The Efficacy and Safety of Psychopharmacological Treatment Options in Psychosis

1. Introduction

Typically, schizophrenia is an often chronic, progressive and debilitating condition with a prevalence rate of about 1% as stated by McGrath et al., (2008) and is defined by multifaceted symptoms that involve thinking, perception, and emotion. Both, the recurrent positive signs (i.e. delusions, hallucinations, disorganized speech and behavior) as well as the persistent negative symptoms (i.e. anhedonia, apathy, bluntness and social based withdrawal), and cognitive symptoms leading to the continuously increasing impairment with regard to personal and role function of patients with schizophrenia (Kahn et al, 2015). Therefore schizophrenia is rated amongst the most severe and expensive illnesses globally (Murray et al., 2012).

However, despite a considerable increase in our understanding of schizophrenia due to numerous basic and clinical research studies over the last decades, the exact etiology and pathophysiology remain somewhat unclear (Kahn et al., 2015). Moreover, treatment and symptom-management options are insufficient to achieve appropriate remission and recovery rates (Jaaskelainen et al., 2013) and medications that effectively treat all dimensions of symptoms are lacking (Kane, 2010).

Antipsychotic drugs that constitute the mainstay in the treatment of schizophrenia act via modulation of the dopamine system (Carlsson & Carlsson, 2006), and treat mainly positive symptoms, agitation, and aggression, allowing for a remission of positive symptoms (syndrome recovery) in 50% of patients after 3 months and 80% of patients after 12 months (911). However, the rates of functional recovery, defined as XXX, lay at only 20% after 6-12 months (Tohen, 2000).

Reasons for this outcome include an insufficient benefit from antipsychotic agents on positive and overall symptoms in a subgroup of patients and on the functionally relevant domains of negative signs and cognitive dysfunction in the majority of patients (Tapp et al, 2003). Moreover, low adherence rates with antipsychotic medication that can partially be traced back to their adverse effect profiles, as stated by Farries, (2005) contribute to antipsychotic inefficacy.

This habilitation thesis aims to summarize the work of the candidate on the efficacy and safety of psychopharmacological treatment options in psychosis. The first two papers evaluate the therapeutic effects of augmentation strategies of ongoing antipsychotic medication versus monotherapy in schizophrenia with the first article focusing on antipsychotic augmentation and the second one on antidepressant augmentation. Both are common clinical strategies when antipsychotic monotherapy is not sufficiently successful. The second part of the thesis refers to safety concerns of antipsychotic and antidepressant mono- and polypharmacy that need to be balanced against efficacy considerations when treating patients with psychosis.

2. Own Work

2.1 Efficacy of psychopharmacological treatment options in psychosis

Over the years different augmentation procedures have been studied under randomized controlled conditions globally. However, there has been little information concerning treatment option among psychotic patients. On the other hand, different pharmacologic rationale for linking antipsychotics with similar putative antipsychotic dopamine and D2 receptor blockade has faced a lot of critics. Consequently, there is scarce mechanistic knowledge of antipsychotic efficacy as well as polypharmacy as an intrinsic trait of various antipsychotics cases causing multiple pharmacodynamics and neurotransmission side effects. However, antipsychotic co-treatment still remains to be a controversial practice because insufficient data supporting its efficacy, long term safety mechanisms, increased costs and mortality.

Additionally, there are two possible approaches concerning co-treatment of antipsychotics: augmentation refers to administering a second agent following a non-response to a first response; whereas co-initiation is the administration of two agents simultaneously. Research attempting to assess the efficacy and success of symptom-management using co-treatment approaches, often cluster augmentation and co-initiation together; thus, there is a lack of conclusive evidence specifically for clinically relevant augmentation strategies available.

However, the Co-treatment with two antipsychotics is a common clinical practice, with a median prevalence of 19.6% and often administered even before clozapine (1822). Possibly because clinicians believe that co-treatment will lead to increased /quicker efficiency, manage residual advantageous signs, or mitigate adverse effects (AEs) that allows for dose minimization of the first antipsychotic.

Despite treatment advances, clinicians and researchers are still trying to comprehend the effects antipsychotic polypharmacy has on the illness, especially regarding efficacy and tolerability. This is vital, as co-treatment has raised concerns and challenges such as AEs, drug-drug interactions, as well as decreased medication adherence due to complex drug regimes. One systematic review concluded that there was a relationship between antipsychotic co-treatment and an increase in AEs, specifically extrapyramidal symptoms, hyper prolactinemia, hyper salivation, sedation/somnolence, cognitive impairment, diabetes, and dyslipidemia, as outlined by Ganguly et al., (2004).

2.1.1 Antipsychotic augmentation vs. monotherapy in schizophreniaGalling B, Roldan A, Hagi K, Rietschel L, Wayzata F, Zheng W, Cao XL, Xiang YT, Zink M, Kane JM, Nielsen J, Leucht S, Correll CU. Antipsychotic augmentation vs. monotherapy in schizophrenia: a systematic review, meta-analysis, and meta-regression analysis. World Psychiatry. 2017 Feb;16(1):77-89

Typically, antipsychotic polypharmacy in schizophrenia is subject to debate as a result of its high costs and its increase in the population, while having little to no information concerning safety precautions and efficacy. Through the research, a systematic literature review was used and random impacts of the meta-analysis of different randomized analysis conducted through a comparison of augmentation of a second antipsychotic case versus continued antipsychotic monotherapy in a condition referred to as schizophrenia. Consequently, the co-primary results obtained were total assumptions either showing an increase or decline and specific response as defined. However, from the analysis, it is clear that antipsychotic augmentation is more superior to monotherapy as a result of the reduction in the number of symptoms as seen through (16 different studies, with a population size of 694 and standard mean difference of 0.53). On the other hand, superiority from the research is only seen in open-label trials, and low-quality experiments were having (p<0.001), but not present in double-blind as well as high-quality experiments (p=0.120 and 0.220). From the research, it was also conclusive that response was the same in anti-psychotic augmentation and the other monotherapy analysis from a study having (population size of 938, risk ration of 1.19, p=0.061 and 95% level of significance). Being irrelevant to double-blind and high-quality research (p=0.99).

However, the final findings and results were replicated and this time round in non-clozapine and clozapine conditions. But, there were no significant changes as a result of the causes or specific causes leading to discontinuation, depressive symptoms as well as general and positive global clinical impressions. On the other hand, negative symptoms increased as the augmentation treatment improved from 18 different studies having (population size of 931, SMD=-0.38, p<0.003 and a significant level of 95%). But research with aripiprazole had no results as seen through 8 different studies having a population size of 532 and significant mean difference of -0.41 fewer than 95% level of significance. Consequently, few differences emerged; whereby D2 antagonist augmentation treatment was related to conditions of less insomnia (p=0.028), but there was an increase in prolactin elevation (p=0.015). At the same time, aripiprazole augmentation treatment gets linked to a reduction in prolactin levels of (p<0.001) and reduced body mass (p=0.030). The evaluation shows that the routine practice involving antipsychotic augmentation especially in schizophrenia does not have double high/blind quality evidence or concrete data for efficacy, with exceptions for negative symptoms decline having aripiprazole augmentation.

2.1.2 Antidepressant augmentation vs. monotherapy in schizophrenia

Galling B, Vernon A, Pagsberg AK, Wadhwa A, Grudnikoff E, Seidman AJ, Tsoy-Podosenin M, Poyurovsky M, Kane JM, Correll CU. Efficacy and Safety of Antidepressant Augmentation of Continued Antipsychotic Treatment in Patients with Schizophrenia. Acta Psychiatry Scand. 2018 (in print)

Even though antidepressants (AD) monotherapy is preferable to a major...