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The Best of Pill Pushing - Antipsychotics - Making the world a bit more sane - (10/12/2018)

By Dr. Ron Gasbarro
The drug(s) in question: The antipsychotics
Society at the time: Mental illness in the early 20th century 
Before the development of modern psychiatric medications in the 1950s, mental illness was a condition no one talked about and no one could control. Patients were often institutionalized and strapped to beds because they could get violent and hurt themselves and others. 
In the early part of the 1900s, behavioral scientists began to understand what might make a person behave in an erratic way, and what kinds of thoughts and opinions might be attached to what outsiders would deem “madness.” The neurologist and founder of psychoanalysis, Sigmund Freud (1856-1939), was a major influence as he developed theories that attempted to explain unusual behavior. In turn, he devised therapies that aimed to help people who might once have been placed in an asylum or prison with no help at all. However, work advocated by Freud could take months or even years to complete, and some people did not appear to improve when they were under the guidance of psychoanalysis. As a result, practitioners began dabbling in radical cures such as electroshock therapy, hydrotherapy, and lobotomy, hoping to rein in mental illnesses altogether. 
In the 1930s, Portuguese neurologist Egas Monitz pioneered the lobotomy – a procedure in which the nerves in the brain's frontal lobe are severed by inserting tools through the eye socket. Widely accepted as a treatment for mental illness through the 1950s, the process attempted to control various behaviors by altering the section of the brain affecting social conduct. An elaborate system of checks, including interviews with social workers, psychologists, psychiatrists, and the patient, ensured that the irreversible operation was absolutely essential. Rosemary Kennedy, sister of President John F. Kennedy, underwent a failed lobotomy in 1941 that left her permanently incapacitated and hidden in an institution for the rest of her life. The fact that Monitz won a Nobel Prize for Medicine in 1949 for developing this procedure flies in the face of the Hippocratic Oath: “First, do no harm.” The last lobotomies were done in the 1970. Psychiatric drugs made the method obsolete.
What is schizophrenia? [WHO, 2015] 
Schizophrenia is a severe mental disorder that affects more than 21 million people worldwide. Schizophrenia is characterized by distortions in thinking, perception, emotions, language, sense of self and behavior. Common experiences include: Hallucinations (Hearing, seeing or feeling things that are not there); delusions (Fixed false beliefs or suspicions that are firmly held even when there is evidence to the contrary); abnormal behaviors (Strange appearance, self-neglect, incoherent speech, wandering aimlessly, mumbling or laughing to self).
Symptoms tend to come on gradually, begin in young adulthood and can last for decades [APA, 2014]. About 20% of people do well with psychotherapeutic treatment and a few recover completely [APA, 2014]. Social problems, such as long-term unemployment, poverty, and homelessness are common [APA, 2014]. The average life expectancy of people with the disorder is 10 to 25 less than the average [Laursen, 2012]. This is the result of increased physical health problems and a higher suicide rate (about 5%). In 2013 an estimated 16,000 people died from behavior related to, or caused by, schizophrenia [GBD, 2015]. 
Schizophrenia is not a split personality 
The term schizophrenia is commonly misunderstood to mean that affected persons have a "split personality". Although some people diagnosed with schizophrenia may hear voices and may experience the voices as distinct personalities, schizophrenia does not involve a person changing among distinct, multiple personalities; the confusion arises in part due to the literal interpretation of "schizophrenia" which “to split the mind.”
Disease impact [APA, 2014]
Worldwide, schizophrenia is associated with considerable disability and may affect educational and occupational performance. People with schizophrenia are over twice as more likely to die early than the general population. This is often due to physical illnesses, such as cardiovascular, metabolic and infectious diseases. Treatment with medicines and psychosocial support can be effective. Facilitation of assisted living, supported housing and supported employment can be effective management strategies for people with schizophrenia.
Cigarette smoking
Studies across 20 countries show a strong association between schizophrenia and smoking, whereby people with schizophrenia are much more likely to smoke than those without the disease [de Leon, 2005]. For example, in the US, 80% or more of people with schizophrenia smoke, compared to 20% of the general population in 2006 [Keltner, 2006]. This has led to increased mortality from cancer and cardiovascular disease compared with the general population [Keltner, 2006]. Various hypotheses have been proposed as to why schizophrenics smoke at rates disproportional to the general population. The self-medication hypothesis argues that people with schizophrenia use nicotine to compensate for the cognitive deficits that result from schizophrenia, the antipsychotic medication used to treat schizophrenia, or both [McCloughen, 2003].
What is the difference between schizophrenia and psychosis?
Psychosis and schizophrenia are not interchangeable terms. The main difference between the two is that schizophrenia is defined as a disease entity. Psychosis is essentially a broad term for the presence of symptoms like hallucinations and delusions. Examination for all possible physical disorders, psychiatric disorders and side effects of drugs or medications using thorough history-taking, clinical examination, blood tests, and imaging procedures leads to a diagnosis of psychosis. Technically speaking, psychosis implies an impaired perception of reality. A person who suffers from psychosis has less self-control than a person with schizophrenia. Duration of psychosis may last to the maximum of days or weeks. The best treatment of psychosis is an antipsychotic drug. In schizophrenia, there are multiple possibilities.
The good, the bad and the ugly
The first breakthrough drug arrives 
Marketed under the trade name Thorazine® by Smith-Kline & French, chlorpromazine received Food & Drug Administration approval for psychiatric treatment in 1954. Recognized as the first antipsychotic drug, chlorpromazine played a prominent role in the deinstitutionalization movement – a federal policy responsible for the release of thousands of mentally ill patients from American asylums during the 1960s and 1970s.
Chlorpromazine works by blocking dopamine receptors in the brain. (Note: Dopamine is an important neurotransmitter [messenger] in the brain to help regulate movement and emotion; its depletion may cause Parkinson's disease.)  In response to blocking the dopamine receptor, the presynaptic neurons release more dopamine into the synaptic cleft, stimulating the postsynaptic neuron to increase dopamine receptor density.
Blocking the receptors does mean that there are more unbound dopamine and more receptors to respond to it. However, after approximately 3 or 4 weeks, the feedback mechanism that regulates dopamine release based on the activity of the postsynaptic neuron (which is suppressed because chlorpromazine blocks its receptors) begins to fail. This means that the neurons begin to fire in irregular patterns or stop firing altogether. The problem with this is that dopamine does not just make you psychotic; it makes your muscles move. Parkinson’s disease is caused by the death of neurons in the brain that use dopamine as their transmitter. Hence, unpleasant side effects can be experienced that eventually led Thorazine to fall out of favor as new molecules were developed. Such side effects include but not limited to: constipation, sedation, low blood pressure, restlessness and the inability to stop moving, sustained muscle contractions and twitching, and tardive dyskinesia. 
Tardive dyskinesia is irreversible and characterized by repetitive involuntary movements like grimacing, tongue protrusion, lip smacking, puckering and pursing of the lips and rapid eye blinking. Notable side effects from chlorpromazine are presented in the following table [APA, 2014]:

Weight gain

5 times more likely than placebo (40% vs. 8%) to have considerable weight gain


3 times more likely than placebo (30% vs. 10%) to cause sedation

Acute movement disorder

3 times more likely than placebo (6% vs. 2%) to cause easily reversible but unpleasant severe stiffening of muscles


2 times more likely than placebo (17% vs. 8%) to cause parkinsonism (symptoms such as tremor, hesitancy of movement, decreased facial expression)

Decreased blood pressure/dizziness

3 times more likely than placebo (15% vs. 5%) to cause decreased blood pressure and dizziness

Impact of drugs on society
Free again! Free again?
Considering the harsh and invasive treatments for schizophrenia at the time, chlorpromazine was seen as a promising alternative [Lindamood, 2005]. While the pre-Thorazine procedures were intended to control hallucinations and aggressive outbursts in patients, none of these treatments were reliable and offered irreversibly damaging side effects. The easily administered drug was a profound shift away from invasive procedures such as lobotomy. The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases [Turner, 2007].
After its introduction into the US marketplace, chlorpromazine quickly rose to become a staple of asylum medicine. Cash-strapped and overcrowded state hospitals flocked to the cost-effective treatment, but it would not take long for chlorpromazine to extend beyond asylum medicine and be used as a treatment to return mental patients to society.
Likened to prisons and seen as a financial burden, state hospitals had fallen out of favor in the US; small community care centers were viewed as the future of mental health care. With reports of chlorpromazine sending schizophrenic hallucinations and delusions into remission, the drug was now seen as a way for the federal government to realize a vision popularly known as the “deinstitutionalization movement.”
In a 1963 New York Times article titled "President Seeks Funds To Reduce Mental Illness," John F. Kennedy argued that the new drugs made it "possible for most of the mentally ill to be successfully and quickly treated in their own communities and returned to a useful place in society." Consequently, changes to the US mental health system were dramatic. Mental hospital populations, at a high of 560,000 in 1953, dropped to 193,000 by 1975. Unfortunately, these figures do not represent the successful treatment and rehabilitation of schizophrenic patients. The hope that was placed in chlorpromazine's ability to treat schizophrenia was dimmed by evidence of serious side effects. By 1964, about 50 million people worldwide had taken it. Chlorpromazine, now in widespread use for over 60 ears, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug, although not a perfect one.
The consequences of freedom 
The advent of modern psychotropic medications was considered the catalyst for deinstitutionalization in the US. Not entirely true. Large numbers of patients began leaving state institutions only after new laws made unpaid patient labor illegal. Thus, when patients no longer worked for free, the economic feasibility of many state institutions ceased and this led to the closing of many state hospitals [Torrey, 2015].
With the closing of state mental institutions, it became increasingly difficult for mentally ill people to receive treatment in a facility. Many of these individuals were left homeless after deinstitutionalization, making up one-third of the homeless population [Torrey, 2015]. Today the most prominent treatment for the severely mentally ill is incarceration in a correctional facility, where mentally ill individuals do not always receive adequate care for their disorder. 
Although deinstitutionalization has been positive for the majority of patients, it also has severe shortcomings. Expectations that community care would lead to fuller social integration have not been achieved; many remain without work, have limited social contacts, and often live in sheltered environments [Torrey, 1997]. The majority of those who would be under continuous care in long-stay psychiatric hospitals are paranoid and delusional to the point that they refuse help, believing they do not need it, which makes it difficult to treat them. 
Moves to community living and services have led to various concerns and fears, from both the individuals themselves and other members of the community. Over a quarter of individuals accessing community mental health services in a US inner-city area are victims of at least one violent crime per year, a proportion 11 times higher than the inner-city average [Teplin, 2005]. The elevated victim rate holds for every category of crime, including rape/sexual assault, other violent assaults, and personal and property theft [Teplin, 2005]. Clearly, better drugs were needed. 
The drugs that came after Thorazine
Following Thorazine, more antipsychotics gained FDA approval including haloperidol (Haldol®), thioridazine (Mellaril®), thiothixene (Navane®) and fluphenazine (Prolixin®) to name a few. While these drugs have a similar side effect profile as Thorazine, most of them were of higher potency and gave prescribers more options in treating patients who did not respond to Thorazine. These, including Thorazine, were the first-generation antipsychotics also known as the typical antipsychotics.  
Typical antipsychotics are mainly used in the treatment of agitation, acute mania and other such conditions. This drug is divided into 3 classes of low potency, medium potency, and high potency. These drugs can cause extrapyramidal motor control disabilities in patients which may be present even after the medication is discontinued. The symptoms of this include body tremors and rigidity. The drug can also result in weight gain, dry mouth, muscle cramping, and stiffness. A fatal side effect of this drug is neuroleptic malignant syndrome symptoms of which is high fever and altered mental status.
Atypical antipsychotics - also called second-generation antipsychotics - are approved by FDA for use in the treatment of depression, bipolar and acute mania. They are less likely to cause extrapyramidal motor control and tardive dyskinesia disabilities in the patient, these adverse events can occur. They may also result in weight gain, dry mouth, muscle cramping and stiffness. The use of the atypicals may result in extreme weakness and abnormal shifts in sleep patterns. Examples of these atypical include clozapine (Clozaril®), risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), aripiprazole (Abilify®), and ziprasidone (Geodon®).  The drugs in this class act on many receptor types including dopamine and serotonin, but they are more selective for dopamine receptors than the typicals
In 1971, the FDA approved the first atypical for the treatment of schizophrenia, clozapine. It is as effective as typical antipsychotics in relieving the positive symptoms of schizophrenia, such as delusions and thought disorders. In contrast, clozapine does not appear to have any effect on negative symptoms, such as hallucinations. The drug has a lower rate of extrapyramidal symptoms and rarely cause tardive dyskinesia. However, it can cause life-threatening agranulocytosis and for that reason, patients on clozapine have to be monitored closely with regard to their blood counts. 
Both atypicals and typicals are effectively used in the treatment of psychosis. Currently, atypical antipsychotic drugs are preferred over typical antipsychotic drugs as the atypical’s safety profile better than that of the typicals. Withdrawal symptoms are much less with the atypicals as compared to typical antipsychotic drugs. However, the debate is still on as to which of these two groups are more potent.
Where the drugs are today
The antipsychotics have been available for over half a century, beginning with the prototype first-generation drug chlorpromazine and now extending to some 20 different compounds. Symptoms such as hallucinations, delusions, and paranoia are reduced reliably by these drugs. Although these symptoms can be frightening and dangerous for patients, family members, and providers, antipsychotics safely and effectively help people through the crisis of acute psychosis.
However, the long-term management of chronic mental illness is another matter [Insel, 2013]. Recently, results from several studies have suggested that these medications may be less effective for the outcomes that matter most to people with serious mental illness: a full return to well-being and a productive place in society [Wunderink, 2013; McGorry, 2013; Harrow, 2013].
For too many patients, today’s treatments have some major flaws [Insel, 2013]. Novel, more targeted treatments are vital if we are to improve outcomes for all – that is the promise of research. Meanwhile, we need to be thoughtful about the treatments we have. Clearly, some individuals need to be on medication continually to avoid relapse. At the same time, we need to ask whether, in the long-term, some individuals with a history of psychosis may do better off medication. This is a tough call, where known risks need to be balanced against potential benefits. Shared decision-making between patients, families, and providers is essential for long-term management of psychotic disorders.
Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com.
American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing; 2014:101–5. 
de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;76:135-57.
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 385: 117-71.
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World Health Organization (WHO). Schizophrenia Fact Sheet; 2016. Available at: http://www.who.int/mediacentre/factsheets/fs397/en/.
Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013 Jul 3. [Epub ahead of print].  

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