podcast schizophrenia

Clozapine for Treatment Resistant Schizophrenia

On today’s episode of the podcast, Dr. Cummings and I talk about clozapine, a medication that treats schizophrenia.

Mikyla Cho B.A., Michael Cummings, M.D., David Puder, M.D.

What is clozapine?

Not only is clozapine the gold standard medication for treatment-resistant schizophrenia, it is also one of the most unique drugs used in psychiatry.

It was synthesized 1958, only eight years after chlorpromazine, the first antipsychotic drug, was created. At that time, researchers tested for antipsychotic properties by taking various compounds and testing to see if lab mice developed dystonia and catalepsy. When researchers tested clozapine, they found that it did not cause dystonia, but instead made the mice sleepy. Because of this, clozapine was almost missed entirely as an antipsychotic medication. Eventually, however, clozapine was found to be more successful than other antipsychotic drugs.

By the 1970s, Austria, Germany, and Finland had produced positive data on clozapine proving its efficacy. However, clozapine was also found to have caused severe neutropenia in sixteen patients in Finland, and even caused the death of eight of those patients. For this reason, clozapine did not enter the United States until it was approved by the FDA in 1989.

Defining “Treatment-Resistant” Schizophrenia

Clozapine was approved largely due to the work of John Kane. In his work, Kane helped define “treatment-resistant” schizophrenia, and ultimately the context in which clozapine has proven benefits. The term “treatment-resistant” can be defined as schizophrenia that has failed to respond to an adequate dosage of two antipsychotic medications given for an adequate duration:

  • The dosage should be a minimum of 600-1000 mg chlorpromazine equivalents.

  • Duration should be a minimum of six weeks.

  • Additionally, patients must have failed a prospective trial of haloperidol 15 mg given daily.

With this definition, Kane and his team found that a patient’s odds of responding to clozapine was 50-60%, whereas the probability of responding to other antipsychotic medications was 0-5% (with an average response of 2%). Today, these rates are essentially unchanged.

In 2017 Howes et al. found similar response rates to clozapine. The team largely followed Kane’s original criteria for treatment-resistant schizophrenia but did not include the failed prospective trial of haloperidol. Additionally, the team measured plasma levels of clozapine to assess patients’ adherence. Ultimately, they found that the odds of responding to clozapine was 40-60% while the odds of responding to other antipsychotics was 7% or less.

In contrast, there have been meta-analyses, including Cochrane, suggesting that clozapine is not more effective than other antipsychotics. However, these studies have failed to strictly define or include “treatment-resistant” schizophrenia criteria. It is likely that schizophrenic patients who were not truly treatment-resistant were included in those studies. In this context, clozapine is not more effective than other antipsychotic medications.

Unique Effects

In addition to being the gold standard for treatment-resistant schizophrenia, clozapine has other unique effects. It has been found to reduce both suicide and violence in patients, independent of the drug’s antipsychotic effects. Criminal behavior is also decreased. Clozapine can also be used to treat psychogenic polydipsia and refractory mixed bipolar states.

Mechanism of Action

Part of the reason that makes clozapine so unique is its mechanism of action. Typically, second generation antipsychotics antagonize dopamine but more selectively than their first generation counterparts. Additionally, atypical antipsychotics antagonize the 5-HT2a receptors, which actually assist with dopamine transduction in the frontal lobe. Although clozapine does have atypical antipsychotic properties, it also works by modulating glutamate signal transduction, particularly in the frontal and temporal lobes. Even at high plasma levels, the concentration of clozapine at the D2 and D3 receptor is only 30-40%. It is the modulation of glutamate that helps stimulate and “awaken” the hypoactive brain of a schizophrenic patient.

Improving glutamate decreases the positive symptoms, improves the negative symptoms, and even helps with cognitive symptoms. Clozapine’s unique mechanism of action may be why Krakowski et al (2006) found that although clozapine, olanzapine, and haloperidol had approximately the same reduction in psychosis for violent schizophrenic patients, clozapine was superior to olanzapine and haloperidol in decreasing violence in the same patients because it significantly mediated the executive function of the frontal lobe.

Other than glutamate, clozapine does affect other key molecules and receptors. The major daily side effects are most likely due to the blockade of the His-1 receptors, and the subsequent sedation may become a dose-limiting side effect for the patient, especially at higher plasma levels of clozapine. Alpha-adrenergic antagonism also contributes to the drug’s side effect profile, such as hypotension. Additionally, although clozapine’s robust and positive effect on glutamate likely overrides much of the drug’s anticholinergic effects, there is still the chance for anticholinergic burden, especially if the patient is taking other anticholinergic medications.

Target Dose and Medication Adherence

It is vital to maintain a therapeutic alliance with a patient on clozapine, as noncompliance is a major factor for treatment failure in schizophrenic patients. For example, the adherence rate for antipsychotic medications in general is less than 40%. This is partially alleviated with long-term injectable agents, but clozapine does not have this option. The only forms of clozapine are tablets, wafers, and liquid agents. Therefore, it is beneficial to schedule regular meetings with patients on clozapine.

One method to assess medication adherence is by checking plasma concentrations and blood levels of clozapine. If patients are adherent, their plasma concentration of clozapine should be fairly consistent. Obtaining blood levels also assures the provider that the current medication dose is optimal, as patients vary in metabolism and absorption rates and other factors, such as smoking and different medications, can also affect hepatic metabolism.

To treat psychosis, the target range of clozapine should be 350-600 ng/mL. If symptoms are not adequately controlled at this level, but patients are tolerating the medication, clozapine can be gradually titrated to approximately 600-1000 ng/mL. After 1000 ng/mL there is a diminishing return of benefits and an increased likelihood of side effects. Rarely, patients will need to go above the 1000 ng/mL level. If the goal is to not treat psychosis but another issue like criminality, then patients will generally respond at much lower doses. For example, in 2014 Brown et al. found that there was a dramatic reduction in violence in seven psychopathic patients with an average clozapine concentration of 171 ng/mL.

Benefits of Clozapine

On-going, uncontrolled psychosis only leads to mental decline. Early in the disease process, patients lose 2% of their brain mass every year for the first five years, and although this decline slows after that point, it never reaches zero. Additionally, although a healthy lifestyle with adequate nutrition and exercise prevents cognitive decline, it is particularly difficult to motivate schizophrenic patients because of the nature of the disease. On average, schizophrenic patients live 20 years less than the general population.

Clozapine helps address both issues. It has been shown to slow the progress of schizophrenia than any other antipsychotic, and it has been shown to prolong a patient’s lifespan. In 2017 Yoshimura et al. found that the efficacy of clozapine begins to decline about 2.8 years after a patient has been shown to be treatment-resistant. This finding along with clozapine’s other benefits create the argument that clozapine should be prescribed sooner rather than later to help patients suffering from treatment-resistant schizophrenia.

You can download an extensive, FREE management summary from the episode here:




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



How to treat violent and aggressive patients

Link to show on: iTunes, Google Play, Stitcher, Overcast, PlayerFM, PodBean, TuneIn, Podtail, Blubrry, Podfanatic

On this week’s episode of the podcast, I interview Dr. Michael Cummings. Dr. Cummings works at a state psychiatric hospital for the criminally insane, so he has extensive experience in treating patients for aggression and violence.

The different types of aggression

The words “aggression” and “violence” are sometimes used synonymously, but in reality, aggression can be physical or non-physical, and directed either against others or oneself. Violence is more of a use of force with an intent to inflict damage.

One study looked at the principle types of aggression and violence that occur in psychiatric patients, and broke it down into three categories:

  • Impulsive violence (the most common category)

  • Predatory violence (purposeful and planned violence)

  • Psychotically-driven violence (least common)

Within 5 state hospitals, 88 chronically or persistently violent patients with 839 assaults, the rate of impulsive violence was 54%, and predatory violence was 29%. Psychotically driven patients logged 17% of total violence (Meyers, M. Cummings et al., 2013). Studies show psychotically driven violence decreases the longer the patients are in care and medicated.

Predatory Violence

Predatory violence is what people typically think of when they think of psychopathy, or someone with antisocial personality disorder. It is violence with a purpose, and that purpose is usually to gain something. They typically show a lack of fear and very little autonomic arousal even when they are being violent.  The amygdala and the temporal lobe is underactive and the communication between them has a weak signal. People with predatory violence also have lower affective empathy.

Some of the early research done by Adrian Reign measured blood pressure, galvanic skin response and heart rate when showing neutral, frightening or peaceful pictures to children. Of those who lacked effective response or autonomic response to those pictures, 75% percent of those individuals became violent criminals by age 18. Interestingly, 25% of them became prosocial and entered jobs as police officers, bomb disposal experts, and so forth.

True psychopaths are a very tiny part of the population. About 2% of women score significantly on the psychopathy checklist. About 2-4% of men have elevated scores on the psychopathy checklist. Not all of those individuals, however, are violent, and many persons who are psychopathic are more interested in profit. Some become the crime bosses (not actually doing the violence themselves) and others end up in politics.

Impulsive violence

Impulsive violence or aggression is actually the most common, and in many ways the most complex, form of violence that occurs in a variety of mental illnesses, including:

  • psychosis

  • mood disorders

  • personality disorders

  • anxiety disorders

  • PTSD

It is essentially an imbalance in impulse generation and a failure of the prefrontal cortex to evaluate the impulse and weigh the consequences. All of us generate a variety of impulses, some good and some bad, including impulses driven by our irritability and anger.

In predatory aggression there is increased medial prefrontal cortex activity whereas in reactive aggression there is decreased activity.

What can cause impulsive violence to be an issue:

  • Traumatic brain injury

  • Some of the dementias including frontotemporal dementias

  • Anoxic brain injury

  • Intellectual disability

  • Personality disorders

  • Drugs

  • Drug detox

Psychotic aggression

Psychotically driven aggression is most often a result of delusional ideation or the belief the person holds that they are in some way being persecuted and being taken advantage of. Psychotic or mentally ill people do have an increased rate of violence compared to the general population. The mentally ill are responsible for around 5% violent crimes, meaning non mentally ill people are responsible for 95%.

Psychotic Delusions leading to violence

Ones study looking specifically at the first episodes of psychosis found that in about 458 patients, anger was associated with certain types of delusions that led to the violence (Coid, 2013).

The underpinnings of delusion-driven violence usually stems from when people have delusional beliefs that are persecutory in nature. When they believe that someone is out to get them, it removes inhibitions against acting out violently, because that person’s view is they are protecting themselves. Typically, this violence comes from the belief they are being spied on or persecuted.

Persecutory delusions associated with a command hallucination is a particularly potent precursor to violent behavior. If your delusion tells you your neighbor is the devil, and your command auditory hallucination is that God is telling you to “kill him and save the world from destruction”  it can lead to a very bad outcome.

IQ and aggression

There is also an association between the IQ and aggression (Huesmann, 1987).

A recent study in state hospitals looked at what correlated with persisting violence, and across all of the types of violent behavior, cognitive deficits (particularly impairments and executive functioning) were associated with elevated rates of violence.

Men are more violent than women

Men are likely more violent than women because they have historically been the hunters, which involves violence. Women were gatherers more often than not, and consequently, men have a standing evolutionary tendency toward more frequent use of violence. Women can be violent, but if you look at the rates of violence between men and women, men are clearly more violent.

The purpose of aggression  

You could say the healthiest outcome for our aggressive and violent impulses is when we use our innate ability to be aggressive to engage in things like a healthy competition. Or even to provide motivation and drive to achieve.

In the beginning, humanity formed tribes, and aggression allowed someone to climb up the dominance hierarchy within the tribe. It also allowed them to protect themselves from other tribes. It was basic for survival.

If we look at animal psychology, there is a lot we can learn about the aggression and dominance hierarchy, like how apes interact with each other, or form alliances. As a way of creating alliances, often an alpha ape will groom other males.  The violence comes out when the clans come against each other. When one ape is wandering from its clan, two apes from another clan may attack one single ape viciously.

In other circumstances, if a dominant ape is taken away from his clan for a couple of days and brought back into the clan, a couple of other apes may have formed a new alliance against the prior leader and attack him.

As human beings, we are also like this. Many of our social interactions and group structures have the same kinds of alliances and effects of absence can play out similarly. Of course as humans, we do have higher verbal centers, and philosophy or spirituality, that allows an individual to be less violent and to transcend their base instincts.

Aggression and autism

People with intellectual challenges most often exhibit impulsive violence, particularly those on the autistic spectrum. The person may have a greater difficulty processing or understanding their own emotions if there are significant intellectual deficits. They may also have elements of not being able to judge a response or to moderate a response. The general pathophysiology of the autistic spectrum disorder suggests that the connections between neurons and the autistic brain is not what it should be, and they are not differentiated so that information processing can be fragmented.

Treatment of aggression

Psychotic aggression treatment

Treating with an antipsychotic medication is helpful and decreases violent episodes. In one study, clozapine helped psychotic aggressive patients with executive dysfunction more, compared to using haldol or olanzapine (Krakowski, 2011).   

Psychopathic aggression treatment

A predatory-violent individual needs to be contained in prison if there is a demonstrated past of persistent violence.

There is evidence that by enhancing intellectual empathy, psychopaths will be less violent. There is also interesting research that by giving oxytocin, the hormone that increases affiliation and collaboration, may have a moderating effect on some psychopathic individuals.

However, in terms of psychopharmacology, we don’t have any specific medications to control that behavior. Some medications, such as clozapine, can affect the underlying issues behind psychotic behavior and thereby reduce it, but there is no direct treatment for psychopathic violence pharmacologically.   

Impulsive aggression treatment

Dr. Cummings discussed the use of Mood stabilizers helping in persons with borderline personality disorder, SSRIs and trazodone helping in dementing illness in the elderly and alpha 2 agonists in people with things like autism or TBI. Alpha 2 agonists (clonidine) can fool the brain stem into thinking enough norepinephrine has been released, then less norepinephrine is secreted, making the brain stem calm down.

Essentially, in an emotional disorder, if you change the affective (limbic) tone, you can decrease the likelihood of emotionally reactive aggression, for example, by using mood stabilizers lithium and divalproex.  

Using an antipsychotic, and not just a mood stabilizer, doesn’t show any benefit for traumatic brain injury patients. Antipsychotics have been used for people with autism spectrum disorder, and some evidence shows that drugs like risperidone can be helpful to control outburst issues. If there is evidence of sexual aggression (or aggression occurring at women after puberty), using an GnRH agonist—antiandrogen treatment—can sometimes be necessary).

Psychotherapy for aggression

There have been a number of anger management therapies that have been used over time. Therapists can help people be aware of their anger and manage their impulses, or push their anger and aggression toward a more prosocial response.

For people with borderline personality disorder, dialectical behavioral therapy, mentalization based therapy or transference therapy are important. For schizophrenic patients, a good therapeutic alliance is important to create medication compliance. I have touched on how to process anger in my microexpression series and will have future episodes focusing more on the psychotherapy approaches to anger.  

Overall in therapy, we must assume that our patients will lie to us sometimes because they are afraid, and double check to insure they are following our prescribed protocol. We must also work hard to build trust and a therapeutic alliance.

Final Thoughts

Violence and aggression deserve much more attention as a specialty than we have given it in the past. It is a major burden for family members and friends.

Please submit any questions you have and we will submit them to Dr. Cummings and to answer.

(In the podcast details about specific medications are discussed for psychiatrists who are interested in advanced psychopharmacology.)

Further reading:

Link to Ideal blood levels are found in Resource Library

“California State Hospital Violence Assessment and Treatment (Cal-VAT) guidelines”




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