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Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop (2021)

Chapter: 2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis

« Previous: 1 Introduction and Background
Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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2

Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

Steven Paul, president and chief executive officer at Karuna Therapeutics, said that while the current generation of antipsychotics and antidepressants have been godsends, “the drugs that we have now to treat schizophrenia and depression, [and] serious mood disorders are just simply inadequate.” Currently available second-generation antipsychotic drugs are only modestly effective in treating positive symptoms of psychosis (e.g., hallucinations, delusions, and disordered speech and behavior) and are associated with substantial side effects, he noted. Paul added that about 20 to 30 percent of patients taking medication for schizophrenia do not see reductions in positive symptoms of the disorder, and a very high percentage of patients discontinue treatment within a few months. The current generation of drugs does provide modest benefits over earlier formulations when they do work, Paul acknowledged, but many patients show no responses at all. In addition, most antidepressants have a delayed onset of action and troubling side effects, leading to reduced adherence; these drugs also carry black box warnings for suicidal ideation in adolescents, he said. Although the field of psychiatry has an improved understanding of the fundamental pathophysiology of disorders such as schizophrenia and depression, this understanding has not yet yielded many new therapeutics, said Paul.

THE LIVED EXPERIENCE OF SCHIZOPHRENIA1

Carlos Larrauri, a psychiatric mental health nurse practitioner and a member of the board of directors for the National Alliance on Mental Illness (NAMI), was diagnosed with schizophrenia at the age of 23. His symptoms began during high school, but he managed to function well. At age 18, he was accepted at The Ohio State University medical school through an early admissions placement program. As his cognitive and mood symptoms worsened, he became depressed, missed classes, and gained

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1 This section is based on the presentation of Carlos Larrauri, National Alliance on Mental Illness.

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

weight, ultimately returning home to his supportive family. He got better and left home again to continue his undergraduate studies. However, his symptoms resurfaced, and he began experiencing florid psychosis with delusions. Fortunately, a family friend alerted his mother, and together, they began to address his mental health challenges, leading to his schizophrenia diagnosis and treatment. Today, he teaches and performs psychiatric mental health care as a nurse practitioner and serves on the board of directors for NAMI. Larrauri also described how he has recently decided to attend law school at the University of Michigan to pursue his goal of mental health care policy reform and advocacy.

Larrauri attributes his recovery to three key factors: early intervention, community-based treatment, and access to health care. After about 1 year from the onset of florid psychosis, he received what he called “lifesaving, necessary medication” and realized that he had a serious brain condition that would require lifelong management. He began receiving multidisciplinary treatment, mostly in community settings. “I never had to see the back of a cop car or crisis stabilization unit,” he said. Finally, the Patient Protection and Affordable Care Act’s provision that expanded coverage to adult-dependent children until the age of 26 ensured that he had access to the medical care he needed.

Although the medication has allowed him to lead a full life and pursue his goals, Larrauri noted the limitations of current treatments. They reduce the intensity, frequency, and duration of positive symptoms (see Box 2-1), such as delusions and hallucinations, he said, but come with serious side effects. Furthermore, the drugs do little to reduce negative symptoms or cognitive symptoms (see Box 2-1). “We still do not have adequate treatments for cognitive symptoms, which are often the most disabling and the most associated with negative or poor functional outcomes,” he said. Current medications are also ineffective in treating other negative symptoms, such as anhedonia (reduced capacity to experience pleasure) and lack of motivational drive, said Larrauri.

LIVING WITH DEPRESSION2

Symptoms of mental illness appeared at about age 10 for Ashley Clayton, a research associate at the Family Violence Research Program at Yale University. She described herself as a “bright kid who happened to be particularly sensitive,” who was liked by friends and loved by family. Her challenges with severe depression began at a very early age. Clayton experienced sexual abuse between the ages of 6 and 13, started showing signs of mental illness when she was about 10, began practicing self-harming

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2 This section is based on the presentation of Ashley Clayton, Yale University.

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

behaviors at age 11, and attempted suicide for the first time at age 13. Her psychiatric symptoms became more severe in high school, landing her in the hospital twice, including once for a nearly lethal suicide attempt. She described receiving her college acceptance letters while in the hospital, and recalled needing to get permission from the hospital to leave the site to attend her high school graduation. In time, her health care team identified effective medications to treat the depression and enable her to attend college.

Despite a diagnosis of treatment-resistant depression, extensive therapy and effective management of her illness helped Clayton thrive in college. She tapered off her antidepressant medications, graduated from college with honors, and headed to Yale University in New Haven, Connecticut, for graduate school. During this period of remission, she found a therapist who helped her work through her trauma, accepted a research position at Yale, and fell in love with the man she would later marry.

Four years later, her depression returned. “I was fatigued, self-critical, and felt hollowed and empty or overwhelmed with sadness,” she said. Most

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

concerning was the accompanying suicidal ideation. Not long after that, the symptoms of her treatment-resistant depression became so severe that she was chronically suicidal. “I admitted myself to the hospital at the end of the year because I was not sure I could keep surviving,” said Clayton. “It is exhausting to have to fight every day not to die.”

Despite multiple medications, other forms of therapy, a loving husband, meaningful work, and friendships, Clayton’s mental health steadily deteriorated over the next 2 years. “I had a life that I desperately wanted to live, but I also had an illness that made living excruciatingly painful,” she said. With her memory and concentration declining, she took a medical leave from work.

A colleague and friend referred her to Gerard Sanacora, professor and director of the Yale Research Depression Program and an expert on ketamine and mood disorders. Through Sanacora, she was able to enroll in a Phase 2 clinical trial testing the antidepressant efficacy of different doses of ketamine administered as a single intravenous infusion. After her first infusion treatment, “I had energy and excitement and felt a strange and unfamiliar sense of self-worth,” she said. “It felt like magic.” The exhilarating effects lasted for 2 weeks, followed by a dramatic decline into what Clayton described as a “labyrinth of suffering.” She recollected that she was, “consumed once again by suicidal thoughts” and “devastated to have lost that sense of self that ketamine had seemingly miraculously restored.” At the conclusion of the clinical trial, Clayton and Sanacora tried to find a way for her to continue receiving ketamine treatment through an interventional psychiatry service offered at Yale, but her insurance provider declined to cover the cost. “Months went by with no progress,” she said, “and I was all but certain I would die by suicide and soon.”

Following the advice of another colleague, she tried electroconvulsive therapy (ECT). More than a dozen ECT treatments provided little help and came with significant side effects. Ultimately, her doctors convinced the hospital administrators to allow her to receive 4 weeks of ketamine treatments free of charge. This regimen provided substantial relief from her treatment-resistant depression. However, the doctors did not know how they could cover the expense. As a result, the program administrators were approving each subsequent appointment beyond those initial 4 weeks on a treatment-by-treatment basis. As the intervals between ketamine treatments increased, she began to crash more frequently and described her state as “exceptionally fragile.” “I was left to face the devastating fact that without better access to treatment, ketamine would not save me,” said Clayton. Eventually, she was able to gain access to the drug on a more consistent basis. Now, 4 years and 116 treatments later, Clayton said she “is alive and mostly well.” While ketamine is not a magic bullet or a cure, “it has kept me out of the abyss and most notably resolved almost completely my

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

suicidal ideation,” she said. “It has restored to me all the good stuff like experiencing joy and awe and the feeling of love deep down in my bones.”

SERENDIPITY IN PSYCHIATRIC DRUG DISCOVERY

Most drugs currently used to treat psychiatric disorders were discovered by serendipity, with the mechanisms of action typically not discovered until 10 or 20 years after their introduction, said Paul. For example, the first antipsychotic drug introduced—chlorpromazine—was discovered by the French Navy Surgeon Henry Laborit, who theorized that antihistamines could have a calming effect during surgery by lowering body temperature, said Paul. Laborit went on to show that Thorazine (chlorpromazine), a derivative of the phenothiazine antihistamine promethazine, did indeed reduce stress during surgery without producing marked sedation. Psychiatrists Jean Delay and Pierre Deniker subsequently showed that in manic patients, Thorazine also displayed antipsychotic effects, separate from its sedative properties and unrelated to histamine.

“The rest was history,” said Paul. The introduction of chlorpromazine sparked the development of many other antipsychotic drugs with different efficacy, tolerability, and side effect profiles, but which all fundamentally worked the same way, he said. Not until nearly 30 years later was the mechanism of action identified, said Paul. “The therapeutic effects of chlorpromazine and virtually all marketed antipsychotics are linked to direct blocking of postsynaptic dopamine receptor D2,” he said (Seeman, 2011). Yet, while D2 receptor antagonists reduce positive symptoms, they provide little relief from negative and cognitive symptoms, he noted. Additionally, they cause a cluster of side effects known as extrapyramidal symptoms—including acute dystonia (involuntary muscle contractions) and tardive dyskinesia (stiff, jerky, repetitive, and involuntary movements [e.g., grimacing and eye blinking]), said Paul. Even newer agents that are partial D2 receptor agonists instead of D2 receptor blockers essentially function as antagonists, he said, which supports the idea that positive symptoms of schizophrenia, such as hallucinations and delusions, result from the hyperactivity of mesolimbic dopamine neurotransmission in the brain.

In the search for additional compounds with antipsychotic properties, the drug clozapine was discovered as the first antipsychotic compound to produce efficacy without extrapyramidal symptoms, said Paul. This “quintessential atypical antipsychotic” is thought to act by reducing D2 receptor occupancy and increasing antagonism at the 5HT2A (serotonin) receptor, he said. Several follow-on atypical antipsychotics have been developed, including olanzapine, risperidone, quetiapine, and aripiprazole, but none has an effect size as large as clozapine, especially in patients with treatment-resistant depression and suicidal ideation, said Paul (Leucht et al., 2013).

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

“We do not really know what the secret sauce of clozapine is,” he said. However, he added that the drug has five black box warnings associated with substantial weight gain and other associated comorbidities. Today, it is primarily used in a limited manner in treatment-resistant patients who have not responded to other therapies, said Paul.

Another example of serendipity in psychiatric drug development involves the tuberculosis drug isoniazid, said Paul. After researchers observed that tuberculosis patients treated with isoniazid showed improved mood, sleep, and appetite, the psychiatrist Nathan Kline began a trial in patients with depression and demonstrated similar mood-enhancing effects. Isoniazid, a derivative of hydrazine, was found to inhibit monoamine oxidase (MAO), which resulted in increased serotonin levels (Ramachandraih et al., 2011). Although isoniazid and some other hydrazine derivatives had the potential to cause liver toxicity, their discovery led to the development of a new class of antidepressants, the MAO inhibitors.

The first tricyclic antidepressant was also discovered through serendipity when psychiatrist Roland Kuhn tested imipramine, a structural analog of chlorpromazine, in psychotic patients, only to demonstrate that although it did not improve psychosis, it had mood-elevating properties in patients with comorbid depression (Cahn, 2006). According to Paul, this led directly to the work of Julius Axelrod and colleagues at NIMH who demonstrated that tricyclic antidepressants block the presynaptic uptake of biogenic amines, including the neurotransmitters norepinephrine and serotonin.

These serendipitous discoveries of treatments for depression eventually gave way to rational drug discovery efforts, according to Paul. Focusing on the monoamine hypothesis3 and using the tools of medicinal chemistry, investigators went on to identify compounds that selectively blocked the reuptake of serotonin and norepinephrine. These included Prozac (fluoxetine), a selective serotonin reuptake inhibitor (SSRI), said Paul. By 1993, he said, Prozac was prescribed to nearly five million patients in the United States and gave rise to the development of many other selective serotonin reuptake therapies that are now the standard of care for depression and other mood disorders. However, Paul said that while these drugs have better side effect profiles, they still have only modest efficacy.

Another somewhat serendipitous discovery came in the late 1960s. At that time, the chemist Leo Sternbach was tasked with developing a tranquilizer to compete with meprobamate, which was the first minor tranquilizer to be approved by the Food and Drug Administration (FDA). His unsuccessful attempts to develop a competitor to meprobamate led to the

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3 The monoamine hypothesis predicts that the underlying pathophysiological basis of depression is a depletion in the levels of serotonin, norepinephrine, and/or dopamine in the central nervous system (Delgado, 2000).

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

discovery of Librium, Valium, and the introduction of benzodiazepines as a new class of anxiolytics, said Paul (Calcaterra and Barrow, 2014). Today, benzodiazepines remain one of the most commonly used treatments for anxiety disorders, said Paul.

Yet, more than 15 years passed before investigators discovered that benzodiazepines work by binding to a subset of gamma-aminobutyric acid (GABA) receptors, said Paul (Mohler and Okada, 1977). GABA is the major inhibitory neurotransmitter in the brain and is synthesized from glutamate, which is the major excitatory synaptic neurotransmitter in the brain. It is hypothesized that most cortical pathology reflects an imbalance in glutamatergic excitation and GABAergic inhibition (Krystal et al., 2017). Both GABA and glutamate neurons thus represent potentially druggable targets for psychiatric disorders that involve synaptic transmission.

UNMET NEEDS IN TREATING PSYCHIATRIC DISORDERS

Although many antidepressant formulations have been available since the 1950s, depression continues to be a leading cause of disability, with a full 30 percent of people with major depressive disorder receiving little or no benefit despite treatment with multiple drugs, said Husseini Manji, global head at Johnson & Johnson Science for Minds. Even when currently available antidepressants work, they often have a slow onset of action, said Manji. One reason for the disappointing history of antidepressant treatment, he said, is that until recently, nearly all of the available treatments worked by the same monoamine-based mechanisms. Only in the past 2 years have treatments emerged with completely novel mechanisms, he said.

Paul added that there is still much to learn about the known therapeutic targets in depression. For example, there are 14 molecularly distinct serotonin receptors, but it is not exactly clear which ones are involved in the antidepressant effects of SSRIs and whether efficacy or safety could be increased by targeting specific subtypes or by using combination approaches. Thus, while it often takes 2–6 weeks to observe a clinical response with SSRIs, it is unclear if this results from different receptors being activated or from some other downstream consequence of receptor activation, said Paul. Noting that the attrition rate of conventional small molecule psychiatric drug candidates remains high, he suggested the consideration of other therapeutic modalities.

Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
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Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
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Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 7
Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 8
Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 9
Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 10
Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 11
Suggested Citation:"2 Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
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Mood disorders - including depression and bipolar disorder - are common, disabling, and potentially lethal disorders, characterized by a shortened lifespan from comorbid medical illness and rising suicide rates. Medications for these conditions have been shown to be insufficiently effective in the majority of people who take them, and there remains a tremendous unmet medical need. Recent advances towards understanding the mechanisms of action for psychiatric medicines have led to the identification of potential novel molecular targets and agents for treating mood disorders. While these promising avenues for further investigation have re-energized scientific research in this area, many open questions remain. In response to this interest, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders convened a workshop in March 2021, Novel Molecular Targets for Mood Disorders and Psychosis.

The goal of this workshop was to explore the landscape of novel pharmacologic treatments for psychiatric disorders, review the challenges and opportunities that have been highlighted by the development of recently approved drugs, and reflect on how to apply those lessons learned towards current and future efforts to identify and validate additional novel molecular targets. With a grounding in the personal experiences of patients living with depression and schizophrenia, workshop participants discussed the scientific, clinical, technological, regulatory, and ethical considerations of this topic. Examples of drug classes discussed in the workshop include antagonists for NMDA (N-methyl-D-aspartate) receptors and GABA (gamma-aminobutyric acid) receptors, as well as modulators for muscarinic and serotonergic receptors. This publication summarizes the presentations and discussions from the workshop.

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