schizophrenia

Schizophrenia Differential Diagnosis & DSM5

On today’s episode of the podcast, I am interviewing with Dr. Ariana Cunningham. We cover the DSM5 criteria for schizophrenia and the differential diagnoses for schizophrenia.

Joseph Wong (MS3), Ariana Cunningham, M.D., David Puder M.D.

Diagnosing schizophrenia  

Doctors and therapists need to be able to rule everything else out before they can land on schizophrenia as an official diagnosis. The specific symptoms are known as “first-rank symptoms,” which we will cover later in the article, that will help with diagnosing patients (Schneider, 1959). Eighty-five percent of people with schizophrenia endorse these symptoms, but be wary of jumping to conclusions, because they are not specific to schizophrenia and, in some studies, are also endorsed by bipolar manic patients (Andreasen, 1991).

DSM5 (Diagnostic and Statistical Manual of Mental Disorders 5th ed.)

Schizophrenia is a clinical diagnosis made through observation of the patient and the patient’s history.

  • There must be 2 or more of the characteristic symptoms below (Criterion A) with at least one symptom being items 1, 2 or 3. These symptoms must be present for a significant portion of time during a 1 month period (or less, if successfully treated).

  • The patient must have continuous, persistent signs of disturbance for at least 6 months, which includes the 1 month period of symptoms (or less, if successfully treated) and may include prodromal or residual periods.

    • For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care, are markedly below the level achieved prior to the onset.

    • If the onset is in childhood or adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational achievement.

Criterion A:

A. Positive symptoms (presence of abnormal behavior)

1. Delusions

2. Hallucinations

3. Disorganized speech (eg, frequent derailment or incoherence)

4. Grossly disorganized or catatonic behavior

B. Negative symptoms (absence or disruption of normal behavior)

5. Negative symptoms include affective flattening, alogia, avolition, anhedonia, asociality.

Development, Course and Risk Factors

Psychotic symptoms of schizophrenia typically occur in young adulthood (late teens to mid-30s) (American Psychiatric Association, 2013). About 80% of schizophrenia presents with acute onset, intermittent symptoms and few/no symptoms while about 20% present with insidious onset, continuous symptoms and poorer outcomes (Bleuler, 1978). In terms of age of onset, it has been well documented that males present earlier than females (early to mid 20s for males vs late 20s for females) (Patel, Cherian, Gohil & Atkinson, 2014).

There are two key factors that have been associated with poorer prognosis. Earlier age of onset, which is highly associated with schizophrenia in males, has been well-documented to be associated with a poorer prognosis (Kao & Liu, 2010). The deficit form of schizophrenia (persistent negative symptoms of schizophrenia) have also been shown to be associated with a poorer prognosis (Kirkpatrick, 2008).

The highest risk factors for schizophrenia have been tied to genetic factors such as having an affected immediate family member or being the offspring of an immigrant from certain countries (Torrey, 2012). Molecular genetics have also been used to show that genetic inheritance is highly associated with schizophrenia, although it is not currently known how much genetic variation increases the risk for schizophrenia (Ripke, 2014). Non-genetic risk factors for schizophrenia include infectious causes such as Toxoplasmosis, living in an urban environment, birth seasonality and maternal exposure to influenza (Torrey, 2012).

Although functional recovery is rarer early on in the course of schizophrenia, the good news is that timely and intensive treatment can impact functional recovery early in the illness (Robinson, 2004). Patients who had more intensive intervention showed greater improvement in quality of life, higher functioning in school/work, and less psychopathology (Kane, 2016).

Differential diagnosis

When I see a patient that presents with these symptoms, the first thing I consider is substance use. I check if they had prior urine drug screens in their medical records, physical signs of substance use (e.g. poor dentition, track marks) and history of motor vehicle accidents. Even if history and physical condition do not suggest substance use, it’s common practice to order a urine drug screen on anyone coming into an inpatient psychiatry unit and look at prior drug screens in the medical record.

Other considerations include psychosis due to another medical condition (e.g. Wilson’s disease), personality disorder (long history of passive suicidal intent dating back to adolescence for borderline personality disorder, odd beliefs associated with Cluster A personality disorders, etc.), mania (e.g. rapid talking, grandiosity, decreased need for sleep) or severe depression (long progressive history with eventual psychosis).

For patients manifesting with some, but not all of the symptoms of schizophrenia, here is a list of differential diagnoses. With schizophrenia being a diagnosis of exclusion, it is important to consider all possible diagnoses.

A. Based on timeline of symptoms (American Psychiatric Association, 2013):

  • Brief Psychotic Disorder: Presence of > 1 positive symptom lasting 1 day to 1 month .  

    • Can be precipitated by stressors or have peripartum onset.

  • Schizophreniform: Same diagnostic criteria as schizophrenia, except lasting for at least 1 month, but less than 6 months. May be the start of schizophrenia, but not all patients with schizophreniform go on to be diagnosed with schizophrenia.

    • Social and occupational decline do not need to be present like they do in schizophrenia.


B. Presence of mood disorder features (APA, 2013)

  • Schizoaffective: Meets criteria for schizophrenia as well as major mood disorder (manic episodes or significant depressive episodes that have occurred at different times in the person’s life).

    • Schizoaffective disorder is differentiated by major mood disorder with psychotic features by the presence of > 2 weeks of psychotic symptoms without major mood episode.

  • Bipolar Mood Disorder: Bipolar I: Meets criteria for current or past manic episode that could be preceded or followed by hypomanic or major depressive episodes. Bipolar II: Meets criteria for current or past hypomanic episode and major depressive episode.  

    • Typically, a manic patient will take a few days to fall asleep when they are in an episode even when on significant medications.

  • Major Depressive Disorder Severe with Psychotic Symptoms: Psychotic symptoms (e.g. delusions or hallucinations) exclusively occur during a major depressive or manic episode, which is differentiated by schizoaffective disorder, which is characterized by > 2 weeks of psychotic symptoms with major mood episode.

    • There is a long period of depression leading up to the psychotic symptoms. The patient usually by the time they have psychosis has been depressed for months if not years. The psychosis and depression will not change in 2-3 days like they can in someone hospitalized with borderline personality disorder.  


C. Personality Disorders (APA 2013):

  • Borderline Personality Disorder (Cluster B): Long-standing pattern of unstable interpersonal relationships, impulsive behavior (e.g. sexual or self-harming), and mood instability (e.g. feelings of emptiness, intense dysphoria) .

    • A borderline personality disorder patient will have negative inner “voices” that will lead them to fear they are hearing things, but they can put on a social veneer and appear put together. A schizophrenic patient cannot put on a social veneer when in a disorganized and psychotic state.

    • These patients also have a history of passive suicidality dating back to adolescence.

  • Schizotypal personality (Cluster A): Long-standing pattern of odd or eccentric beliefs and/or perceptual disturbances that do not rise to the level of delusions or hallucinations.

    • Shares many similar symptoms as schizophrenia, but schizotypal personality disorder can be distinguished from schizophrenia as the personality disorder is present before the onset of psychotic symptoms and persists even when the psychotic symptoms vs. a period of persistent psychotic symptoms in schizophrenia.  

  • Schizoid personality (Cluster A): Long-standing pattern of little interest in social relationships or intimacy.

    • Shares similar symptoms as schizophrenia such as flattened affect, but does not present with psychosis.

    • Schizoid personality disorder can be distinguished from schizophrenia as the personality disorder is present before the onset of psychotic symptoms and persists even when the psychotic symptoms vs. a period of persistent psychotic symptoms in schizophrenia.  

D. Other considerations:

  • Substance-induced psychosis: Symptoms occur during intoxication or acute withdrawal and do not persist after the individual is sober.

    • The people who are coming off of methamphetamines typically want to sleep the first few days and are irritable coming off of meth, while people with schizophrenia will talk with you for a bit, and be awake during the day (although sometimes lying in bed doing nothing).  

    • THC has been associated with an increased risk of developing psychosis. A meta-analysis of 18 studies involving 66,816 individuals gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to nonusers (Marconi, 2016).

  • Psychosis due to a general medical condition or medication: Symptoms can occur with other medical conditions such as CVA or TBI, Wilson’s disease, porphyria, or syphilis infection (watch for it in HIV patients) as well as medications (e.g. steroids) and certain dietary supplements.

  • Delusional disorder: One or more delusions (false belief system) that are fixed and persistent, lasting for > 1 month.

    • Can be differentiated from schizophrenia by the lack of other symptoms besides delusions. An exception to this is that patients may have olfactory or tactile hallucinations consistent with the delusion, but they won’t have auditory hallucinations that is most commonly associated with schizophrenia (Chaudhury, 2010; Opjordsmoen, 2014).

    • Functioning is also not impaired compared to schizophrenia.

  • Pervasive developmental disorders: May present with symptoms resembling psychosis or negative symptoms; however, an important factor to consider before diagnosing schizophrenia is the patient’s developmental pattern.

    • For example, for a 3 - 5 year old child, imaginary friends are common for that developmental stage and shouldn’t be instantly labelled as a visual hallucination- so when you listen to their vocabulary consider what age they are even if they look physically much older (Taylor & Mottweiler, 2008).

    • “An additional diagnosis of schizophrenia should only be made in a patient with autism spectrum disorder or communication disorders if psychotic symptoms are present for at least a month” (APA 2013).

For more on schizophrenia check out these other episodes:

Schizophrenia with Dr. Cummings: Controversies, Brain Science, Crime, History, Exercise, Successful Treatment

The History and Use of Antipsychotics with Dr. Cummings  



Do I have Schizophrenia?

On today’s episode of the podcast, Ariana Cunningham and I continue our discussion from the first episode about schizophrenia, focusing on the clinical manifestations of the disease.

Ariana Cunningham, M.D., David Puder, M.D., 

Clinical manifestations 

Many people worry that they have schizophrenia. I receive messages or inquires often of people asking about symptoms and manifestations. If you have those types of questions, or if you’re a mental health professional who needs to brush up on symptoms and medications, this article should help you.

There are many clinical observations of how schizophrenia presents itself. Cognitive impairments usually precede the onset of the main symptoms[1], while social and occupational impairments follow those main symptoms. 

Here are the main symptoms of schizophrenia:

  • Hallucinations: a perception of a sensory process in the absence of an external source. They can be auditory, visual, somatic, olfactory, or gustatory reactions.

  • Most common for men “you are gay”

  • Most common for women “you are a slut or whore”

  • Delusions: having a fixed, false belief. They can be bizarre or non-bizarre and their content can often be categorized as grandiose, paranoid, nihilistic, or erotomanic 

  • Erotomania = an uncommon paranoid delusion that is typified by someone having the delusion that another person is infatuated with them.

  • This is a common symptom, approximately 80% of people with schizophrenia experience delusions.

  • Often we only see this from their changed behavior, they don’t tell us this directly.

  • Disorganization: present in both behavior and speech. 

  • Speech disorganization can be described in the following ways:

  • Tangential speech – The person gets increasingly further off the topic without appropriately answering a question.

  • Circumstantial speech – The person will eventually answer a question, but in a markedly roundabout manner.

  • Derailment – The person suddenly switches topic without any logic or segue.

  • Neologisms – The creation of new, idiosyncratic words.

  • Word salad – Words are thrown together without any sensible meaning.

  • Verbigeration – Seemingly meaningless repetition of words, sentences, or associations

  • To note, the most commonly observed forms of abnormal speech are tangentiality and circumstantiality, while derailment, neologisms, and word salad are considered more severe.

  • Cognitive impairment:

  • Different processing speeds 

  • Verbal learning and memory issues

  • Visual learning and memory issues

  • Reasoning/executive functioning (including attention and working memory) issues

  • Verbal comprehension problems

  • Mood and/or anxiety: mood and anxiety disorders occur at a higher rate in schizophrenic patients than in the general population, and for this reason it is important for providers to . Estimates of the lifetime prevalence of depression in schizophrenia vary widely—from 6 to 75%—based on differing study characteristics including varying definitions of depression, patient settings, and durations of observation (Conus et al, 2010Hausman et al, 2002McRenolds, 2013). There is a higher prevalence of anxiety in patients with early-onset schizophrenia than in patients with later onset. 

  • Suicidality: People with schizophrenia have a higher rate of suicide than the general population. Generally, 5% of 10% of all completed suicides are people with schizophrenia (Hor et al, 2010; Arsenault et al, 2004).

There are also some associated signs we want to make sure you are aware of, even though they aren’t considered central to the diagnosis of schizophrenia:

  • Neurological signs aka “soft signs” include slight impairments of sensory integration and motor coordination (Heinrichs et al, 1988). Some examples of this include: R-L confusion, agraphesthesia (the inability to recognize letters or numbers traced on the skin, usually on the palm of the hand), olfactory dysfunction, astereognosis (the inability to identify familiar objects by touch alone). Be sure if you see one of these symptoms that you consider the possibility that they could be a side effect of medications.

  • Catatonia is another important state sometimes associated we would like you to be familiar with. A helpful tool to use when evaluating a patient is the Busch Francis Catatonia rating scale which lists all the criteria associated with catatonia and 0-3 rating scale for each.

  • Interestingly, another association we see in people with schizophrenia is that there are higher rates of diabetes, hyperlipidemia, and hypertension. In fact the life expectancy is reduced 10-20 years compared with the general population. The main medical mortality is heart disease.

In conclusion

On the podcast episode, we discuss the clinical manifestations of schizophrenia and what you would be looking for when making a diagnosis. The more we understand about this disorder—how the symptoms manifest, in what order they often present, and how to differentiate these signs from adverse drug reactions, and expected comorbidities—the better. Improved understanding of this will improve diagnosis and equip providers to implement treatment sooner, thus improving the prognosis and projected functionality of patients with schizophrenia.

In the next podcast we will be discussing the following topics:

  • How the disease progresses?

  • DSMV definition and diagnostic criteria

  • Differential diagnoses

  • Symptom management:

  • Pharmaceutical

  • Non pharmaceutical

Here are some further episodes on schizophrenia:

How Psychiatric Medications Work with Dr Cummings

Schizophrenia with Dr. Cummings

Schizophrenia in Film and History



Schizophrenia in Film and History

In today’s episode of the podcast, Ariana Cunningham and I talk about schizophrenia. Ariana is a psychiatry resident who is also on my research team.

David Puder, M.D., Ariana Cunningham, M.D.

What is schizophrenia?

It is a psychotic disorder that typically results in hallucinations and delusions, leaving a person with impeded daily functioning. The word schizophrenia translates roughly as the "splitting of the mind," and comes from the Greek roots schizein ( "to split") and phren- ( "mind").

The onset of the disease typically occurs in young adulthood; for males, around 21 years of age, for females, around 25 years of age.

We don’t know exactly what causes schizophrenia. There are certain predictors for it, and as I discussed the basics and pharmacology a previous podcast, frequent marijuana use can increase the risk of a psychotic or schizophrenic illness to about 4 times what it would be without THC use.

History of schizophrenia

Sometimes, in ancient literature, it can be difficult to distinguish between the different psychotic disorders, but as far as we know, the oldest available description of an illness resembling schizophrenia is thought to have existed in in the Ebers papyrus from Egypt, around 1550 BC. Throughout history, in groups with religious beliefs, the misunderstanding of the psychopathologies caused people to paint those with mental health disorders as receiving divine punishments. This theme of divine punishment continues today in some parts of the world.  

It wasn’t until Emil Kraeplin, a german psychiatrist (1856-1926) that schizophrenia was suggested to be more biological and genetic in origin. In around 1887, Kraeplin differentiated what we call schizophrenia today from other forms of psychosis. At that time, he described schizophrenia as dementia of early life.

In 1911, Eugen Bleuler introduced schizophrenia as a word in a lecture at a psychiatric conference in Berlin (Kuhn, 2004). Bleuler also identified the positive and negative symptoms of schizophrenia, which we use today.

Kurt Schneider, a German psychiatrist, coined the difference between endogenous depression and reactive depression. He also improved the diagnosis of schizophrenia by creating a list of psychotic symptoms typical in schizophrenia that were termed “first rank symptoms.”

His list was:

  • Auditory hallucinations

  • Thought insertion

  • Thought broadcasting

  • Thought withdrawal

  • Passivity experiences

  • Primary delusions

  • Delusional perception (the belief that a normative perception has a certain significance)

Sigmund Freud furthered the research, believing that psychiatric illnesses may result from unconscious conflicts originating in childhood. His work eventually affected how the psychiatric world and society generally viewed the disease.

The lack of understanding of the disease is a dark history, and it is still deeply stigmatized, but psychiatry has made massive leaps in understanding schizophrenia and changing how it is viewed in modern society.

Nazi germany, the United States, and other Scandinavian countries (Allen, 1997) used to sterilize individuals with schizophrenia. In the Action T4 program in Nazi Germany, there was involuntary euthanasia of the mentally unwell, including people with schizophrenia. The euthanasia started in 1939, and officially discontinued in 1941 but didn’t actual stop until military defeat of Nazi Germany in 1945 (Lifton, 1988). Dr. Karl Brandt and the chancellery chief Philipp Bouhler expanded the authority for doctors so they could grant anyone considered incurable a mercy killing. In reading about this event, it seems that this caused approximately 200,000 deaths.

In the 1970’s, psychiatrists Robins and Guze introduced new criteria for deciding on the validity of a diagnostic category (Kendell, 2003). By the 1980’s, so much was understood about the disease that the DSM (Diagnostic and Statistical Manual of Mental Disorders) was revised. Now, schizophrenia is ranked by World Health Organization as one of the top 10 illnesses contributing to global burden of disease (Murray, 1996).

Unfortunately, it is still largely stigmatized, leading to an increased schizophrenia in the homeless population, some estimates showing up to 20% vs the less than 1% incidence in the US average population.

In conclusion

On the podcast episode, we discuss the media’s portrayal of schizophrenia. Although media paints mentally ill as often violent, on average people with mental illness only cause 5% of violent episodes. This is just one example of how the stigma is furthered.

The more we understand about this disorder—what causes it, how we can help, how we can provide therapy and medicate and treat patients—the better. Getting rid of the stigma by learning the history and also moving beyond preconceived ideas to the newest science will also help de-isolate people with schizophrenia and help support them in communities, giving them a chance at a normal, healthy life.




The History and Use of Antipsychotics

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In my last post, Dr. Cummings and I talked about what psychopharmacology is, how medicine works in our body, and what factors affect medicine absorption rates.

In the latest podcast, Dr. Cummings and I talked about antipsychotics, the particular branch of psychopharmacology that deals with medicines that treat psychotic experiences and other mental disorders, such as:

  • Schizophrenia

  • Severe depression

  • Severe anxiety

  • Bipolar disorder

  • Psychosis exhibiting hallucinations and delusions

The history of first generation antipsychotics

The use of antipsychotics as medication began in 1933 in France. The research around developing antihistamines evolved into the introduction of promethazine. This drug produced sedative side effects, so doctors started prescribing it before surgeries as a calming agent.

Eventually, a doctor studied the derivatives of promethazine, altered it, and developed chlorpromazine. It was mostly used as a pre-surgery anti-anxiety pill, until psychiatrists took note of the calming effect of the drug and began prescribing it to their patients.

Prior to chlorpromazine, the options for treating psychotic patients were electroconvulsive therapy, hydrotherapy, and putting patients in an insulin coma. None of those are antipsychotic in nature.

When two psychiatrists, Dr. Delay and Dr. Deniker, gave 38 psychotic patients a test round of chlorpromazine, they noticed the patients were calmer, and also less psychotic—they had less delusional thinking, fewer hallucinations, and fewer psychomotor-agitation symptoms. Deniker and Delay began giving talks on the benefits of the drug, and in 1955, chlorpromazine became available in the United States. Chlorpromazine is still used today as a treatment for different mental illnesses and mood disorders.

Once the government saw the positive effects of chlorpromazine, it began to shut down mental health facilities. There was no longer as large of a need to house psychotic patients, and they saw an opportunity to cut costs. However, they did not create adequate sources in the community for ongoing care. California alone is estimated to have 40-60% of homeless people that have a mental disorder.

Once chlorpromazine became a success, pharmaceutical companies rushed to create their own version of an antipsychotic drug. Because chlorpromazine was the grandfather of the first generation of antipsychotic drugs, the rest of that generation can be categorized by their ability to merely block dopamine D2 receptors in the brain.

In repeated studies, dopamine antagonism is responsible for 92% of their effectiveness. It also led to the thought that people were psychotic because they had too much dopamine. Since then we have found that their are much more complex psychopharmacological dynamics going on in psychosis.   

Second generation antipsychotics

The next set of antipsychotics that came on the market were clozapineolanzapine, risperidone, and other related drugs. Those medications had less effects on motor movement than the first generation drugs.

Clozapine is a poor antagonist of dopamine- blocking 30-40% of dopamine receptors but also promotes the activation of glutamate through activation of NMDA receptor, which increases activity in the frontal lobe (which helps with schizophrenia’s negative symptoms).  

Clozapine had more system-wide changes than just dopamine suppression, and it had more positive response from patients. It was more effective—40-60% of people who won’t respond to a first generation antipsychotic, do respond to clozapine.

However, in Finland in 1975, 6 people taking clozapine died due to agranulocytosis (lowered white blood cell count, leading to a severe lack of immunity). A lowered neutrophil count (called agranulocytosis) can show potential problems with fighting off normal bacteria we live with all the time.  When patients are on clozapine, initially they need weekly blood checks for this reason.

Despite the risks, clozapine can be an incredible drug—I have one patient who was schizophrenic and homeless, and she is now back in school and recently graduated with a perfect GPA! People who had been dysfunctional for decades, who are given clozapine, can become extremely high functioning.  Key to success here was her willingness to work with me, despite having to try different things before something worked. 

A trial run on a antipsychotic should be done at a minimum of 6 weeks, and blood tests must be conducted to make sure that the concentration of the medicine is at good therapeutic-dose levels. Dosage alone is sometimes not enough because we all metabolise drugs so differently.  I have uploaded recommended levels in my resource page.

Third generation antipsychotics

What is deemed the third generation of antipsychotics, aripiprazole and brexpiprazole are partial dopamine receptor agonists.  They keep dopamine at a max of 25% in the brain which due to the high affinity to the receptor it does not vary much based on dose.  

The good thing about this generation of drugs is that they don’t lower blood pressure, cause insulin resistance, and are not sedating in nature.

It works for some people, it doesn’t for others. But when it does work, it works really well.

Side effects of psychiatric medicines

Akathisia is the inability to stay still, characterized by a feeling of inner busyness. It is a miserable side effect, exhausting to the patient.

If someone is experiencing this, they should immediately call their psychiatrist or go to an emergency room.

One of Dr. Cumming’s patients described it as “ants running up and down the bones of his legs.” It usually involves an anxious feeling, and a desire to move the lower extremities of the legs. Akathisia can be caused by any drug that lowers dopamine (including SSRIs).

This syndrome is so complex because it involves several compounds, including dopamine, norepinephrine, acetylcholine, and serotonin inputs. Options for treatment include: choosing a lower dosage, picking another dopamine antagonist that is less strong (quetiapine or clozaril), or prescribing a drug like amantadine, propranolol, mirtazapine or clonazepam (more nuance in the podcast on this).

It is a harmful disorder, and one to watch out for in patients. If a patient is sent home from the hospital experiencing these symptoms, but is not properly vetted for akathisia, a doctor could be subject to serious legal repercussions.

The questions to test a patient for akathisia are:

  • Is the person moving? Can they not sit still?

  • What is their internal sense of restlessness and anxiety?

  • How much are they distressed by these feelings?

Acute dystonia involves muscle spasms and it affects movement, causing the posture to twist abnormally. It can be painful for patients to experience. This occurs because of too little dopamine in the basal ganglia part of the brain.

Parkinsonism involves muscle stiffness and slower movements. It’s usually uncomfortable, but not a miserable side effect. This also occurs because of too little dopamine in the basal ganglia part of the brain.

The future of antipsychotics

With each generation of new medicines, we’ve gotten closer to being able to help people stabilize their psychosis. We haven’t been able to achieve complete wellness.

Dr. Cummings says he has hope that with further advances in the medical field, we will be able to identify who is at risk. There is hopeful data that we may be able to one day prevent the development of schizophrenia.


History of Antipsychotics (notes by Arvy Tj Wuysang).

  • 1933, France

    • Initiative to develop antihistamine as treatment began

    1. 1947

      • Promethazine

        • Produced sedation and calmness in animal models

        • Not highly effective in humans, but found to provide calmness in preoperative settings

    2. 1950

      • Discovery of Promethazine Derivatives, especially Chlorpromazine

        • Initially tried in a surgical military hospital in France by Dr. Henri Laborit (1914-1995)

        • Successful in making people calm and indifferent to impending surgery

        • The medication was tried it in a volunteer

          • The individual reported favorable effects, until he stood up and promptly fainted

          • Determined as not safe in pre-operative setting because it was too effective as alpha-adrenergic antagonist in lowering blood pressure

    3. 1952

      • Dr. Pierre Deniker (1917-1998), psychiatrist, with Dr. Jean Delay (1907-1987), his superintendent in Sainte-Anne’s Hospital in Paris, led the Chlorpromazine introduction as a psychopharmacologic agent

        • They were interested in the calming effect of the drug

        • Tried the drug in psychotic agitated patients

          • Treatment options in those days were limited to:

            • Electroconvulsive Therapy

            • Hydrotherapy

            • Insulin coma

          • None of which were antipsychotic in nature

        • Tried it in 38 patients, made patients calmer, and less psychotic!

          • Especially effective for positive psychotic symptoms like hallucinations, delusional thinking, psychomotor agitation

        • Findings were impressive enough that Deniker began giving talks about the drug, including a conference in Montreal, that led to its introduction in North America

    4. 1955

      • Chlorpromazine was approved for usage as antipsychotic in the US

      • Subsequently used worldwide

      • Led to the deinstitutionalization of a lot of psychotic patients

        • Created a problem of lack of follow up of psychotic patients

          • I.e. California has around 357,000 homeless individuals, estimated 40-60% suffer from mental disorder with schizophrenia spectrum highly represented in that percentage

          • State spends about $200,000 per year per person to care for people committed to state hospitals. Funds committed to patients that are discharged from state hospitals are very minimal.

      • Led to development of a whole host of antipsychotic agents

    5. 1960s

      • There was an explosion in the invention of antipsychotic drugs

      • US FDA took a stance, did not allow approval of antipsychotic drugs that are not clearly better than chlorpromazine or haloperidol

      • 1st generation antipsychotics all work by blocking Dopamine D2 receptors in the brain, counts for 92-23% of variance in mechanism

      • Led to the simplistic dopamine hypothesis of psychosis

    6. 1958

      • 2nd generation antipsychotic discovered by Eichenberger and Schmutz from the Swiss pharmaceutical company Wander AG, Clozapine

      • Created because 2 other -antadine antipsychotics have been successful, Loxitane (Loxapine) and Perlapine

      • Clozapine was initially thought of as a failure because it did not produce dystonia in white lab mice, as expected in 1st generation antipsychotics where it blocks dopamine effects in the brain

      • Clozapine found to be a poor antagonist to dopamine, only blocks 30-40% of dopamine receptors. Although, it promotes release of glutamate, by binding to an allosteric site for glycine in the NMDA receptor, which in turn increases activity in the frontal lobe and suppresses dopamine release in the mesolimbic system.

      • A number of small studies in the 1960s found that patients that don’t respond to 1st generation antipsychotics responded well to Clozapine treatment by showing better response of both positive and negative symptoms of schizophrenia.

    7. 1970s

      • 1972, Clozapine usage was introduced in Austria

      • 1974, Clozapine usage was introduced in Germany

      • 40-60% of people that did not respond well to 1st generation antipsychotics, responded well to Clozapine

      • 1975, 5 people in Finland died after Clozapine treatment due to agranulocytosis

        • Clozapine found to trigger formation of antibodies targeting bone marrow cells that make neutrophils and essentially shut down a person’s immune system

        • Must monitor Absolute Neutrophil Count closely when prescribing Clozapine

          • Monitor weekly for 6 months, then every 2 weeks for another 6 months, and monthly for another year (in the USA)

          • Risk for agranulocytosis decreases with time: peaks at 4 months of exposure at about 1.3%, .38% after 1 year of exposure, .06% after 2 years of exposure

    8. Clozapine usage in the US today

      • Siskind, D., McCartney, L., Goldschlager, R., & Kisely, S. (2016). Clozapine v. first-and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. The British Journal of Psychiatry, 209(5), 385-392.

      • 15-20% of patients in California State Hospitals are on Clozapine, 53% in New York State

      • Response rates to drugs other than Clozapine is pretty miserable in State Hospitals

      • Olanzapine response rate even at high plasma concentrations is only 9%, compared to 40-60% for Clozapine. Every other antipsychotics’ response rate is between 0-5% for the severely psychotic, mentally ill patients.

      • If patients meet Kane criteria (after John M. Kane)---treatment failure after two clearly adequate trials of antipsychotic treatment with minimum of 6 weeks duration with therapeutic plasma concentration---odds that they will respond to anything other than Clozapine is fairly low.

      • Common mistake that clinicians make is to go by dosage as a measure of whether a person is receiving adequate medication

        • Dosages only weakly correlates with plasma concentration since the metabolism of antipsychotic drugs is so variable

        • Measuring plasma concentration to reach therapeutic levels is crucial in antipsychotic drugs administration, especially in patients who are seemingly refractory to treatment, to ensure adequate treatment

      • Akathisia as side effect of antipsychotics

        • Very rarely happens with Clozapine use

        • Akathisia is a very miserable side effect of antipsychotics, described as “ants crawling up and down the bone of your legs” by a particular patient

        • Characterized both by internal sense of anxiety and a near irresistible urge to move

        • Barnes Akathisia Rating Scale, most commonly used to measure akathisia symptoms. Based on three main factors:

          • Objective movement

          • Internal sense of restlessness and anxiety

          • How much are they distressed by these feelings

        • Akathisia is a concerning and common reason for malpractice

        • Underlying pathophysiology of akathisia is distinct compared to other extrapyramidal symptoms, involves not only dopamine and acetylcholine. It also involves norepinephrine and serotonin inputs to basal ganglia, makes it a difficult syndrome to treat successfully.

        • Treatment options for akathisia:

        • Akathisia may present as side effect in SSRIs and antiemetics (compazine)

  • Expected or Therapeutic plasma concentration ranges for antipsychotics and mood stabilizers

  • Aripiprazole (Abilify)

    • 3rd generation antipsychotics, partial dopamine agonist

    • Has high affinity for dopamine receptors, higher than 1st and 2nd generation antipsychotics. If Aripiprazole is present at therapeutic concentrations, 1st and 2nd generation will have very little interaction with dopamine receptors.

    • Keeps dopamine signaling at about 25% of dopamine’s maximum signal transduction, tends to produce all or nothing response in terms of treating psychotics. Not much ability to vary where dopamine is blocked because of it’s high affinity.

    • Side effect profile is very favorable. Largely metabolically neutral, tend not to cause weight gain, glucose intolerance, and lipid abnormalities. Low affinity for alpha receptors or histamine receptors, is not very sedating and does not lower blood pressure.

    • Use outside of schizophrenia

      • I.e. risperidone and olanzapine also exhibit utility as mood stabilizer and antidepressant.

      • 3rd generation antipsychotics also tend to improve mood, driven by quality of the molecules and in part by the desire of pharmaceutical companies to broaden their market

      • Use in dissociative state, such as Borderline Personality Disorder

        • Antipsychotics can help bring patients out of dissociative state in short period of time

        • Borderline patients was found to have a significant limbic dysfunction, hence antipsychotics may be helpful

  • Future of Schizophrenia Spectrum Treatment

    • There is great need to identify individuals at risk for the disease and treat them with lower dose of antipsychotics. Hopeful data is currently present in support of this approach to lower the incidence and prevalence of schizophrenia.

 

 

 

 

 

 

 

Schizophrenia with Dr. Cummings: Controversies, Brain Science, Crime, History, Exercise, Successful Treatment

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In this episode, Dr. Puder addresses the fascinating realm of schizophrenia with Dr. Cummings, a previous guest in the show. Dr. Cummings is a psychiatrist with a wealth of experience from working at Patton State Hospital in California, one of the biggest forensic hospitals in the world.

  • Defining Schizophrenia

    • Swedish survey about misperceptions of the environment found that roughly 50% of the population have had misperceptions that could be considered psychotic in nature.

  • The Loss of Brain in Schizophrenia

    • Schizophrenic patients lose 2% of brain mass per year for the first 5 year in the course of illness.

  • Living with Schizophrenia and Perception of Reality

  • Are Negative Symptoms in Schizophrenia Precipitated by Medications?

  • The Pathology, Biology, and Genetics of Schizophrenia

  • Cannabis Use and Risk For Schizophrenia

  • Counter-arguments Against Robert Whitaker’s “Anatomy of an Epidemic”

    • Emil Kraepelin, and the Early Studies on Schizophrenia

      • The majority of schizophrenic patients during Kraepelin’s observation became vegetative in their 40s.

      • After the advent of antipsychotic medications, schizophrenic patients are able to function until their 70s-80s

    • Gitlin 2001 Neuroleptic Discontinuation Study

      • Exacerbation or relapse was almost universal within 2 years in those who discontinued antipsychotics

  • Schizophrenia Prevention in High Risk Population

    • Australian study on children of schizophrenic parents (Yung, 2011)

  • Australian Study on Children of Schizophrenic Parents

  • Crime, Violence, Mass Shootings and Schizophrenia

  • Medical Management of Schizophrenia

  • 1st Break Psychosis

  • Long-acting Injectable Antipsychotics in Early Illness

  • Medication Adherence

  • Exercise

    • Exercise for schizophrenia increased hippocampal size by 12% vs. -1% for non exercising groups of patients (Pajonk, 2010)

  • Lifestyle, Diet Optimization

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