The Challenges of Drug Development for Psychiatric Disorders

Drug development for psychiatric diseases remains a difficult and slow process. The COVID-19 pandemic has highlighted the rapid rise of global mental health diagnoses, while the drugs available make little impact. The complexity of pathology and poor patient retention are two of many factors which continue to comprise progress. 

Introduction 

According to Mind, 1 in 4 people will experience a mental health problem of some kind each year in England. During the COVID-19 pandemic, the prevalence of mental health issues rose considerably – the global prevalence estimate for depression rose to 28.0% and 36.5% for stress symptoms. 

Unfortunately, for many psychiatric disorders, treatment focuses on minimal symptom management and drugs are typically only a short-term solution. For conditions like bipolar disorder, patients often require combination therapies as tailored treatment is yet to be developed. Patients with bipolar disorder seeking pharmacological intervention have the option of antidepressants, antipsychotics, anticonvulsants and lithium treatment, some of which are combined. 

The choice of a single drug or combination therapy, is dependent on a number of factors including the type of bipolar and the severity and frequency of the depression and mania phases. The complexity of psychiatric conditions like bipolar disorder make it very difficult to develop a drug which can treat one symptom without counteracting another. 

According to a recent study, mental illness is expected to become the leading cause of disability worldwide by 2030. However, an ever increasing number of pharma companies are withdrawing for psychiatric drug development. Costly late-stage trial failures is one of the main reasons for this industry shift, resulting in a growing patient population with limited effective therapies. 

In addition, the increasingly difficult hurdles for product approval is one of many factors which have contributed to the decline in pharma psychiatric R&D. As a result, psychiatric disorders continue to represent an unmet clinical need.

Preclinical challenges 

The complexity of brain pathology is one of many reasons why drug development for psychiatric conditions often fails at the clinical stage. Understanding the neural mechanisms for conditions like depression is key for determining target identification and validation. 

Schizophrenia for example, is a complex disorder involving the dysregulation of multiple pathways in its pathophysiology. Even today, the pathophysiology of this psychiatric condition is yet to be defined due to the complex interaction between multiple networks and neurotransmitter systems, resulting in a wide range of clinical manifestations. Due to this issue, it is very hard for pharma companies to progress from the R&D stage to preclinical research – if the pathophysiology cannot be fully understood, then it is difficult to model the disease state in an animal. 

Modelling the human brain has historically been a challenging endeavor and continues to comprise the success of drug development for psychiatric conditions. One of the main challenges is ensuring that the preclinical model is as close to representing the human brain as possible. This is hugely important in understanding the pharmacokinetics of drugs within the disease model and predicting these properties in human patients. 

Rodent models continue to be the go-to animal model for psychiatric diseases. In terms of the genetic architecture, neural network structure and behavioural phenotypes, these models are more similar to humans than other non-mammalian models for example, the zebrafish and Drosophila. 

Of course however, these models are not without challenges that comprise preclinical translatability. The development of animal models for psychiatric disorders is arguably more challenging than other areas, as a defining pathology or biomarkers for many disorders have yet to be discovered.

Biomarkers have proven to be important in improving prevention, diagnosis, drug response and drug development for many therapeutic areas like oncology, and could be applicable in the same way for psychiatric disorders. Studies into biomarkers for psychiatric disorders is ongoing but progress is slow. 

Cognitive impairments expressed by humans can be evaluated in animals, using tests to monitor their spatial memory, focused attention and so on. Unfortunately, other manifestations in psychiatric conditions are more difficult to measure from animal models. 

This is a key problem for many psychiatric disorders including combat-related PTSD, in which symptoms like intrusive thoughts are not possible or very difficult to measure. Other examples include hallucinations in schizophrenia, and suicidal ideation in depression. 

Clinical trial and patient retention  

Psychiatric disorders have historically had great difficulty onboarding and retaining patients for clinical trials. Major depression is one of the most prevalent and debilitating disorders which, in a 2015 review, showed a drop-out rate of almost 20% across 45 randomised clinical trials interventions. The impact of low enrolment and high dropout rates in psychopharmacological trials leads to poorer outcomes and can disproportionately affect the patient population in the long-term. 

Various novel clinical trial designs have been proposed for psychiatric clinical trials. Across the literature, it has been that a different approach from the conventional randomised clinical trial (RCT) design may be more suitable. 

One of the challenges with psychiatric clinical trials is defining the inclusion and exclusion criteria. In order to ensure the clinical trial is investigating the desired disorder, a strict inclusion/exclusion criteria is designed for those recruited. 

Unfortunately this can present a challenge for psychiatric clinical trials. Many patients suffering from mental health conditions are often comorbid with multiple others – this can significantly impact patient recruitment numbers. 

For example, individuals suffering from OCD but comorbid with depression may be excluded from recruitment for an OCD drug trial. However a significant proportion of the OCD patient population in general may be diagnosed with multiple disorders – this begins to raise the questions of whether the selected study population is fully representative of the patient cohort.  

There remain a whole host of scientific and clinical challenges that continue to create hurdles for psychiatric drug development. However, neuroscience and psychiatric research represents one of the fastest growing therapeutic areas in the industry – it is hoped that continued investment in R&D and understanding the challenges of clinical research will accelerate psychiatric drug development from research to market.  

Charlotte Di Salvo, Lead Medical Writer
PharmaFeatures