- ‘New lead’ in hunt for better schizophrenia drugs
- Mu-opioid receptors
- How does this relate to schizophrenia?
- Study limitations and the future
- Current research and development of new treatments for schizophrenia
- Current treatments
- Current research
- “Game-changing” new schizophrenia drug passes Phase 2 human trials
- Iloperidone: A New Drug for the Treatment of Schizophrenia
- New Schizophrenia Medication Gains FDA Approval
- Drug Passes Latest Hurdles After Initial Difficulties
- Approval Comes With Warning About Risks
- A Novel Therapy With Fewer Side Effects
- Promising Signs But Proceed With Caution
- New Psychotropic Drug for Schizophrenia Promising in Early Testing
‘New lead’ in hunt for better schizophrenia drugs
The so-called negative symptoms of schizophrenia, which include anhedonia, can be particularly debilitating. One recent study attempted to identify their neurological roots.
Share on PinterestUsing PET scans, scientists investigated the origins of schizophrenia’s negative symptoms.
Schizophrenia is a mental health condition that affects an estimated 1% of the United States population.
Scientists tend to divide symptoms into two broad categories: positive and negative.
Positive symptoms include delusions, racing thoughts, and hallucinations.
Negative symptoms include a lack of motivation, a lack of desire to engage in social interactions, and anhedonia, which is an inability to experience pleasure.
Currently, healthcare providers treat schizophrenia with antipsychotics. These drugs can improve positive symptoms, but they do little to address the negative ones.
In fact, as it stands, there are no drugs that specifically target negative symptoms. One of the primary reasons for this gap is a corresponding gap in our understanding of why negative symptoms arise.
Recently, a group of researchers investigated a class of receptors that earlier studies have implicated in negative symptoms.
The body produces opioids, which activate various groups of receptors, including mu-opioid receptors (MORs). MORs in a region of the brain called the striatum appear to play a pivotal role in the experience of pleasure and reward.
MORs also seem to be important in both the anticipation and enjoyment of a reward.
For instance, a study wherein scientists genetically engineered mice to lack MORs found that the animals were less motivated to eat. Another study discovered that when researchers blocked the MOR system in rats, they showed less interest in socializing with other animals.
Conversely, when scientists stimulated the MOR system in rats, it enhanced their reward responses.
Other studies in humans have added to this evidence. As an example, when researchers stimulated a participant’s opioid system, it increased the pleasurable experience of viewing rewarding images and boosted motivation to view them.
Overall, as the authors of the latest study write, “both preclinical and human studies show a potential role of MOR in mediating anhedonia, amotivation, and asociality.”
How does this relate to schizophrenia?
Some earlier studies, which examined the brains of people with schizophrenia after death, found reduced MOR availability. However, studies have produced conflicting results.
In the latest study to investigate this, scientists from the MRC London Institute of Medical Sciences in the United Kingdom took a new approach. They used PET scans to assess MOR levels in 19 participants with schizophrenia and 20 people without schizophrenia.
This was the first study to assess MOR availability in live participants with schizophrenia. They published their findings in the journal Nature Communications.
In brief, they found “significantly lower MOR availability in the striatum of patients with schizophrenia relative to controls.”
In a secondary analysis, they revealed a reduction in MOR availability in other brain regions involved in processing pleasure, including the insular cortex, amygdala, midbrain, and orbitofrontal cortex.
Study limitations and the future
The authors do outline certain limitations of their study. For instance, all the participants with schizophrenia were taking antipsychotic medication at the time.
Although they note that there is no evidence to suggest that these drugs interact with the MOR system, they say that future studies should recruit individuals who have never taken antipsychotics.
They also note that because tobacco can affect MOR signaling, and the participants with schizophrenia smoked more cigarettes, this might have influenced the results.
However, they also explain that there was “no correlation between MOR availability and number of tobacco cigarettes smoked.”
Overall, the study authors conclude that ” availability is reduced in the striatum and other brain regions involved in hedonic processes.” This conclusion supports previous findings and, hopefully, could lead to improved treatments for people with schizophrenia.
“We desperately need treatment approaches for schizophrenia. This is a promising new lead that could help us develop a new treatment.”
Senior study author Oliver Howes
Current research and development of new treatments for schizophrenia
By Mark Ashton and Adam Todd
Coloured positron emission tomography brain scan of a schizophrenic patient during hallucination (Wellcome Dept of Cognitive Neurology/ Science Photo Library)
The World Health Organization estimates that there are 24 million people affected by schizophrenia worldwide, with many sufferers in the 15–35 years age range. The disorder is complex and individuals exhibit a range of symptoms, both positive and negative.
Positive symptoms include delusions, hallucinations (often auditory), irrational thought patterns, which are often accompanied by the idea that an external agency has interfered with those thoughts, and abnormal behaviour, which is occasionally aggressive.
The negative symptoms include social withdrawal and a flattening of emotional response. In addition to the positive and negative symptoms, there is also often more general cognitive dysfunction, including depression, anxiety and memory impairment.1
Although the exact cause of schizophrenia is unknown, it is known to involve a combination of genetic and environmental factors, which result in changes in a number of brain structures and in the chemistry and physiology of the brain. A number of in vivo studies using various neuroimaging techniques have reported that the whole brain and grey matter volume is reduced in individuals with schizophrenia.
Areas that appear to be susceptible to this reduction include the hippocampus, amygydala, the superior temporal gyri, the prefrontal cortex, the thalamus, the anterior cingulate and the corpus callosum.2
The leading theory to account for the pathophysiology of schizophrenia involves an excess of the neurotransmitter dopamine and, although direct evidence for the role of dopamine is sparse, there is a large body of indirect evidence from a number of sources.
The three main dopaminergic pathways are the nigrostriatal pathway (important for motor control), the mesolimbic/mesocortical pathways (involved in emotion and drug-induced reward mechanisms) and the tuberohypophyseal neurons, which run from the hypothalamus to the pituitary gland.
The effects of dopamine are mediated by interaction with a group of dopamine receptors, D1–D5. These G-protein-coupled receptors are divided into two groups, the D1 family (made up of D1 and D5) and the D2 family (made up of D2, D3 and D4).
An excess of dopamine is thought to occur either through excess production (presynaptic dopamine overactivity) or through postsynaptic dopamine overactivity mediated either by increased D2 receptor density or increased postreceptor action.
A weakness of the theory, as originally formulated, was that it only provided an explanation for one set of symptoms, namely the positive symptoms.2
However, later versions of the dopamine theory were able to account for both sets of symptoms. For example, it has been suggested that schizophrenia is the result of an imbalance between excessive stimulation of D2 receptors in subcortical regions and an under-activation of D1 receptors in cortical regions — the over-stimulation resulting in the positive symptoms, while the deficient stimulation of the cortical D1 receptors leads to the negative symptoms.3
An alternative description of the underlying neurochemical basis of schizophrenia suggests the involvement of a hypofunctional glutamate system, particularly decreased neurotransmission at the N-methyl-D-aspartate (NMDA) glutamate receptor.4
Various pieces of evidence exist that lend support to this hypothesis, but particularly striking is the observation that administration of ketamine (NMDA receptor antagonist) can induce symptoms in healthy volunteers that resemble some of the positive and negative symptoms of the condition.
It is, however, worth noting that, due to the reciprocal interactions between the dopaminergic and the glutamatergic systems, many of the effects could still be the result of changes in the dopaminergic systems.
Another neurotransmitter that has been implicated in the pathophysiology of schizophrenia is the inhibitory transmitter ?-aminobutyric acid (GABA). GABA is widely used in the brain and spinal cord and exerts its effects by acting on a family of ionotropic receptors (GABAA, GABAB and GABAC), whereby it is involved in the modulation of anxiety, muscle tension, epileptogenic activity and memory functions. Numerous post-mortem studies of schizophrenic patients have shown a reduced level of GABA expression.2
5-Hydroxytryptamine (5-HT, serotonin) is a neurotransmitter that can act in an inhibitory or excitatory fashion depending on which receptor it targets. It mediates a range of physiological functions, including feeding behaviour, mood and emotion, sleep or wakefulness, sensory pathways, body temperature, and various behavioural responses.
All but one of the 5-HT receptors (5-HT1–7) are G-protein-coupled receptors (5-HT3 is a ligand-gated cation receptor). Various members of this family of receptors have been implicated in having a role in the pathophysiology of schizophrenia.1,6
There are many antipsychotic drugs currently on the market available to treat schizophrenia, some of which have been available for many years. Generally speaking, there are two broad classes of antipsychotics available: conventional antipsychotics and atypical antipsychotics.
Conventional antipsychotics are thought to act by targeting D2 receptors in the brain and interfering with dopaminergic neurotransmission. Examples of conventional antipsychotic drugs include chlorpromazine, prochlorperazine, haloperidol and trifluoperazine. Unfortunately, although blockade of D2 receptors in the brain can help treat symptoms associated with schizophrenia, it may also cause extrapyramidal symptoms, something that can be troublesome for patients.
Extrapyramidal symptoms consist of parkinsonian symptoms (eg, tremor), dystonia, dyskinesia, akathisia (restlessness) and tardive dyskinesia (involuntary movements of the face, tongue and jaw). These symptoms can be difficult to predict because they are often dependent on a number of things, such as dose, drug and patient factors. Some of the symptoms may stop on cessation of therapy, but other symptoms, such as tardive dyskinesia, may be irreversible.
Atypical antipsychotics include aripiprazole, olanzapine and quetiapine. They are often better tolerated than the conventional antipsychotic agents. They are generally associated with lower incidence of extrapyramidal symptoms and, as a result, are a welcome alternative to conventional agents.
Clozapine, another atypical antipsychotic, is also used in the treatment of schizophrenia, but only in patients unresponsive to, or intolerant of, conventional antipsychotic drugs because it has been associated with agranulocytosis.
Cariprazine is a novel atypical antipsychotic that is currently under development by Gedeon Richter Ltd, Forest Laboratories Inc and Mitsubishi Tanabe Pharma Corp. It differs from all the current second generation antipsychotics, which, with the exception of amisulpride, bind to D2 and 5-HT2A receptors.
Cariprazine exhibits partial agonism at D2, D3 and 5-HT1A receptors and antagonism at 5-HT2B receptors, with animal data suggesting that the levels of activity at D2 and D3 receptors are low, while the agonist activity at 5-HT1A is high.
The hope with cariprazine is that it will provide an effective way of mitigating some of the cognitive deficit that is often associated with schizophrenia in addition to providing an antipsychotic benefit.7
Lurasidone is an atypical antipsychotic that was granted approval at the end of 2010 by the US Food and Drug Administration for the treatment of schizophrenia. It has a high affinity for the D2, 5-HT2A and 5-HT7 receptors, where it acts as an antagonist, while it acts as a partial agonist at the 5-HT1A receptor.
Lurasidone appears to be well tolerated and associated with few of the side effects that are observed with many other members of this class.8
A potential new class of treatments for schizophrenia that operate via a novel mechanism appear to be emerging and a number of pharmaceutical companies have active development programmes in this area.
Eli Lilly’s LY2140023 appears to be the most advanced candidate in this class, with recruitment to a phase III trial under way. LY2140023 is a prodrug of the orthosteric agonist (LY-404039), which operates at the metabotropic glutamate receptor 2/3 (mGluR2/3) and is active as long as it is bound to the receptor.
Along with other mGluR agents, the precise mechanism by which they operate is still unclear, although these agents may be exerting their effects by modulation of the dopaminergic system because it has previously been demonstrated that mGluR2/3 agonists inhibit dopamine release.
An important feature of LY2140023 was there was no weight gain, which is normally associated with olanzapine. In fact, many patients who received LY2140023 actually observed modest weight loss.9
Rasagiline (selective monoamine oxidase inhibitor-B) is currently licensed for the treatment of Parkinson’s disease where it is used to treat cognitive deficit.
A current trial is examining the possibility of using rasagiline as an adjunct therapy to treat the cognitive impairment and negative symptoms associated with schizophrenia and is due to report in 2011.
Raloxifene, a selective oestrogen receptor modulator, is being investigated as an adjunct therapy for use in the treatment of schizophrenia in postmenopausal women. Raloxifene is known to modulate the effects of oestrogen in the central nervous system, thereby improving emotional symptoms, memory and information processing.
A larger trial, following on from an earlier smaller study, is expected to report this year (2011).
A phase III trial involving the synthetic retinoid bexarotene is currently under way to evaluate its usefulness as an adjunct therapy for use with standard antipsychotic treatment. The study is a follow-up to a previous successful pilot programme.
Over the years a great deal of progress has been made in the management of schizophrenia. The introduction of atypical antipsychotics has proved successful since they are generally associated with fewer extrapyramidal side effects than the conventional agents.
It would also appear that the pharmaceutical industry still considers this disease as an attractive target for drug design and there are, indeed, many novel agents in early development. For this progress to continue, it is vital research into developing new agents is maintained.
Mark Ashton is senior lecturer in medicinal chemistry and Adam Todd, MPharmS, is senior lecturer in pharmacy practice and clinical therapeutics, both at the School of Pharmacy, University of Sunderland
email [email protected]
1 D’Agostino A, Bozzo J. Therapeutic targets for schizophrenia. Drugs of the Future 2008:33;981–9.
2 Keshavan MS, Tandon R, Boutrous NN, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008 part 3: neurobiology. Schizophrenia Research 2008:106;89–107.
3 Abi-Dargham A, Laruelle M. Mechanism of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. European Psychiatry 2005:20;15–27.
4 Labrie V, Roder JC. The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neuroscience and Biobehavioral Reviews 2010:34;351–72.
5 Ginovart N, Kapur S. In: The dopamine receptors, edited by Neve KA, Neve RL, London: Springer; 2009.
6 Mnie-Filali O, Lambas-Señas L, Scarna H, Haddjeri N. Therapeutic potential of 5-HT7 receptors in mood disorders. Current Drug Targets 2009:10;1109–17.
7 Grunder G. Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression. Current Opinion in Investigational Drugs 2010:11;823–32.
8 Newman-Tancredi A. The importance of 5-HT1A receptor agonism in antipsychotic drug action: rationale and perspectives. Current Opinion in Investigational Drugs 2010:11;802–12.
9 Mezler M, Geneste H, Gault L, Marek GJ. LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Current Opinion in Investigational Drugs 2010:11;833–45.
FRIDAY, Sept. 18, 2015 (HealthDay News) — A new antipsychotic drug to treat schizophrenia and bipolar disorder in adults has been approved by the U.S. Food and Drug Administration.
The drug, Vraylar (cariprazine), is a capsule taken once a day.
“Schizophrenia and bipolar disorder can be disabling and can greatly interfere with day-to-day activities,” Dr. Mitchell Mathis, director of the division of psychiatry products in the FDA’s Center for Drug Evaluation and Research, said in an agency news release.
“It is important to have a variety of treatment options available to patients with mental illnesses so that treatment plans can be tailored to meet a patient’s individual needs,” Mathis said.
Schizophrenia, a chronic and disabling brain disorder that usually develops in early adulthood, occurs in 1 percent of the general population, according to the U.S. National Institute of Mental Health. People with the condition often see or hear things that are not there. They are also withdrawn or paranoid, believing others are trying to read their mind or control their thoughts.
Vraylar belongs to a class of drugs known as atypical antipsychotics. Others in this group include Abilify (aripiprazole), Seroquel (quetiapine) and Risperdal (risperidone).
The drug’s effectiveness in treating schizophrenia was tested among more than 1,750 patients in three six-week clinical trials. It was shown to reduce schizophrenia symptoms compared to the placebo. The drug’s maker, Forest Labs, and distributor, Actavis Pharma, are based in New Jersey.
The most commonly reported side effects in the schizophrenia trials were tremor, slurred speech and involuntary muscle movements.
Bipolar disorder, also known as manic-depressive illness, leads to dramatic mood swings or shifts in energy and activity levels. People with bipolar disorder have alternating episodes of depression and mania, or “highs,” characterized by irritability, increased activity, restlessness, impulsive behavior and racing thoughts. Almost 3 percent of U.S. adults have bipolar disorder, the mental health institute says.
In three three-week trials involving more than 1,000 bipolar patients, Vraylar reduced disorder symptoms, the FDA said.
The most common drug-related side effects in the bipolar disorder trial included tremor, slurred speech, an urge to move (akathisia), indigestion, vomiting, drowsiness and restlessness.
All FDA-approved drugs for schizophrenia and bipolar disorder must carry a black box warning indicating an increased risk of death if these drugs are used by older people with dementia-related psychosis, the agency noted.
“Game-changing” new schizophrenia drug passes Phase 2 human trials
A new drug designed to treat acute psychosis in schizophrenic patients is reporting impressively positive results from a Phase 2 clinical trial. After several decades of challenging development, the drug is hoped to be one of the most novel schizophrenia treatments to reach the market in years.
Called KarXT, the new drug is an oral coformulation of two compounds – xanomeline and trospium. Both drugs are relatively new compounds designed to interact with muscarinic receptors across the body. The research originally emerged in the 1990s but early studies testing xanomeline revealed the adverse side effects were intolerable.
Xanomeline, a muscarinic receptor agonist, was found to be very effective at treating psychosis associated with schizophrenia, but the extreme peripheral gastrointestinal side effects of the drug put a hold on clinical investigations. The newer KarXT formulation blends an already approved drug called trospium with xanomeline.
Trospium is a muscarinic receptor antagonist, but it notably does not cross the blood-brain barrier. So the idea behind this new formulation is that trospium should help counteract the broader physiological side effects of xanomeline, without disrupting the primary drug’s efficacy in the brain.
So far, KarXT’s trial results have been quite impressive. The Phase 2 randomized, placebo-controlled trial encompassed 182 schizophrenic patients experiencing acute psychosis. Efficacy in the trial was calculated using a scale called the Positive and Negative Syndrome Scale (PANSS).
Generally, a reduction on the PANSS scale of between five and ten points would be considered clinically meaningful. In the past, antipsychotic drugs have been approved with as little as a five point reduction on the scale. The Phase 2 results for KarXT report the drug delivering an 11.6 point mean reduction on PANSS scores compared to placebo.
Adverse side effects were still reported in the trial, however, overall dropout rates between active and placebo groups were similar. And, 91 percent of the KarXT group effectively escalated to the highest dose.
“The results of the Phase 2 trial are impressive and encouraging because they indicate that KarXT, if approved, could represent a game-changing therapeutic advance in the treatment of patients with schizophrenia,” says Jeffrey Lieberman, from Columbia University and a member of Karuna Therapeutics’ scientific advisory board.
KarXT is currently being trailed for a number of uses, with acute psychosis in schizophrenia being the most advanced outcome to date. Phase 1 human trials are underway testing the drug for other symptoms of schizophrenia, as well as trials testing efficacy for Alzheimer’s related psychosis.
There is still plenty of work ahead for the research team before the drug can reach the market. Larger Phase 3 trials will inevitably take several years to complete, and there is not guarantee these early results will hold in larger cohorts. Still, the initial Phase 2 results are excitingly positive and if the trials continue to be successful the new drug could reach the market in as little as five years.
“We are extremely pleased with these results, as the 11.6-point PANSS score separation from placebo far exceeded the five-point minimum improvement that has historically supported approval of current antipsychotics,” say Karuna’s chief medical officer Stephen Brannan. “With this information, and following our anticipated end-of-Phase 2 meeting with the FDA in the second quarter of 2020, we will work to initiate a Phase 3 clinical trial of KarXT in patients with schizophrenia by the end of 2020. We also plan to further analyze these results to better understand the potential of KarXT in patients with schizophrenia experiencing negative and cognitive symptoms, and to explore other CNS disorders that could benefit from this approach, such as psychosis in Alzheimer’s disease as well as the management of pain.”
The Phase 2 trial results for KarXT have yet to be published in a scientific journal.
Source: Karuna Therapeutics
Iloperidone: A New Drug for the Treatment of Schizophrenia
Abstract and Introduction
Purpose. The pharmacology, pharmacokinetics, pharmacogenomics, clinical efficacy, and safety and tolerability profile of iloperidone for the treatment of schizophrenia are reviewed.
Summary. Iloperidone is an atypical antipsychotic that recently received marketing approval from the Food and Drug Administration for the acute treatment of schizophrenia. Iloperidone is a pure antagonist and the first antipsychotic to have pharmacogenomic studies indicate predictive response based on six identified polymorphisms. Pharmacokinetic studies have determined that iloperidone is well absorbed orally, with a bioavailability of 96%. Phase II and III clinical trials have shown iloperidone to improve symptoms of schizophrenia, based on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale, and Clinical Global Impressions–Severity scores (p < 0.05). Iloperidone has established tolerability at recommended dosages of up to 24 mg daily; however, the dosage must be slowly increased over seven days, and twice-daily administration is required to avoid orthostatic hypotension. The most common adverse effects associated with iloperidone were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight gain. Safety studies have also found that iloperidone increases the risk of Q-Tc interval prolongation, similar to that seen with ziprasidone. Minimal changes in glucose and lipid abnormalities were seen in short-term (4- and 6-week) and long-term (52-week) studies, indicating a low chance of metabolic disturbance with iloperidone.
Conclusion. Iloperidone may be a viable and safe option for the treatment of schizophrenia in adult patients, especially for patients who cannot tolerate other antipsychotic agents. However, iloperidone lacks a clear benefit over other antipsychotic agents.
Schizophrenia is a severe, debilitating mental disorder. According to the National Institute of Mental Health, approximately 1.1% of the U.S. population is afflicted with this disease. Schizophrenia is diagnosed based on symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition—Text Revision (DSM-IV- TR). Symptoms are categorized as positive (e.g., hallucinations), negative (e.g., flat affect), and cognitive (e.g., impaired attention).
Based on observations in drug therapy, high levels of dopamine in the brain have been associated with schizophrenia, but dopamine is not the only neurotransmitter whose levels are altered in patients with schizophrenia. An acute psychotic episode is thought to be due to the brain’s inability to inhibit hypersensitivity to stimuli through several pathways. Serotonin, glutamine, acetylcholine, and dopamine all play a role in this period of hypersensitivity. These pathways allow for additional drug targets to be identified. The treatment of schizophrenia has included both typical (first-generation) and atypical (second-generation) anti-psychotics. Atypical antipsychotics have shown efficacy in treating psychosis, causing few or no extrapyramidal symptoms and little to no increase in prolactin levels. Further, atypical antipsychotics decrease both positive and negative symptoms.
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), conducted to determine the effectiveness of antipsychotics in patients with schizophrenia, found that the efficacy of typical and atypical antipsychotics is similar but that adherence to therapy is highly affected by tolerability, with approximately 74% of patients discontinuing their medication before 18 months of treatment. These results indicate the need for better treatment strategies in patients with schizophrenia.
Iloperidone has been studied for nearly 20 years. In May 2009, the Food and Drug Administration approved the marketing of iloperidone for the acute treatment of schizophrenia in adults. This article reviews the clinical pharmacology, pharmacokinetics, pharmacogenomics, efficacy, and safety of iloperidone.
New Schizophrenia Medication Gains FDA Approval
While several antipsychotic drugs are currently on the market, none have been a surefire solution to fighting the distortion in thoughts, hallucinations, and feelings of fright and paranoia associated with schizophrenia. About 30 percent of those who take medication may experience a relapse, according to the Treatment Advocacy Center.
Related: What Life’s Really Like With Schizophrenia: A #NoFilter Memoir
This week, however, the U.S. Food and Drug Administration (FDA) approved a new drug — Caplyta (lumateperone), which will give people living with schizophrenia a new approach to treatment. It is expected to be available in early 2020.
“Schizophrenia is a challenging disease to manage — it is marked by cycles of relapse and incomplete recovery,” says Andrew Satlin, MD, chief medical officer at Intra-Cellular Therapies, the biopharmaceutical company that manufactures the drug. “Caplyta offers healthcare providers a new, safe, and effective option for treating people living with schizophrenia.”
Drug Passes Latest Hurdles After Initial Difficulties
The FDA greenlighted the medication in a daily oral dose of 42 milligrams after it showed significant benefit over placebo in two trials. The drug demonstrated clinical efficacy on the Positive and Negative Syndrome Scale (PANSS), a tool used to measure symptom severity in schizophrenia.
The “positive” symptoms (although not positive in the traditional sense of the word) are psychotic behaviors that include hallucinations, delusions, thought disorders, and movement disorder, while the negative symptoms are connected to emotions and behaviors and include reduced feelings of pleasure, limited speaking, and “flat affect.” Antipsychotics typically relieve the positive symptoms, according to the Treatment Advocacy Center.
Previously, the drug had mixed results in studies. In a test of 696 patients in 2016, Caplyta failed to meet its primary end point. In July 2019, the FDA cancelled an advisory committee meeting regarding the medication in order to review more information.
Related: People With Schizophrenia Can Benefit From Coordinated Care Teams
Approval Comes With Warning About Risks
The FDA issued a black box warning, the agency’s most serious type of advisory, which notes an increased mortality in elderly patients with dementia-related psychosis. The warning states that Caplyta is not approved for the treatment of patients with dementia-related psychosis.
A Novel Therapy With Fewer Side Effects
Caplyta works through a unique targeting of serotonin, dopamine, and glutamate neurotransmitters in the brain.
“Although the exact way the drug works is unknown, it is thought to improve dysfunction through several effects on nerve cell chemicals and their receptors,” says Dr. Satlin.
The dominant therapeutic approach for schizophrenia has been to modulate dopamine neurotransmission.
“We need more medications like this one that work differently and don’t just mediate the dopamine receptors,” says Linda Stalters, a master of science in nursing and the chief executive officer of Schizophrenia and Related Disorders Alliance of America (SARDAA). “Patients are screaming to have more and better medications.”
Related: Schizophrenia Quotes From People With the Disorder
While the latest studies, according to a press release, showed that Caplyta caused some tiredness (24 percent in the drug group versus 10 percent in the placebo group) and dry mouth (6 percent versus 2 percent), the medication had promising results when it came to metabolic changes. Weight gain, fasting glucose, triglycerides, and total cholesterol were about the same in both the Caplyta and placebo groups.
“Often one of the side effects with schizophrenia medication is metabolic disorder where patients start gaining a lot of weight, and with that comes high cholesterol, diabetes, high blood pressure, and cardiovascular disease,” says Stalters.
Caplyta also did not cause akathisia, a feeling of jitteriness among patients, which is extraordinarily uncomfortable and makes people “jump out of their skin,” the company says. Satlin adds that the drug had a favorable profile when it comes to restlessness and other movement issues.
Related: Schizophrenia Awareness Week Occurs Every May
Promising Signs But Proceed With Caution
Scott Krakower, DO, an assistant unit chief in the psychiatry department at Zucker Hillside Hospital in Glen Oaks, New York, sees promise in this new agent to improve quality of life and function for patients.
“The current drugs aren’t always effective,” he says. “Some patients have no response, partial response, or weight gain or restlessness — so it’s always good to have more options, provided they are safe.”
Research has shown that people with schizophrenia often have trouble sticking to their treatment plan. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study found that 74 percent of patients had discontinued medication within 18 months due to insufficient efficacy, intolerable side effects, or for other reasons.
“If there are more agents out there that are better tolerated and there isn’t weight gain, there may be more compliance,” says Dr. Krakower. “And that is something we are aiming for in patients with schizophrenia.”
Despite the positive indications so far, Krakower also warns that the true effectiveness of the drug can only be gauged once it’s being used by a broader population.
“Whenever any new medication comes out on the market, we have to be very cautious — there is a possibility the agent won’t work out,” he says. “Patients should still be considering all the options out there for schizophrenia and they should speak to their practitioner to decide on what is the best medication.”
New Psychotropic Drug for Schizophrenia Promising in Early Testing
By Megan Brooks
NEW YORK—A new psychotropic drug for treating adults with schizophrenia met its primary endpoint and was “generally well tolerated” in a phase 2a study, according to its developers, Sunovion Pharmaceuticals Inc. and PsychoGenics Inc.
The mechanism of action of SEP-363856 does not involve serotonin- or dopamine-receptor antagonism and is therefore different from currently available antipsychotic agents, they explain in a news release announcing the results.
“For more than 60 years, the treatment of schizophrenia has focused on blocking dopamine receptors. Finding a schizophrenia medication that works outside of a direct action on the dopamine system would be highly desirable, and SEP-363856 may represent such a breakthrough,” Dr. Shitij Kapur, dean of the faculty of medicine, dentistry and health sciences at the University of Melbourne in Australia, commented in the release.
SEP-363856 has shown broad efficacy in animal models of psychosis and depression. The molecular targets responsible for the antipsychotic and antidepressant efficacy of SEP-363856 in pre-clinical models appear to include agonist activity at both the trace amine associated receptor-1 (TAAR1) and the serotonin (5-HT) 1A receptors.
The SEP 361-201 study was a four-week, double-blind, placebo-controlled trial involving 245 adults hospitalized with an acute exacerbation of schizophrenia. They were randomly allocated to SEP-363856 (50 mg or 75mg once daily) or placebo.
Dr. Antony Loebel, head of global clinical development at Sunovion, presented the data during a poster session December 13 at the American College of Neuropsychopharmacology (ACNP) annual meeting in Hollywood, Florida.
After four weeks, patients taking SEP-363856 showed statistically significant and clinically meaningful improvement in the Positive and Negative Syndrome Scale (PANSS) total score (primary outcome) compared with placebo (-17.2 vs. -9.7; P=0.001, effect size = 0.45).
Safety and tolerability of SEP-363856 were generally similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2-based mechanism of action, Dr. Loebel reported.
“The results of the Phase 2 trial are consistent in showing improvement in positive and negative symptoms, without the traditional side effects associated with dopamine blockers,” Dr. Kapur said in the release. “The results need to be replicated in further studies and broader populations, but, if these results hold, it could be a remarkable advance for patients and health care providers, as well as a great new avenue for exploration of new scientific mechanisms for psychotic disorders.”
“Following the results of Study 361-201, Sunovion plans to advance the development of SEP-363856 as quickly as possible. We have not yet initiated the Phase 3 program or disclosed details about its design,” Dr. Loebel told Reuters Health by email.
SEP-363856 is also being studied for Parkinson’s disease psychosis, with additional indications under consideration, the companies said.
American College of Neuropsychopharmacology (ACNP) 2018
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