Introduction
Schizophrenia is a complex mental disorder that affects nearly 1% of people worldwide and is one of the top 15 leading causes of disability (WHO). Substance use disorder (SUD) comorbidities are commonly seen in individuals with schizophrenia, with lifetime SUDs affecting 47% of patients. SUDs are 4.6 times more common in people with schizophrenia compared to the general population, and males as well as people with lower levels of education are at an increased risk. A dual diagnosis of substance use in schizophrenia complicates the course of treatment and in many cases is associated with poorer outcomes including increased psychotic symptoms, more cognitive impairment, and poorer treatment compliance, including nonadherence to antipsychotic medications, which is a common cause of psychotic symptom relapse and hospitalization. More recent studies have identified the risk of substance-induced psychosis and development into schizophrenia, especially in cannabis use disorder.
Fictional Case
Ms. AB is a 19-year-old white female college student who was admitted to the hospital in an acutely psychotic and agitated state. She is in her second year and has become increasingly isolated and bizarre. She started smoking marijuana at the age of 17, and since entering college her pot use has been daily.
In the past month, her roommate observed that she would lock herself in their room, and the room smelled of pot. She has become increasingly suspicious of the other students in her dorm, and she told her Resident Assistant that she felt the other students were stealing from her and trying to poison her. The Dean of Students called her parents and the police, and she was brought to the emergency department.
Fortunately, Ms. AB recognized her cannabis use disorder and entered drug treatment and continued her antipsychotic medication. Within 3 months, her psychosis had cleared and she returned to college.
Theories to Explain Substance Use Disorder Comorbidity: Self-Medication Versus Addiction Vulnerability Hypothesis
Some individuals may be more predisposed to developing an SUD, as well as to developing psychotic disorders. The addiction vulnerability hypothesis outlines preexisting vulnerabilities, such as impulsivity, genetic predisposition, epigenetic states, and overlapping neurobiology that bias an individual to not only mental illness but also problematic substance use. Moreover, the presence of a mental illness itself is a vulnerability factor for substance use, despite the heterogeneity across comorbidities. For example, dysfunctional hippocampal and frontal cortex functioning leading to dysregulated dopaminergic and glutamatergic signaling has been hypothesized to underpin schizophrenia. These abnormalities mimic the reinforcing effects of long-term substance use, as well as facilitate reduced inhibitory control over substance use behavior, placing those with schizophrenia at a vulnerability to the development of an SUD.
The self-medication hypothesis describes how individuals use substances due to dysfunctional self-regulatory tendencies and affective states. Individuals medicate the distress and pain associated with “self-regulation” difficulties that are prominent in those with mental illness, such as general self-care, emotion regulation, self-esteem, and interpersonal difficulties. When an individual’s distress becomes heightened and he/she experiences emotional dysregulation, substances are more likely to be used to mitigate the feeling due to lack of coping skills, prompting a vulnerability to “self-medication.” Alternatively, the theory that substance use directly causes schizophrenia has minimal evidence; however, substances promote much more severe presentations of the disorder and disorder-like episodes.
Although the addiction vulnerability hypothesis carries more neurobiological support, the self-medication hypothesis also contributes to our understanding of substance use co-occurring with psychosis. The relief that is associated with substance use is not a true therapeutic effect, but rather a temporary and immediate relief that replaces one’s absent self-regulatory and coping processes. The perception of self-medication is more of a driving influence than actual improvement of symptoms.
The initial relief of one’s affective state positively reinforces substance use behavior, eventually leading to an allostatic state in which a neurobiological affect deficit is produced ( Fig. 8.1 ). This deficit occurs due to physiologic changes, such as decreased dopamine, endogenous opioid peptides, serotonin and increased dynorphin, as well as decreased GABA and neuropeptide Y, and increased corticotrophin releasing factor (CRF). Koob has conceptualized addiction into a theory that involves a binge and intoxication stage, a withdrawal and negative affect stage, and a preoccupation and anticipation stage, all of which are fueled by negative reinforcement. Negative reinforcement, which is the removal of an aversive stimulus by substance use, maintains addiction. This also explains how substance use may be used as a form of “self-medication” in maintaining addiction, in that individuals use substances to alleviate withdrawal symptoms (see Table 8.2 ). Moreover, based on the dual process model of addiction, an individual’s automatic processes, also described as one’s impulsive behavior, overshadow more executive, controlling cognition, which also maintains addictive behavior and is prominent in schizophrenia.
Substance Use in Schizophrenia and Related Disorders
Approximately half of those diagnosed with schizophrenia present a lifetime SUD. Psychosis can be differentially presented, leading to a spectrum of clinical diagnoses. More chronic diagnoses, such as schizophrenia and schizoaffective disorder, are presented over a longer period of over 6 months. More acute diagnoses, such as brief psychotic disorder and schizophreniform disorder, may be present for a shorter period of time and either continue into a more chronic diagnosis or remission. Moreover, substances with psychotomimetic properties, such as alcohol, cannabis, cocaine, amphetamine, and hallucinogens, can further provoke psychotic reactions and invoke a substance-induced psychosis.
Substance-induced psychosis is a psychotic episode resulting from intoxication or withdrawal of a substance. The rates of first-episode psychoses as a result of substance use in the general population range from 7% to 25%. Moreover, the prevalence of substance-induced psychosis is higher among those with a mental illness. In some cases, substance-induced psychosis may transition into more chronic psychosis or classified mental disorder, such as schizophrenia, depending on the user and the substance. Certain substances have a greater risk of conversion from a substance-induced psychosis toward a chronic illness. For example, studies have found that approximately 32% of those presented with substance-induced psychosis transitioned toward bipolar or schizophrenia-spectrum disorder, with 47% of these cases as a result of cannabis use. See comparison of the clinical features of substance-induced versus idiopathic (e.g., schizophrenia) psychosis in Table 8.1 .
| Primary Psychosis (e.g., Schizophrenia) | Substance-Induced Psychosis |
|---|---|
| Drug urine toxicology sometimes positive | Positive substance urine toxicology |
| Variable reported substance use (25% prevalence of positive c urine toxicology in schizophrenia) | Heavy substance use within past month |
| Symptoms appear before heavy substance use | Symptoms appear only during periods of heavy substance use/sudden increase in potency |
| Symptoms persist despite drug abstinence | Symptoms abate or are reduced with drug abstinence |
| Antipsychotics markedly improve symptoms | Antipsychotics may/may not improve symptoms |
| Most often present with delusions, hallucinations, and thought disorder | Often associated with visual hallucinations and paranoid ideation (e.g., features of an “organic” psychosis) |
| Less insight about psychotic state | More aware of symptoms/insight about disease |
| Disorganized thought form (e.g., loose associations, tangential or circumstantial speech) | Thought form more organized and sequential |
Rates of substance use are on average higher across individuals with a mental illness compared to the general population; however, substance use rates are particularly prevalent across individuals with a psychotic disorder. There may be predisposed characteristics placing these individuals at a higher risk to substance use, such as developmental and genetic abnormalities, as well as environmental and social factors that facilitate this comorbidity. Regardless of the predispositions, substance use in psychotic disorders is associated with overall poorer outcomes, including higher rates of criminality, violence, hospitalization, relapse, suicide, medical comorbidities, and mortality. Moreover, comorbid substance use has been associated with higher scores on measures of positive and negative symptoms of psychosis.
Comorbid psychotic disorder and alcohol use, cigarette smoking, cannabis use, other recreational substance use (e.g., cocaine, methamphetamine, etc.), or polysubstance use is commonly observed, although research is limited and successful treatment options are lacking.
Alcohol
Alcohol use disorder (AUD) is the most common co-occurring disorder next to nicotine in people with schizophrenia, with approximately one-third of individuals developing AUD at some point in their lives. Various studies have suggested alcohol use rates are as high as 86% in patients with schizophrenia and 65% of individuals with schizophrenia have an AUD. The acute intoxication of alcohol produces greater and longer-lasting euphoria and stimulatory effects in individuals with schizophrenia. These positive responses may contribute to the risk of developing AUD in this population along with alcohol’s availability as a legal drug.
Although acute alcohol use induces positive feelings, it is the most common substance, next to cannabis, to induce psychosis especially in heavy, long-term alcohol users. A Finnish report found that about 4% of individuals with AUD experience alcohol-induced psychosis, and of those 95% experience varied hallucinations and 51% experience delusions. Psychosis related to alcohol occurs during acute intoxication, withdrawal, and in chronic users. In most cases, alcohol-induced psychosis is dose dependent to alcohol withdrawal states, also known as alcohol withdrawal delirium. Alcohol withdrawal symptoms range from minor to severe depending on the severity of the SUD, with severe symptoms resembling a psychotic state including delirium tremens, delusions, and hallucinations that peak within a week after alcohol abstinence. More rarely, alcohol-related psychosis, or alcohol hallucinosis, presented shortly after acute intoxication, occurs in about 4% of individuals with an AUD. The symptoms include hallucinations, paranoia, and fear. Only 5% of individuals experiencing an alcohol-induced psychosis risk a schizophrenia spectrum diagnosis.
Other reports have also shown the negative impact alcohol use has on physical health in patients with schizophrenia. Patients with a dual diagnosis have a twice greater chance of developing hypertension, chronic obstructive pulmonary disease, and coronary artery disease. Furthermore, multiple studies have indicated the detrimental effects of alcohol on neurocognitive functioning, including impaired verbal learning, working memory, executive function, sensory gating, and higher levels of psychopathology (especially mood disturbance) and positive symptoms.
Cannabis
Cannabis use rates have been suggested to be as high as 80% in schizophrenia compared to the general population, and it is specifically prevalent in younger individuals and males.
Delta-9-tetrahydrocannabinol (THC), a partial agonist of CB1 receptors, and cannabidiol (CBD) are the two primarily researched cannabinoids (i.e., the pharmacologic constituents of cannabis). CBD has exhibited therapeutic benefits across mental and physical disorders, while THC is psychoactive and has been correlated with psychotomimetic effects and negative implications in psychosis.
Heavy cannabis use among the general population has been described to induce brief psychotic states, and individuals with a psychotic disorder are particularly vulnerable to relapse and aggravation of preexisting symptoms. For example, among individuals with schizophrenia, comorbid cannabis use has been shown to be correlated with increased hallucinations and confusion and increased reported depression, lack of thought control, and social dysfunction. This has been confirmed in clinical trials of cannabis administration in schizophrenia. For example, THC intravenously administered in individuals with schizophrenia on stable antipsychotic medication has shown to acutely heighten positive, negative, and general symptoms, as well as alter perception and worsen attention, memory, and motor stability. Moreover, THC has been associated with an increased risk of psychosis in a dose-dependent manner: regular cannabis users and heavy cannabis users are two and four times more likely to develop psychosis, respectively.
However, other reports note how individuals with schizophrenia or first-episode psychosis with a history of cannabis use have been reported to have better cognitive functioning compared to nonusers and to those who exhibited later onset of cannabis use. For example, one study described how comorbid schizophrenia and cannabis use disorder were correlated with higher scores on tests of processing speed, verbal fluency, and verbal learning and memory, as well as higher scores on the global functioning scale. These results have been interpreted in that cannabis use in schizophrenia may represent a higher-functioning subgroup of patients.
There is also an increased risk for earlier psychotic symptom presentation observed in conjunction with cannabis use in the general population. Results from one of the largest longitudinal studies involving over 50,000 male participants indicate that those who smoked cannabis by the age of 18 had twice the risk for receiving a diagnosis of schizophrenia, while those who used chronically were at six times the risk compared to nonusers. Notably, the administration of intravenous THC in healthy individuals has been shown to directly induce psychotic symptoms, both self-reported and assessed by the Positive and Negative Symptom Scale (PANSS).
It has been suggested that there are different classes among those with psychotic disorders who use cannabis. One study suggests there is the group that uses to counteract the distressing symptoms of the disorder, while another group uses before the onset of the disorder, and cannabis use may have influenced presentation of symptoms.
Tobacco
Schizophrenia is known to be associated with high rates of smoking, as high as 88%, and high rates of tobacco use disorder, resulting in increased rates of morbidity and early mortality. Dysregulation of nicotinic acetylcholine receptor (nAChR) systems has been proposed to increase susceptibility to smoking in schizophrenia. It is thought that the high prevalence of smoking in this population is a result of genetic factors, reductions in negative symptoms when smoking, higher cravings, and remediating cognitive deficits associated with the disorder. Furthermore, smoking is a common self-medication method used to ameliorate the adverse effects of antipsychotics. High-dose cigarettes have also been found to significantly decrease PANSS negative symptoms scores as well as SANS global scores and have no effect on positive symptoms.
There has been no clear evidence whether tobacco use disorder may induce psychosis. It has been suggested that there is an increased risk for psychosis and earlier onset of a psychotic illness in individuals who are chronic cigarette smokers. However, there needs to be more careful examination of tobacco use and first-episode psychosis.
Hallucinogens
Psychedelics
Psychedelics include a variety of compounds, such as lysergic acid diethylamide (LSD), psilocybin, and mescaline, and primarily act on the serotonergic system in the brain. Contrary to other substances, psychedelics have not been generally associated with long-term damage to the brain or body, nor have they been described as eliciting addictive behavior or withdrawal symptoms. From a report in the United States of over 130,000 respondents, there was no correlation between psychedelic use and increased rates of mental illness, including psychosis. Controlled studies have reported similar findings, with no major correlations between use and mental illness. Normally, these substances induce an altered state of consciousness, with impairment in judgment posing the greatest risk for users. At larger doses, however, psychotomimetic effects can be observed. For example, LSD has been described to elicit psychotic symptoms in an acute setting, similar to those observed in individuals with a psychotic disorder. Psilocybin has also been shown to induce psychological consequences such as dysphoria, stress, and anxiety.
Phencyclidine
Phencyclidine, also known as PCP or angel dust, is an NMDA antagonist and induces symptoms that can mirror those observed in schizophrenia. Effects of use can range from altered perception, euphoria, and dysphoria to delusions and hallucinations, as well as cognitive dysfunction that individuals with schizophrenia commonly experience, which can remain prevalent even after abstinence. Moreover, PCP has been used as a model of schizophrenia, as the drug commonly induces psychotic episodes, involving positive and negative symptoms, as well as cognitive disruptions.
Ketamine
Ketamine is similar to psychedelics in that it is also a hallucinogenic drug, but its neurobiological action differs in the brain. Ketamine is a dissociative anesthetic that has been associated with psychedelic and psychotic effects. Symptoms such as hallucinations and paranoia are commonly reported following drug administration. Ketamine has been shown to induce psychotic episodes, involving positive symptom presentation, in individuals with diagnosed schizophrenia. Moreover, ketamine has been shown to exacerbate existing symptoms in schizophrenia. Acutely, ketamine has also been shown to induce schizophrenia-like and dissociative symptoms in healthy individuals, and has been shown to induce psychosis in healthy chronic users.
3,4-Methylenedioxy-methampthetamine
3,4-Methylenedioxy-methampthetamine, also known as MDMA or ecstasy, is a synthetic amphetamine that has both stimulant and hallucinogenic properties. Originally, ecstasy was used in psychotherapy for various disorders such as PTSD. Presently it is used as a recreational drug, especially among adolescents, and similarly to psychedelics, it does not have a strong addictive potential. During intoxication, ecstasy can induce intense euphoria as well as dissociative symptoms, primarily derealization, which exceed those seen in schizophrenia. Although rare, chronic and high-potency doses of ecstasy may lead to an MDMA-induced psychosis that usually persists until it wears off. There have been only a handful of case reports that have shown persistent induced psychosis after single use of MDMA. Research on the relationship between ecstasy and schizophrenia is scarce due to the low likelihood of ecstasy being used as a drug of abuse, especially in this population. In most cases ecstasy pills are tainted with other substances such as amphetamines and cocaine, which is more likely the cause of a persistent psychotic disorder, especially if one has a genetic predisposition to schizophrenia.
Opioids
Opioids are an increasingly common problem among people with psychotic disorders, but the prevalence compared to the general population is lower. Nonetheless, because people with schizophrenia use illegal drugs like cannabis, cocaine, and methamphetamine, these illegal drugs are often tainted with illegal high-potency opioids like fentanyl, and therefore clinicians have to be aware that psychotic patients may be at risk for opioid intoxication or opioid use disorder. Thus, these patients should be screened for opioids using urine toxicology and self-report measures and should be given naloxone kits to prevent overdoses.
Cocaine
Cocaine is classified as a stimulant that influences the central nervous system, with wide-ranging effects on the brain and body. More than half (up to three-fourths) of cocaine users have reported transient psychotic symptoms. Cocaine has been described to induce symptoms such as paranoia, suspiciousness, and hallucinations, especially among early-onset and heavy users. This phenomenon has been termed cocaine-induced psychosis or CIP, potentially due to heightened dopamine levels cortically and cortically in the brain caused by cocaine’s blocking of dopamine uptake. There has also been cocaine-induced psychotic disorder or CIPD, involving primarily auditory and visual hallucinations as well as paranoia, in those who experience psychotic symptoms over a greater period of time.
Because of this, cocaine use has been described as particularly detrimental to the induction and course of psychotic disorders, as psychotic disorders have been linked to dysfunctional dopaminergic activity as well. In a large survey of psychiatric patients, almost half of the individuals with schizophrenia presented with substance abuse behavior, while 17% of those individuals used cocaine. This rate remains consistent in hospitalized patients with schizophrenia, with roughly 20% abusing cocaine. Although not the most prevalent comorbidity, the deficits experienced in psychotic disorders in concurrent cocaine users is quite significant. For example, cocaine users with schizophrenia exhibit very low remission rates compared to other substances. Moreover, cocaine use has been associated with further psychosocial impairments, as well as lower scores on measures of attention, memory, and problem solving.
Amphetamines
Methamphetamine and amphetamine are psychostimulants that have strong addictive potentials. Although similar to cocaine, amphetamines are more potent and have a longer duration of euphoria, increased energy, alertness, and libido. Drug-induced psychosis has been reported in 46% of regular users of amphetamines. Symptoms include: lack of concentration, delusions of persecution, increased motor activity, disorganization of thoughts, lack of insight, anxiety, suspicion, and auditory hallucinations. Other serious adverse consequences of acute intoxication include violence and suicide.
Methamphetamine, a derivative of amphetamine, is much stronger and has quicker intoxicating effects. Individuals dependent on methamphetamine are more likely to lose their jobs, become homeless, and turn to crime. Similarly to amphetamine, prevalence of meth-induced psychotic disorder in methamphetamine users is 36.5%, with a lifetime prevalence of 42.7%. Symptoms of substance-induced psychosis for methamphetamine users include affective symptoms, psychomotor agitation, and primarily positive psychotic symptoms including: auditory and visual hallucinations, persecutory delusions, ideas of reference, and disorganized speech.
The rate of methamphetamine use disorder is 43.3% in patients with schizophrenia. About 38.8% of individuals experiencing methamphetamine psychosis eventually get diagnosed with schizophrenia due to the persistent and extended psychosis that methamphetamine may cause. This is seen predominately in patients who use the smoking or intravenous method of administration and have a family history of schizophrenia. Long-term amphetamine users risk cognitive impairment due to reductions in striatal dopamine transporter activity, including deficits in episodic and working memory, executive functions, visuoconstruction, and psychomotor tasks.
Clinical Features and Assessment of Substance Use Disorders in Psychosis
Many individuals struggling with schizophrenia, schizoaffective disorder, etc. have high rates of comorbidity with other SUDs. Dual-diagnosis patients are typically male, younger at illness onset, show more extrapyramidal, positive, and depressive symptoms, fewer negative symptoms, a lower quality of life, a higher incidence of violent behavior, homelessness, and unemployment as well as lower treatment compliance. There are, however, certain drugs that are more likely to cause psychotic symptoms than others. These include methamphetamine, cannabis, cocaine, amphetamine, alcohol, and psychedelic and recreational drugs. Furthermore, poly-drug use may increase risk of developing psychosis and complicates treatment in individuals with a dual diagnosis.
Some early signs and symptoms of a substance-induced psychosis include, among others, isolation, poor hygiene, worsening in work or school performance, paranoia or hostility, emotional outbursts or lack of emotional expressions, and inability to concentrate or communicate. The Diagnostic and Statistical Manual of Mental Disorder , 5th Edition (DSM5) is a source to help clinicians diagnose patients with an SUD and psychotic-related disorders (see Table 8.2 ). Symptoms of a SUD are withdrawal, marked tolerance, cravings, hazardous use, and social and interpersonal problems.
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