Table of Contents
What is Psychosis?
Psychosis is a nonspecific term to describe a mental state in which an individual’s connection with reality is weakened or lost. Symptoms of psychosis include disturbances in perceptions, thoughts, moods, and behaviors. It is important to note that symptoms of psychosis are traditionally separated into positive symptoms (hallucinations, delusions, and disorganized speech/behaviors) and negative symptoms (avolition, social withdrawal, depressed mood, apathy, blunting of affect, and catatonia).
Perceptual disturbances include hallucinations and illusions. Hallucinations occur when an individual perceives a stimulus when no stimulus is present (e.g., hearing voices when no one is there or seeing things that aren’t real). Sensory hallucinations may occur in any of the senses. Illusions, on the other hand, occur when an individual misperceives a stimulus when there actually was one (e.g., misperceiving a piece of lint for a spider).
Delusions are disturbances of thoughts that can occur during psychotic episodes. Delusions are fixed, false beliefs. They are illogical and sometimes bizarre and persist despite refuting evidence (e.g., believing one is God or believing one’s food is being poisoned). Delusional systems or delusional themes can develop that are complex and elaborate.
In addition to hallucinations and delusions, there may be disorganized, illogical speech and bizarre behaviors.
Negative symptoms of psychosis include social withdrawal (isolating), apathy, alexithymia (i.e., inability to describe emotions), blunting of affect (i.e., minimal emotional expression), inappropriate behaviors (e.g. standing in one position for long periods of time), avolition (i.e., no motivation or lack of goal-directed behavior), depression, anxiety, and sleep disturbances.
What Causes Psychosis?
Psychosis, or psychotic episodes, may be associated with illicit drug use, medical problems, medications, and/or primary psychiatric disorders.
(1) Illicit drugs: Magic mushrooms/psilocybin, ecstasy/MDMA, methamphetamine, cannabis).
(2) Medical conditions: Thyroid disease, encephalitis, brain tumors, dementia/neurocognitive disorders, seizures/epilepsy)
(3) Medications: Steroids, opioids, anticholinergic toxicity, certain antibiotics.
(4) Primary psychiatric disorders: Schizophrenia, Bipolar disorder, or severe Depression.
Below is a review of the most common primary psychiatric disorders associated with psychosis.
Pathophysiology of Psychosis
Pathophysiology and Neuropsychopharmacology of Psychosis and Related Disorders
As with most neuropsychiatric disorders, Schizophrenia and related psychotic disorders likely result from genetic vulnerability combined with environmental stressors during early development. It is important to note that the pathophysiology of Schizophrenia remains hypothetical and complex, but there are two prominent theories that have evolved and these theories have informed the pharmacological treatment of Schizophrenia. They are, the dopamine hypothesis and the NMDA receptor hypothesis.
Dopamine Hypothesis and NMDA Receptor Hypothesis
The Dopamine hypothesis suggests dopaminergic dysfunction within the major dopamine pathways in the brain (see below). The dopamine theory of psychosis is likely a small part of a bigger picture, but helps new learners understand the pharmacology of antipsychotics.
The NMDA Receptor hypothesis suggests hypofunctioning NMDA Receptors located on GABA interneurons within the cerebral cortex may contribute to psychosis. The NMDA Receptor hypothesis is supported by the observed clinical effects of NMDA receptor antagonists such as PCP and Ketamine, which mimic most of the symptom domains of schizophrenia (positive symptoms, Negative symptoms, cognitive symptoms, etc). It is important to know that GABA interneurons make up the majority of neurons within the cerebral cortex where they play a key role in modulating glutamatergic neurotransmission. GABA interneurons are also found within the Basal Ganglia where they also play an important role in modulating neurotransmission of glutamate and other neurotransmitters. The dopamine hypothesis and the NMDA Receptor Hypothesis are not mutually exclusive, as downstream changes in glutamate neurotransmission due to hypofunctioning NMDA receptors may alter dopaminergic tone in key areas of the brain. However, here we discuss the dopamine theory of psychosis as it helps new learners understand the basics of antipsychotic mechanisms.
Here we review the dopamine hypothesis as it relates to the pharmacological treatment of Psychotic disorders (by no means is this theory comprehensive or all inclusive).
Dopamine and Psychosis
Dopamine neurons represent a very small fraction of neurons in the brain and project to many areas of the brain within discrete pathways. About 80% of dopamine is found within the basal ganglia. There are many dopamine projections in the brain but here we limit our discussion to the four dopamine pathways most relevant to psychopharmacologists. Recall that dopamine is a monoamine neurotransmitter derived from L-Tyrosine and plays important roles in motivation, reward, movements, emotional expression, cognitive functions, and more. Let’s first review the four major dopamine pathways in the brain:
1. Mesolimbic Tract: The mesolimbic dopamine tract begins with dopamine cell bodies located within an area of the brainstem known as the ventral tegmental area (VTA, see neuroanatomy in previous lessons). These dopamine neurons project to an area of the ventral striatum known as the nucleus accumbens. Dopamine released within the nucleus accumbens is partially responsible for the reinforcing aspects of many drugs of abuse. It turns out that too little dopamine in this area may lead to anhedonia, lack of interest, and low motivation. Too much dopamine in this area has been found to contribute to the positive symptoms of psychosis. Therefore, blocking the D2 dopamine receptors in the mesolimbic tract with antipsychotics decreases positive symptoms. For antipsychotics to be effective, approximately 80% of striatal D2 receptors must be blocked.
2. Mesocortical Tract: The mesocortical dopamine tract begins with dopamine cell bodies located within the ventral tegmental area (same as mesolimbic) but these neurons project to areas of the prefrontal cortex where they play a role in cognitive (dorsolateral PFC) and emotional (ventromedial PFC) processing. Too little dopamine in the mesocortical tract contributes to the negative symptoms of psychosis: Decreased emotional expression, Decreased emotional responsiveness, Decreased interest, Decreased cognitive abilities, and Decreased socialization. Blocking dopamine D2 receptors in the mesocortical tract with antipsychotics worsens negative symptoms. This is why haloperidol and other high potency agents often cause blunting of affect and cognitive dysfunction.
3. Nigrostriatal Tract: The nigrostriatal dopamine tract begins with dopamine cell bodies located within the substantia nigra (in the midbrain). Dopamine cell bodies within the substantia nigra project to areas of the striatum (i.e., putamen and caudate nucleus). Dopamine in this tract is very much involved in the initiation and modulation of movement. Atrophy and destruction of dopamine neurons within the substantia nigra is seen in the hypokinetic movement disorder called Parkinson’s Disease. Too little dopamine in the nigrostriatal tract leads to slowed movements (bradykinesia), pill rolling tremor, shuffling gait, and other symptoms we call “extrapyramidal symptoms (EPS).” We call them “extrapyramidal” because this system is outside of the primary motor pathways (i.e. corticospinal tract or pyramidal system). Blocking D2 receptors in the nigrostriatal tract with medications or poisons causes or exacerbates EPS. EPS includes dystonia, Parkinsonism, Tardive Dyskinesia, and Akathisia.
4. Tuberoinfundibular Tract: The tuberoinfundibular tract begins with dopamine cell bodies located in the hypothalamus where they project and release dopamine into the pituitary circulation. Normally, Dopamine acts on lactotroph cells in the pituitary via D2 receptors and inhibits Prolactin Release. Blocking D2 receptors with antipsychotics increases Prolactin release from pituitary and may lead to side effects of hyperprolactinemia such as Galactorrhea, Menstrual irregularity, Sexual dysfunction, Vision changes, Infertility, and Headache.
Where did the dopamine theory of psychosis come from?
The concept of dopamine hyperactivity emerged from a convergence of basic neuroscience findings, clinical observations, and advances in neuroimaging techniques. It was well known that dopaminergic drugs (L-Dopa, cocaine, amphetamines) induce psychosis in man that mimics the paranoia seen in patients with schizophrenia. In laboratory animals, administering high doses of amphetamines causes species-specific stereotyped, repetitive behaviors. In rodents, for example, high doses of amphetamine induce repetitive chewing, biting, grooming, and circular locomotion (i.e., running in circles in a cage). It was discovered that medications like chlorpromazine and haloperidol reduced these stereotyped behaviors in laboratory animals. In fact, chlorpromazine and haloperidol caused slowed movements and rigidity, called “neurolepsis,” hence the term neuroleptic.
In 1952, Delay and Deniker published the first clinical trial demonstrating chlorpromazine’s antipsychotic effects. These findings combined with chlorpromazine’s ability to reduce stimulant-induced stereotyped behaviors in laboratory animals further supported dopamine’s role in psychosis. It wasn’t until later that chlorpromazine was found to be an antagonist at dopamine D2 receptors. In fact, early studies demonstrated that the higher a drug’s potency of dopamine D2 receptor antagonism, the more it reduced the positive symptoms of psychosis in humans. The problem was, the more potent the drug at blocking D2 receptors, the more likely the emergence of side effects such as slowing of movement, rigidity, and catatonia similar to the neurolepsis seen in mice (more on this later).
(A) Two (or more) of the following, each present for a significant portion of time during a 1 -month period (or less if successfully treated). At least one of these must be (1 ), (2), or (3):
- Disorganized speech (e.g., frequent derailment or incoherence).
- Grossly disorganized or catatonic behavior.
- Negative symptoms (i.e., diminished emotional expression or avolition).
(B) For a significant portion of the time since the onset of the disturbance, level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational functioning).
(C) Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or by two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
(D) Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either 1 ) no major depressive or manic episodes have occurred concurrently with the active-phase symptoms, or 2) if mood episodes have occurred during active-phase symptoms, they have been present for a minority of the total duration of the active and residual periods of the illness.
(E) The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.
(F) If there is a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if successfully treated).
Specify if Catatonia is present
Schizophrenia criteria but symptoms present for only 1-6 months
Brief Psychotic Disorder
Schizophrenia criteria but symptoms present for <1 month
(A) An uninterrupted period of illness during which there is a major mood episode (major depressive or manic) concurrent with Criterion A of schizophrenia.
Note: The major depressive episode must include Criterion A1 : Depressed mood.
(B) Delusions or hallucinations for 2 or more weeks in the absence of a major mood episode (depressive or manic) during the lifetime duration of the illness.
(C) Symptoms that meet criteria for a major mood episode are present for the majority of the total duration of the active and residual portions of the illness.
(D) The disturbance is not attributable to the effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.
Bipolar type: Manic episode is part of the presentation. Major depressive episodes may also occur.
Depressive type: Only major depressive episodes are part of the presentation.
(A) The presence of one (or more) delusions with a duration of 1 month or longer.
(B) Criterion A for schizophrenia has never been met. (If hallucinations are present, they are not prominent and are related to the delusional theme (e.g., delusional parasitosis where the sensation of being infested with insects is associated with delusions of infestation).
(C) Apart from the impact of the delusion(s) or its ramifications, functioning is not markedly impaired, and behavior is not obviously bizarre or odd.
(D) If manic or major depressive episodes have occurred, these have been brief relative to the duration of the delusional periods.
(E) The disturbance is not attributable to the physiological effects of a substance or another medical condition and is not better explained by another mental disorder, such as body dysmorphic disorder or obsessive-compulsive disorder.
Erotomanic type: Central theme of the delusion is that another person is in love with the patient
Grandiose type: Central theme of the delusion is the conviction of having some great (but unrecognized) talent or insight or having made some important discovery.
Jealous type: Central theme of the individual’s delusion is that his or her spouse or lover is unfaithful.
Persecutory type: Central theme of the delusion involves the individual’s belief that he or she is being conspired against, cheated, spied on, followed, poisoned or drugged, maliciously maligned, harassed, or obstructed in the pursuit of long-term goals.
Somatic type: Central theme of the delusion involves bodily functions or sensations.
Mixed type: No one delusional theme predominates.
Unspecified type: Dominant delusional belief cannot be clearly determined or is not described in the specific types
With bizarre content: Delusions are deemed bizarre if they are clearly implausible, not understandable, and not derived from ordinary life experiences
Treatment of Psychotic Disorders
Treatment of psychosis depends upon the underlying cause. If medication-induced, then stopping the problematic medication is the treatment. If due to drug intoxication the treatment is supportive until the drug is out of the body–followed by interventions such as drug rehabilitation.
If the psychotic episode occurs as a result of a primary psychotic disorder such as schizophrenia or a mood disorder such as bipolar disorder with psychotic features, then a combination of medications and psychosocial interventions should be considered.
Psychosocial interventions include group therapy, social skills training, recreational therapy, case management, and/or placement in a structured environment. Although the psychosocial treatment of psychosis is essential to recovery, it is not reviewed here in-depth.
Below is a brief outline of the medical treatment of psychosis.
Acute Psychosis (During the episode)
First line: Atypical Antipsychotics due to lower Extrapyramidal Side Effect, Tardive Dyskinesia, and neuroleptic malignant syndrome (also better tolerated)
Second line: Typical Antipsychotics
Treatment Resistant Psychosis (2 failed trials of antipsychotics): Clozapine
Benzodiazepines are used as augmentation agents (especially if mania or stimulant intoxication is present)
Electroconvulsive Therapy (ECT) in severe cases
First line: Atypical Antipsychotics due to lower Extrapyramidal Side Effect, Tardive Dyskinesia, and neuroleptic malignant syndrome (also better tolerated). Evidence supports the use of long acting injectables (Risperdal Consta, Invega sustenna, Invega Trinza, Abilify Maintenna, Aristada, Relprevv)
Second line: Haldol Decanoate (Long acting injectable)
Treatment Resistant Psychosis (2 failed trials of antipsychotics): Clozapine
Electroconvulsive Therapy (ECT) in severe cases
- McCarron, Robert M., et al. Lippincott’s Primary Care Psychiatry: for Primary Care Clinicians and Trainees, Medical Specialists, Neurologists, Emergency Medical Professionals, Mental Health Providers, and Trainees. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009.
- Focus Psychiatry Review, Dsm-5: Dsm-5 Revised Edition by Deborah J. Hales (Author, Editor), Mark Hyman Rapaport (Author, Editor)
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC.
- Arciniegas, Yudofsky, Hales (editors). The American Psychiatric Association Publishing Textbook Of Neuropsychiatry And Clinical Neurosciences. Sixth Edition.
- Bear, Mark F.,, Barry W. Connors, and Michael A. Paradiso. Neuroscience: Exploring the Brain. Fourth edition. Philadelphia: Wolters Kluwer, 2016.
- Blumenfeld, Hal. Neuroanatomy Through Clinical Cases. 2nd ed. Sunderland, Mass.: Sinauer Associates, 2010.
- Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
- Higgins, E. S., & George, M. S. (2019). The neuroscience of clinical psychiatry: the pathophysiology of behavior and mental illness. Philadelphia: Wolters Kluwer.
- Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
- Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
- Neuroscience, Sixth Edition. Dale Purves, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, Richard D. Mooney, Michael L. Platt, and Leonard E. White. Oxford University Press. 2018.
- Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
- Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
- Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
- Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th
- Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st 2012. APP.
- Benjamin J. Sadock, Virginia A. Sadock. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia :Lippincott Williams & Wilkins, 2000.
- Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
- Stein, Lerer, and Stahl. Essential Evidence-Based Psychopharmacology. Second Edition. 2012.
- Meyer, Jerrold, and Quenzer, Linda. Psychopharmacology: Drugs, the Brain, and Behavior. Sinauer Associates. 2018.