patients from three steady-state PP1M studies (twice as high as oral paliperidone). C/D ratios were: 1) higher by a factor of 1.26 in 12 geriatric patients, 2) lower in obese patients, and 3) 50% lower in three patients taking carbamazepine. No clinically meaningful PP3M pharmacokinetic data have been published.

Expert commentary: Half-life studies and more TDM PP1M studies using steady state are urgently needed. Early TDM studies may help orient PP1M dosing but steady state may not be reached until after the ninth injection (8 months). PP3M may take > 1 year to reach steady state. Any clinician considering switching patients to PP1M: 1) should switch from oral risperidone to PP1M rather than from oral paliperidone to PP1M, and 2) become proficient in paliperidone TDM to use during switches. TDM is highly recommended for patients with abnormal clearance (from obesity, geriatric age, or potent inducers).     

Pharmacokinetic drug evaluation of paliperidone in the treatment of schizoaffective disorder

Introduction: This paper reviews the pharmacokinetics, receptor binding, clinical efficacy and safety of paliperidone in the treatment of patients with schizoaffective disorder.

Areas covered: We reviewed the literature using keywords ‘paliperidone’, ‘schizoaffective disorder’ and ‘clinical trials’ with a focus on seminal data papers and information that is clinically relevant to the treatment of schizoaffective disorder. The purpose of this paper is to provide a clinically oriented review of the pharmacokinetic and pharmacodynamic properties of paliperidone including receptor binding, clinical efficacy, safety and tolerability.

Expert opinion: Paliperidone is currently the only medication FDA approved specifically for the treatment of schizoaffective disorder. Paliperidone is an active metabolite of risperidone, is minimally metabolized in the liver and is primarily known to be cleared through the kidneys. For this reason, paliperidone could be considered for some patients with schizoaffective disorder who also have hepatic impairment. After correcting for the reduced protein binding that is characteristic of hepatically impaired patients, the Cmax was 12% lower than in healthy subjects while the AUC and CL/F were comparable [14]. In addition, the availability of long acting injectable formulations may be useful for patients who are non-adherent with oral medications. The cost of paliperidone may be a disadvantage.     

Pharmacotherapy of mood disorders and psychosis in pre- and post-natal women

Introduction: Untreated mood and psychotic disorders can have substantial adverse impacts on the patient, the fetus and the family, while treatment can ameliorate such problems. To address concerns by clinicians about the risks of psychotropic medications, this review addresses the risk/benefit analysis of somatic therapies for psychiatric disorders during pregnancy and lactation.

Areas covered: All available research was reviewed on the impact on pregnancy and breastfeeding of mood and psychotic disorders, and of antidepressants, mood stabilizers, antipsychotic drugs, and electroconvulsive therapy. References cited in other reviews, case series, formal studies, pharmacologic discussions, and theoretical pieces were added. Available case control and other studies were critically reviewed and diverse explanations for their findings were considered.

Expert opinion: The potential benefits of treatment of mood and psychotic disorders often outweigh the risks after alternative therapies have been considered. Some medications, particularly paroxetine and valproate, pose greater risks during pregnancy, while the teratogenic risks of lithium have probably been overstated. There is more experience with first than with second generation antipsychotic drugs during pregnancy and lactation. Nursing an infant is possible while taking a number of antidepressants, mood stabilizers or antipsychotic drugs.     

A systematic review of the effectiveness of rivastigmine for the treatment of behavioral disturbances in dementia and other neurological disorders

ABSTRACT

Background: Dementia is frequently associated with behavioral disturbances, some of which have a significant impact on patient quality of life and the likelihood of institutionalization. Cholinergic systems, among other neurotransmitters in the brain, appear to be involved with different behaviors, such as psychosis, depression, agitation, and personality changes.

Scope: This paper reviews the clinical data on the effectiveness of rivastigmine, a dual inhibitor of acetylcholinesterase and butyrylcholinesterase, in ameliorating behavioral disturbances in different patient populations. Relevant articles were identified through MEDLINE searches with no date restrictions.

Findings: In particular, rivastigmine has shown efficacy in treating behavioral disturbances in patients with a wide range of dementias –Alzheimer's disease, vascular dementia, fronto-temporal dementia, mixed dementia, Lewy body dementia, Parkinson's disease with dementia, and schizophrenia with dementia. Most of the studies have been open-label clinical trials with behavior as a secondary endpoint. The behavior domains that most consistently showed improvement were apathy/indifference, anxiety, delusions (psychosis), and hallucinations. The major limitation of this review is that the effects on behavioral symptoms were usually secondary endpoints in clinical trials.

Conclusion: The efficacious effects of treatment with rivastigmine on various behavioral disturbances provide supporting evidence that cholinergic mechanisms, among other neurotransmitters, are involved in the manifestation of some behavioral and psychological symptoms of dementia.     

Pimozide as a replacement for maintenance therapy in chronic schizophrenia

Summary

An open 12-week study was carried out to investigate the use of pimozide (12?mg once daily) as a replacement for antipsychotic maintenance therapy in 30 chronic schizophrenics who had responded poorly to previous neuroleptic monotherapy or polytherapy. After 8 weeks of treatment with pimozide, all 18 symptoms of the Brief Psychiatric Rating Scale were improved from previous treatment values. These differences were statistically significant for conceptual disorganization, depressive mood, hostility and motor retardation. Eleven patients who clearly responded well during the trial and consequently continued pimozide monotherapy were judged, 1 year later, to be functioning as well, or better, than with pre-trial drug treatment.     

Aripiprazole for the treatment of bipolar disorder: a review of current evidence

Introduction: Several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission.

Areas covered: This paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice.

Expert opinion: Aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic–maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.     

An updated review of antidepressants with marked serotonergic effects in obsessive–compulsive disorder

Introduction: Since the recognition of the effectiveness of clomipramine in treating obsessive–compulsive disorder (OCD), a number of recent empirical studies have confirmed a key role of the serotonergic (5-HT) system in the pathophysiology of OCD. The current study presents a review of the existing double-blind studies testing 5-HT antidepressants in OCD.

Areas covered: A systematic review was performed to identify double-blind, placebo-controlled, randomized clinical trials investigating the efficacy of antidepressants with marked 5-HT effects [clomipramine, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine and vilazodone] in the short-term treatment of OCD. The search provided 29 studies investigating eight different 5-HT antidepressants. While the findings show reliable efficacy of clomipramine and SSRIs in the treatment of OCD symptoms, no double-blind studies were identified investigating the efficacy of desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine or vilazodone.

Expert opinion: While our results support the effectiveness of older antidepressants with marked 5-HT effects in OCD, it also suggests that newer agents should be tested more comprehensively.