FDA Approved Drugs
Drugs that treat schizophrenia are called antipsychotics. The first antipsychotic drug, chlorpromzaine was discovered by accident in the ealry 1950. Subsequent research showed that chlorpromazine’s antipsychotic properties were due to its antagonism of dopamine receptors in the brain. That finding resulted in the development of other typical antipsychotics, which treat positive symptoms but not negative symptoms and have a number of problematic side effects, including extrapyramidal symptoms (“EPS”), tardive dyskinesia, prolactin elevation (hyperprolactinemia), and sudden decrease in blood pressure (orthostatic hypotension).
Researchers discovered clozapine in the early 19601. It was the first “atypical” antipsychotic, in that it had a diminished propensity to cause EPS and was useful for treating both positive and negative symptoms of schizophrenia. However, Clozapine had serious potential side effects including orthostatic hypotension, frank hypotension, and agranulocytosis (a life threatinging decrease in white blood cells). Due to those side effects clozapine was withdrawn from clinical trails in the 1970s. The FDA did finally approve clozpine in 1990, but only for treatment resistant or treatment intolerant patients, subject to regorous blood testing.
Risperidone: In 1994, the FDA approved risperidone, the first post-clozpine atypical antipsychotic. Risperidone is a medication that works in the brain to treat schizophrenia. It is also known as a second-generation antipsychotic (SGA) or atypical antipsychotic. Risperidone rebalances dopamine and serotonin to improve thinking, mood, and behavior. Risperdal, the brand name for Risperidone, is a second-generation antipsychotic (SGA) drug used to treat schizophrenia and bipolar disorder. Sometimes, the drug gets subscribed to those with autism, dementia, or obsessive-compulsive disorder. Developed by Johnson and Johnson subsidiary Janssen-Cilag, the FDA approved the drug in December 1993.
Starting in 2010, Johnson & Johnson became the subject of thousands of lawsuits by men alleging that Risperdal use caused them to experience a condition known as gynecomastia or growth of excessive breast tissue. This change is said to be due to elevated prolactin levels caused by taking risperidone. There is research that suggests a link between Risperdal and increased prolactin levels. See Forbes
Since then the FDA has approved seven other atypical antipsychotics: olanzapine (1996), quitiapine (1997), ziprasidone (2001), aripiprazole (2002, paliperidone (2007), asenpaine (2009) and iloperidone (2009). Although clozpine remains the “gold standard” with respect to efficacy, the other atypical antipsychotics are considered at least as effective as typical antipsychotics for treating positive symtoms while also treating negative symptoms and causing fewer EPS side effects.
In 2002, the FDA approved Abilify® which has the active ingredient aripiprazole. Abilify® is marketed by Otsuka Pharmaceutical Co., Ltd. not only for the treatment of schizphrenia but also bipolar disorder, irritability associated with autistic disorder in pediatric patients, and as an add-on treatment for depression. It has been commercially successful. In 2009, its sales were $3.3 billion.
Brexpiprazole (Rexulti): is a medication that has similar effects to two other atypical antipsychotics, cariprazine (Vraylar) and aripiprazole (Abilify) but brexpiprazole does not have approval in the United States for treating bipolar mania. Past studies suggest that brexpiprazole is an effective adjunctive treatment for major depressive disorder and schizophrenia. The active drug in Rexulti is brexpiprazole. This drug belongs to a class of medications called atypical antipsychotics. (A medication class is a group of drugs that work in a similar way.) Rexulti is currently only available as a brand-name medication.
Drugs in Clinical Trial
Current antipsychotic medicines rely on the same primary pathway and approach of inhibiting D2 dopamine receptors, and frequently 5HT-52A serotonin receptors, and are often used by physicians to address a wide range of psychiatric conditions, including schizophrenia and bipolar disorder, among others. However, these drugs have many side effects such as weight gain.
Investigators have recently been working with different neurotransmitters such as acetylcholine, located in the cholinergic pathway. Within the cholinergic pathway, acetylcholine interacts with a type of receptor called the muscarinic receptor. There are five distinct muscarinic receptors, M1-M5, found in the brain as well as various peripheral tissues.
Muscarinic receptor agonists emerged in the 1990s as a promising new approach for treating psychosis and cognitive impairment. The link between muscarinic receptor stimulation in the central nervous system (CNS), particularly the stimulation of M1 and M4 receptors, and the reduction of symptoms of psychosis and improvement in cognition, has been well studied and is supported by research from preclinical studies and clinical trials. However, the successful development of a therapy targeting muscarinic receptors has been limited by undesirable side effects that are believed to arise primarily as a result of stimulation of muscarinic receptors in peripheral tissues.
Recently, Karuna Therapeutics has been investigating therapy targeting muscarinic receptors which do not have these adverse side effects. Their lead drug KarXT (xanomeline-trospium) is the lead candidate, currently being evaluated in Phase 3 clinical trials as both a monotherapy and adjunctive therapy for the treatment of schizophrenia, as well as for the treatment of psychosis in Alzheimer’s disease.
Cobenfy (Bristol Myers Squibb) is a medication approved by the FDA for teh treatment of schizophrenia in adults. It is a combination of xanomeline and trospium chloride and works by activating muscarinic receptors in the brain. This is a diferent approach compared to conventional antipsychotics that block dopamine receptors. Xanomeline activates the receptors while trospium chloride helps prevent xanomeline from affecting other parts of the body.
Natural Products
Sodium benzoate may be beneficial as an add-on therapty (1 gram/day) in schizophrenia.