Breaking Boundaries: Innovations and Updates in Schizophrenia Treatment

Key Highlights 

• INVEGA and VRAYLAR (US)/REAGILA (EU) (cariprazine) accounted for the major share of the revenue market for schizophrenia patients in 2023. However, according to DelveInsight, this share is expected to decline by 2034 due to the launch of new emerging therapies.
• Schizophrenia has a robust drug development pipeline, which targets glycine transporter, D-amino acid oxidase (DAAO) inhibitor, or other neurotransmitter systems involved in schizophrenia that are expected to influence market dynamics.
• A few potential emerging schizophrenia therapies such as Boehringer Ingelheim’s Iclepertin (BI-425809), Sumitomo Pharma America/Otsuka Pharmaceutical’s Ulotaront (SEP-363856), Reviva Pharmaceutical’s Brilaroxazine (RP-5063), and others for schizophrenia may change the lives of millions of people living with the condition globally.

Schizophrenia: Unpacking the Global Health Burden 

According to the World Health Organization (WHO), schizophrenia is defined as a chronic and severe mental disorder that significantly impairs the perception of reality and causes people to think, feel, and perceive the world differently than the general population.

Contrary to public perception, neither is schizophrenia a split or multiple personality disorder, nor is it caused by childhood experiences, poor parenting, or lack of willpower, nor are the symptoms identical in each patient. In addition, the vast majority of people with schizophrenia are not violent and do not pose a danger to others. Experts believe schizophrenia results from a combination of genetic and environmental causes. The chance of having schizophrenia is 10% if an immediate family member (a parent or sibling) has the illness. The risk is as high as 65% for those who have an identical twin with schizophrenia. Furthermore, research is ongoing to identify the genes that increase the risk of getting this illness.

When schizophrenia is active, signs of schizophrenia include positive symptoms (hallucinations, delusions, disorganized thinking), negative schizophrenia symptoms (flat affect, alogia, avolition, anhedonia, social withdrawal), cognitive symptoms (Impaired memory, impaired attention, impaired processing speed), and others. Paranoid schizophrenia is a subtype of schizophrenia that includes delusion and usually involves persecution. This subtype of schizophrenia was previously recognized as a distinct condition, but it is now considered a symptom of schizophrenia rather than a separate diagnostic category. However, with treatment on time, most of these symptoms are greatly improved with a diminished likelihood of a recurrence.

Diagnosing schizophrenia requires a thorough evaluation by a mental health professional, as no single test can definitively identify the condition. Diagnosis is typically based on the observation of key symptoms such as delusions, hallucinations, disorganized speech, severely disorganized or catatonic behavior, and negative symptoms that persist for an extended period. For a diagnosis to be made, these symptoms must significantly impair the individual’s daily functioning, last for at least six months, and not be attributable to other medical conditions, medications, or substance use. Mental health specialists refer to diagnostic guidelines from standard manuals like the DSM-5 or ICD-10 to confirm whether a person’s symptoms match the established criteria for schizophrenia. Early identification and intervention can shorten the course of the illness and enhance the chances of recovery. However, diagnosis can be difficult due to the absence of reliable biomarkers and consistently validated therapeutic approaches.

Unraveling the Surge: Contributing Factors to the Rising Prevalence of Schizophrenia

In the past decade, there has been a notable rise in the cases of schizophrenia worldwide. Several factors contribute to this trend. DelveInsight estimates that there were approximately 3.8 million diagnosed prevalent cases of schizophrenia in the 7MM (US, Germany, France, Italy, Spain, UK, and Japan) in 2023, of which nearly 2.1 million cases were male and 1.7 million were female. Furthermore, the assessment showed about 37% of these cases were mild, 33% were moderate and 29% were severe schizophrenia.

One reason for the rise in diagnosed prevalent cases is due to increased awareness and understanding of mental health issues after the COVID-19 pandemic outbreak which led to more accurate diagnosis and reporting of schizophrenia cases. Additionally, changes in lifestyle, social media influence, and associated stressors have been linked to a higher risk of developing the disorder. Moreover, improved access to healthcare services in towns and cities has facilitated earlier detection and intervention. 

Another possible factor is that genetic predisposition, coupled with environmental factors such as substance use and exposure to toxins, continues to play a significant role in the prevalence of schizophrenia.

Current Approaches to the Schizophrenia Treatment and Management 

Mitigating the symptoms and improving cognitive and social functioning in people with schizophrenia necessitates a customized strategy that takes into account the variety of ways the illness presents itself. However, achieving these goals requires a tailored approach that recognizes the heterogeneity of the disorder and the unique needs of each patient. Although many patient’s schizophrenia treatment revolves around medication management, the precise kind and dosage of medication used will depend on several variables, including the severity of the symptoms, the response to treatment, and any possible side effects. In addition to pharmacotherapy, psychosocial interventions play a crucial role in addressing functional impairments and promoting recovery. These may include cognitive-behavioral therapy to target cognitive distortions and enhance coping skills, social skills training to improve interpersonal relationships and community integration, and supported employment or education programs to facilitate vocational or academic pursuits. Thus, understanding that every person’s path to wellness is different highlights the significance of providing patient-centered, holistic care that honors each person’s particular experiences and goals. This approach will not only ensure optimal management of symptoms but also will minimize the risk of adverse effects, contributing to better outcomes for individuals with schizophrenia.

The traditional schizophrenia medications include the use of antipsychotics that are categorized into two classes: first-generation antipsychotics (FGAs), or typical antipsychotics, and second-generation antipsychotics (SGAs), or atypical antipsychotics. FGAs such as chlorpromazine, fluphenazine, haloperidol, perphenazine, clozapine, and others are FDA-approved atypical antipsychotic medications for treatment-resistant schizophrenia. Clozapine remains an important medication, particularly for patients who have not responded adequately to other antipsychotic medications. However, this medication may be used suboptimally due to the need for constant titration and monitoring. While many of these medicines effectively reduce positive symptoms, they have no impact on negative and cognitive symptoms of schizophrenia. These agents are also known to cause side effects such as extrapyramidal signs (EPS) and tardive dyskinesia. As a result, SGAs such as REXULTI/RXULTI (brexpiprazole), CAPLYTA (lumateperone), LATUDA (lurasidone hydrochloride), SAPHRIS (asenapine), ABILIFY MYCITE (aripiprazole tablets with sensor), VRAYLAR/REAGILA (cariprazine), SECUADO (asenapine), INVEGA SUSTENNA/TRINZA/HAYFERA (paliperidone palmitate), ARISTADA/ARISTADA INITIO (aripiprazole lauroxil), PERSERIS (risperidone), FANAPT (iloperidone), LYBALVI (olanzapine and samidorphan), and others were developed to manage both positive and negative symptoms as well as neurocognitive symptoms. While EPS effects are found to be minimal with the use of these agents, they are known to cause side effects, such as weight gain and sexual dysfunction, along with other metabolic disorders. It has also been observed that in the case of some patient groups such as the elderly, the use of FGAs and SGAs has resulted in a higher risk of developing pneumonia. 

The FDA has, in 2023, approved RYKINDO (risperidone), ABILIFY ASIMTUFII (aripiprazole), and UZEDY (risperidone). These drugs are being seen as a breath of fresh air for the market, demonstrating the ongoing efforts to improve the management of schizophrenia. Nevertheless, many people with schizophrenia still endure long-lasting symptoms, functional deficits, and adverse drug reactions despite these advances. 

Adding to this, on September 26, 2024, Bristol Myers Squibb announced that the FDA approved COBENFY (xanomeline and trospium chloride), an oral medication for treating schizophrenia in adults. The FDA approval is especially notable as it marks the first novel drug for schizophrenia in 35 years, introducing a new class of treatment by selectively targeting M1 and M4 receptors in the brain without blocking D2 receptors. 

Unmet Needs and Challenges in Schizophrenia Treatment

• Schizophrenia often goes underreported due to the stigma surrounding mental illness and misconceptions about symptoms. Diagnostic challenges and variability in healthcare practices contribute to under-recognition and underdiagnoses of schizophrenia cases. 
• A substantial gap persists in meeting medical requirements such as managing symptoms faster, reducing safety risks, improving adherence, and alleviating patient distress associated with uncontrolled psychotic symptoms.
• Patients often have comorbidities, necessitating multiple medications, and drug interactions pose risks of reduced efficacy and safety concerns, constraining treatment options and fostering non-adherence. Precise drug titration becomes imperative to mitigate compliance challenges amidst patient distress.
• The neural processes involved in the pathophysiology of schizophrenia are not well understood, and several mechanisms are thought to play a role.
• Several neural transmitters appear to be involved, particularly dopamine and glutamate. However, other theories consider the dysfunction of interneurons, the immune system, and oxidative stress.

“We believe that antipsychotic medications have always focused on the neurotransmitter dopamine. They work by blocking some of the brain’s dopamine receptors, resulting in problematic side effects. Due to these side effects, some people stop taking the medication, resulting in a relapse. Moreover, some patients do not respond to dopamine-targeting medications at all.”- Key Opinion Leader

Over the years, pharmaceutical companies have continuously researched new approaches to schizophrenia medications, focusing on innovative mechanisms of action (MOAs), routes of administration (ROAs), improved dosing regimens, and faster onset of action. These efforts aim to enhance the efficacy of medications for schizophrenia while promoting better patient adherence and compliance. Given the significant cardio-metabolic risks associated with many existing schizophrenia treatment drugs, the development of schizophrenia medication with novel MOAs or alternative ROAs is critical. Optimizing dosing schedules and minimizing side effects can address the complex needs of individuals taking schizophrenia meds, ultimately improving both their mental and physical well-being. This drive for innovation reflects the importance of delivering more effective and safer drugs for schizophrenia in the long-term management of the condition.

Exploring Research Frontiers: Recent Advancement in Schizophrenia Treatment 

Drug development proves to be a protracted, costly, and precarious endeavor, especially within the realm of psychiatry. A significant proportion of psychiatric drug candidates fail to progress beyond the mid-stage of clinical development, that is, the stage that involves definitive testing of how well the drug works in people with that mental health problem. However, the bright side is that in this ever-changing world of mental healthcare, the market dynamics for schizophrenia therapy are expected to undergo a significant transformation in the coming years due to the innovative approaches, updates, and launch of emerging therapies in the 7MM. 

The schizophrenia therapeutics landscape is undergoing a notable influx of potential emerging drugs, each presenting unique mechanisms and strategic approaches in the quest for more effective treatment options. Novel mechanisms of action are being explored, such as muscarinic trace amine-associated receptor agonism, serotonin receptor antagonism/inverse agonism, and glutamatergic modulation. In addition to pharmacological advancements, targeted psychotherapy is gaining recognition for its effectiveness in easing schizophrenia symptoms. At present, prominent industry players, including Boehringer Ingelheim, Karuna Therapeutics, Reviva Pharmaceuticals, Minerva Neurosciences, and Newron Pharmaceuticals, among others, are advancing their products through the late phases of schizophrenia clinical development in treating patients. 

KarXT (Xanomeline–trospium), a combination therapy of two different drugs including xanomeline and trospium chloride, is a novel drug that offers a unique approach to reducing symptoms and minimizing side effects by modulating dopamine transmission through the muscarinic acetylcholine system in the brain. Since trospium does not cross the blood-brain barrier, it is free of the side effects of centrally acting anticholinergics, including those related to cognition. When used with xanomeline, trospium is intended to counteract the peripheral muscarinic activity of xanomeline. KarXT aims to address the historical challenges associated with xanomeline’s side effects, such as nausea and vomiting, by incorporating trospium. The development of this novel therapy will target neuroplasticity and oxidative stress in schizophrenic patients. The drug is set for a potential launch in 2024 (US), 2025 (EU4 and the UK), and 2026 (Japan) as per DelveInsight analysis. The drug candidate is also being investigated for dementia-related psychosis in Alzheimer’s diseases. 

Another schizophrenia drug candidate, Ulotaront (SEP-363856), a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity, is a promising drug candidate for the treatment of schizophrenia. Additionally, it has been granted a Breakthrough Therapy Designation by the FDA for its potential to address negative symptoms in schizophrenia patients. 

“SEP-363856, a TAAR1 agonist with 5-HT1A agonist activity, has a unique, non-D2/5-HT2A mechanism of action that may help patients with both positive and negative symptoms of schizophrenia. Even though the primary endpoint of the Phase III trial was not met, Ulotaront, however, proved to be generally safe and well-tolerated in its investigations. Moreover, it is believed to be a novel psychotropic substance that has demonstrated effects on glutamate signaling, dopamine, and serotonin, indicating its potential to modify mood, cognition, and reward processing in ways that are relevant to schizophrenia and other mental illnesses.”- Key Opinion Leader

Furthermore, there has been new interest in modernizing previously approved antipsychotics for schizophrenia. One such example is olanzapine, which is based on BEPO technology (Bioresorbable diblock mPEG-PDLLA) that controls and guarantees the regular delivery of active pharmaceutical ingredients at the optimal therapeutic dose for several days, weeks, or months. Under development by Teva Pharmaceutical/Royalty Pharma, Olanzapine long-acting injectable (LAI) (TEV-749) is an investigational long-acting olanzapine that acts by blocking dopamine D2 receptors, reducing positive symptoms like hallucinations, and serotonin 5HT2A receptors, alleviating negative symptoms such as anhedonia and avolition. It promises an alternative for severe schizophrenia patients, offering a controlled release with a favorable safety profile. Other examples include Lyndra Therapeutic’s LYN-005 (long-acting oral risperidone), Rovi Pharmaceuticals Laboratories OKEDI/RISVAN (risperidone ISM), and others. 

Brilaroxazine (RP5063), a novel multimodal neuromodulator developed by Reviva Pharmaceuticals has potent affinity and selectivity against key serotonin and dopamine receptors implicated in schizophrenia and other psychiatric disorders including sexuality and cardiovascular effects. In its interim Phase III (RECOVER) results, the drug candidate received a favorable safety profile with no drug-related or treatment-emergent serious adverse events observed on using brilaroxazine in schizophrenia patients. The Phase II (REFRESH) trial results demonstrated statistically significant improvements in all major symptom domains, including PANSS total score, positive and negative symptoms, and Clinical Global Impression – Severity score (CGI-S) when compared to placebo. Expected to launch in 2026 in the US; as per DelveInsight’s analysis, the brilaroxazine has the potential to change the schizophrenia market dynamics. Another contender, Valbenazine (NBI-98854) by Neurocrine Biosciences in collaboration with Mitsubishi Tanabe Pharma, acts as a selective VMAT2 inhibitor and holds significant schizophrenia market potential, aiming for a share of USD 504.7 million in 2034 as per our company’s market analysis in the 7MM. 

The future of schizophrenia treatment looks promising, driven by ongoing research and deeper understanding of the disease mechanisms. Pharmaceutical companies are not only working on optimizing current medications for schizophrenia, but also focusing on developing novel therapies that target neuroplasticity and inflammation in schizophrenic patients. These advancements have the potential to revolutionize the market by offering more precise treatments with fewer side effects, addressing both the mental and physical challenges posed by the condition. As the development of innovative schizophrenia drugs continues, the goal is to provide patients with therapies that not only manage symptoms more effectively but also improve long-term outcomes.