Clairélaine Ouellet-Plamondon, MD, FRCPC

Schizophrenia is a severe psychiatric disorder that affects approximately 

 The 12-month prevalence of substance use disorders (SUDs) among the general US population is approximately 12% for alcohol and 2% to 3% for illicit drugs.

 It is interesting to note that nearly 50% of people with schizophrenia also suffer from a comorbid substance-related illness during their lifetime.

 There are complex interactions between substance use and psychiatric disorders, 

Patients who receive a dual diagnosis-a psychiatric disorder and an SUD-are faced with serious challenges related to treatment and prognosis. Many clinicians focus solely on treating either the psychiatric illness or the SUD. This lack of integration of psychiatric and addiction treatment is a significant issue for dual-diagnosis patients; growing evidence suggests a 

Psychiatric illness appears to be a vulnerability factor for substance abuse, and because substance abuse can lead to an exacerbation of psychiatric symptoms, there is a critical need to understand the factors that influence both the onset and duration of substance abuse and psychiatric illness, particularly how they interact to influence prognosis.

Schizophrenia is characterized by the disturbance of cognition and sometimes behavioral and emotional processes. Positive symptoms of schizophrenia can include hallucinations, paranoia, and delusions, while negative symptoms can include blunted affect, cognitive deficits, social avoidance, and anhedonia. Reductions in brain volume typically occur in patients with schizophrenia (as a function of the illness, medications, or both), primarily in the prefrontal cortex (PFC) and temporal lobes, which may contribute to the cognitive deficits commonly seen in patients.

There are 4 central dopamine (DA) systems: mesolimbic, tuberoinfundibular, mesocortical, and nigrostriatal.

 The mesolimbic pathway projects from the ventral tegmental area and substantia nigra of the midbrain to the nucleus accumbens (NAc), olfactory tubercle, and amygdala.

The DA hypothesis may be insufficient to explain the complexity of schizophrenia. However, there is mounting evidence to support DA dysfunction in schizophrenia. In particular, schizophrenia appears to be associated with hyperactive subcortical mesolimbic DA pathways in the brain and deficient DA function in the PFC.

 Moreover, all effective antipsychotic medications are antagonists of the DA D

Mesocortical DA modulates working memory and executive function, and dysregulation of this pathway may underlie some of the positive and negative symptoms associated with schizophrenia.

 The nigrostriatal pathway extends from the substantia nigra to the dorsal striatum via the median forebrain bundle, and overactivity of striatal DA release may be a key factor in the development of schizophrenia (

DA influences motor activity and attention in humans and plays a critical role in stress.

 In animals that are subjected to stress, DA is released in the cortical and limbic areas of the brain and may exacerbate symptoms associated with schizophrenia that could be a result of too many demands on the already diminished population of dopamine neurons.

The DA system also plays a large role in the reward- and pleasure-seeking system, particularly the D

 receptors. Many drugs of abuse block the function of the DA transporter, resulting in a large increase of DA in the synapse and increased D

 receptor signaling that mediates the reward pathway, usually in the NAc.

 recently reported that striatal DA release is increased in patients with schizophrenia, primarily in the precommissural caudate, and reduced in the ventral striatum in individuals with addiction. They measured the change in amphetamine-induced D

 receptor availability in both dual-diagnosis schizophrenia patients and in schizophrenia-only patients using positron emission tomography. Dual-diagnosis patients reported greater increases in happiness and energy following drug administration, but amphetamine reduced D

 receptor availability across both groups.

Many hypotheses have been put forth to explain the link between substance abuse and schizophrenia. The two hypotheses that we discuss are the self-medication hypothesis (SMH) and the addiction vulnerability hypothesis (AVH).

 The SMH posits that drugs of abuse relieve psychological suffering and that a person’s preference for a particular drug involves some degree of psychopharmacological specificity.

 By contrast, the AVH suggests that the of schizophrenia may increase vulnerability to drug reward and reinforcement, thus promoting concurrent expression of these disorders.

The SMH entails relief of negative symptoms, such as anhedonia, depression, blunted affect, and neurocognitive deficits.

 This hypothesis claims that drug addiction is a secondary process, or a reaction, to schizophrenia; the dysfunctional leads to aversive symptoms and to self-medication. Khantzian

 suggested that “it is not so much a psychiatric condition that one self-medicates, but a wide range of subjective symptoms and states of distress that may or may not be associated with a psychiatric disorder.”

People with schizophrenia may be targeting the negative symptoms and/or motor adverse effects of antipsychotic medications. The SMH explains comorbid drug addiction through a negative reinforcement model, in which drugs may serve to reduce aversive symptoms associated with the psychiatric disorder.

Over the past few decades, the SMH has drawn criticism. Since support for the SMH has focused on subjective, self-report measures, many researchers question the validity of this hypothesis. Amelioration of negative symptoms and adverse effects of medication is among the reasons Khantzian provides for individuals with schizophrenia who use drugs.

 Tobacco use is common in patients with schizophrenia, and nicotine may alter nicotinic acetylcholine receptor abnormalities in schizophrenia.

The effects of smoking abstinence on visuospatial working memory (VSWM; a cognitive process dependent in part on prefrontal DA) were examined in smokers with schizophrenia and smokers without schizophrenia (controls).

 Smoking abstinence in the schizophrenia group was associated with a decreased VSWM; in the control quitters, VSWM improved. The findings indicate that nicotine may have beneficial effects on cognition in smokers with schizophrenia. Although these data appear to support the SMH, it is important to note that cognition is subconscious and an individual with schizophrenia is unlikely to describe the effects of smoking on such unconscious processes.

Another shortcoming of the SMH is that when dual-diagnosis patients stop using their drug of choice, their psychiatric symptoms improve or remain unchanged rather than worsen after drug withdrawal is complete.

 Moreover, findings from prospective clinical trials suggest that patients with schizophrenia who quit smoking have no significant changes in positive and negative symptoms.

 Results from a retrospective study show that smokers with schizophrenia significantly decreased their reported daily cigarette use when they switched from neuroleptics to the atypical antipsychotic clozapine.

 If the SMH were supported, it would be expected that smokers would not decrease their daily smoking in response to medication (and may in fact increase smoking), since the SMH suggests that individuals use drugs to relieve medication adverse effects.

The AVH differs from the SMH in that it does not assume there are any beneficial (or detrimental) reasons for comorbid drug addiction. While the SMH posits that dual-diagnosis patients become addicted to relieve deficits, such as mood and anxiety symptoms, the AVH claims that dual-diagnosis patients become addicted to drugs despite the negative consequences of the drug.

With its focus on the common pathophysiology of addiction and schizophrenia, the AVH does not rely on the positive aspects of a drug as mediating the addictive process. The AVH suggests that addiction and schizophrenia are primary disease symptoms with common abnormalities. In addition, environmental influences can have a strong effect on the development of either one of the comorbid diseases. The combination of environmental and genetic influences may predispose an individual to a comorbid drug addiction, often before prodromal psychotic symptoms appear.

Animal studies provide some of the best data with respect to modeling the comorbidity process; neo-natal ventral hippocampal lesions (NVHLs) in rats mimic symptoms similar to those of schizophrenia.

 Rats with NVHLs responded more actively to an initial cocaine injection than did controls, and they had greater patterns of behavioral sensitivity after 7 days of injections.

 Such altered patterns of behavioral sensitization may result from abnormal present in schizophrenia, which promotes greater vulnerability to addiction.

In the brains of individuals addicted to drugs, the NAc is in an activated state, whereby DA inputs to the NAc are increased. DA inhibits hippocampal and PFC glutamatergic input and decreases NAc GABAergic outflow to the ventral pallidum and thalamus. In this disinhibited state, the reward circuitry is dysfunctional, and DA levels continue to rise, producing increased drug reinforcement.

Developmental abnormalities in both the hippocampal and PFC circuitry in schizophrenia may impair projections to the NAc. This results in hyperresponsiveness to basal and drug-stimulated DA release.

 Therefore, the abnormal underlying schizophrenia can result in dysfunctional basal DA and GABA resting states similar to those of an addicted individual. This process increases the vulnerability of patients with schizophrenia to drug addiction. Furthermore, the individual with schizophrenia may be more sensitive to the rewarding and reinforcing properties of addictive drugs because of excessive mesolimbic functioning.

One observation that supports the AVH is that generally the onset of drug abuse occurs before the onset of psychiatric symptoms, consistent with a common in schizophrenia and addictions.

 A study of 45,570 Swedish conscripts supports the AVH-the risk of schizophrenia among cannabis users was elevated 6-fold compared with non-users.

It is possible that cannabis may induce schizophrenia per se, but a more likely explanation is that individuals with a predisposition to schizophrenia are more likely to use cannabis, as a function of the common underlying both disorders.

Identifying reasons for comorbid drug addiction in schizophrenia has been difficult. Many theories have been proposed to try to explain the root cause of drug addiction in patients with schizophrenia, but no one theory has been put forth that encompasses all aspects of drug addiction in these patients. The SMH falls short by assuming that drug addiction in schizophrenia operates on a negative reinforcement model. Nonetheless, it is clear that the prognosis for schizophrenia is much better when patients achieve drug abstinence, including in the domains of depression, quality of life, and community integration.

Clearly, more research on the interrelationships between substance use disorders and schizophrenia is needed to support or refute the SMH or the AVH-and to establish the sequence of onset of the comorbid disorders. In other words, which came first, the chicken or egg? The answer to this question may have important implications for how we assess and treat people with drug addiction and schizophrenia.

This work was supported in part by operating grants from the Canadian Institutes of Health Research (CIHR, MOP#115145) and the Ontario Mental Health Foundation to Dr George, and by the Chair in Addiction Psychiatry at the University of Toronto to Dr George.

Ms Bridgman is a fourth-year undergraduate student in neuroscience and psychology at the University of Toronto; Dr Ouellet-Plamondon is a Fellow in Schizophrenia and Addiction Psychiatry at the Centre for Addiction and Mental Health in Toronto and the department of psychiatry at the University of Toronto; Ms Morozova is a fourth-year undergraduate student in psychology at the University of Toronto; and Dr George is Professor and Co-Director of the division of brain and therapeutics in the department of psychiatry at the University of Toronto, and Chief of the schizophrenia division at the Centre for Addiction and Mental Health. Ms Bridgman reports no conflicts of interest concerning the subject matter of this article. Dr George reports that he is on the Data Monitoring Committee for Novartis, has received investigator-initiated contract support from Pfizer Canada, is on the Speakers Bureau for Pfizer Inc, and is a Member of the Grant Review Committees for the National Institutes of Health and the Canadian Institutes of Health Research.

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It is clear that the prognosis for schizophrenia is much better when patients achieve drug abstinence, including in the domains of depression, quality of life, and community integration.

Understanding the Neurobiological Basis of Drug Abuse: Comorbidity in Schizophrenia

In the past 12 months, there has been substantial progress in our understanding of molecular processes related to the pathogenesis of major psychiatric and substance use disorders, and impressive translation of this knowledge toward developing better treatment. For example, our basic understanding of brain glutamate systems has yielded tremendous advances. Glutamate is the major excitatory neurotransmitter in the brain.

 It is involved in the neuro-circuitry of memory, emotions, and cognition and is implicated in myriad psychiatric conditions, including depression, anxiety, schizophrenia, drug addiction, and neuropsychiatric disorders.

This article reviews the recent knowledge about glutamate in different psychiatric conditions based on research published in the past year.

Stress is an important risk factor in the genesis of anxiety disorder. Animal studies have shown that stress precipitates glutamate release in limbic regions that may in part act to stimulate the hypothalamus-pituitary-adrenal axis and contribute to glucocorticoid-induced neurotoxicity.

 Recent studies have found dendritic remodeling, synaptic spine reductions, glial loss, and possibly volumetric reductions from glutamate excess following stress.

 Therefore, new drugs that target glutamatergic neurotransmission may be promising candidates for pharmacological treatments for patients who have stress-related anxiety disorders.

Work by Riaza Bermudo-Soriano and colleagues

-methyl-D-aspartate receptor (NMDA-R) antagonists (memantine), NMDA-R partial agonists (D-cycloserine), and metabotropic glutamate receptors 2 and 3 (mGluR2/3) allosteric modulators (LY354740 and LY544344) may be candidates for the treatment of anxiety disorders. In preliminary human studies, presynaptic autoreceptor mGluR2/3 agonists seem to be associated with clinical efficacy.

The monoamine hypothesis for mood disorders has been the dominant model since the 1960s.

 This has been challenged because monoamine antidepressants are only effective in 50% to 60% of depressed patients, and only about 70% respond after 4 acute treatment steps based on STAR*D algorithms.

 There is now evidence that glutamate dysfunction is involved in the limbic and prefrontal circuits of depressed individuals. For example, there is an increase of extracellular glutamate during acute and chronic stress and during depression.

Animal and human studies have indicated that targeting the glutamate system may hasten onset of action of antidepressant treatment.

 There is a growing interest in ketamine-a nonselective NMDA-R antagonist. Subanesthetic doses appear to enhance the strength of cortical synapses through NMDA-R– and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-dependent and neurotrophic mechanisms and may rapidly reverse prefrontal cortex–based deficits in depression at the neurocircuitry level. The result may be the amelioration of clinical symptoms.

 replicated their previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response and a rapid diminution in suicidal ideation. Limitations included a small sample (N = 15) and short duration (2 weeks); also, improvement remained significant over placebo for only 3 days.

 concluded that for depressive symptoms in treatment-resistant depression, ketamine produced rapid reductions in depressive symptoms and had a relatively benign adverse-effect profile. However, the sustainability effect remains unknown. Testing the safety and tolerability of repeated-dose ketamine remains a high priority of future investigations.

The mesocorticolimbic dopamine system is central to our understanding of addiction. Nonetheless, glutamate is also of interest because it modulates dopamine activity and is involved in the development and maintenance of drug dependence, particularly in reinstatement to drug-seeking behavior.

 Decreasing glutamatergic transmission by modulation of glutamate receptors may be effective in attenuating the reinforcing effects of drugs of abuse and in preventing reinstatement to drug-seeking behavior.

-acetylcysteine (NAC), a glutamate modulator that acts on the glutamate/cysteine exchanger, on cocaine seeking in the early and late stages of the acquisition and maintenance of cocaine self-administration in rats. NAC dose-dependently decreased the propensity to seek cocaine but had no effect on the reinforcing properties of cocaine. The researchers suggest that NAC can decrease the tendency to relapse and may also help break drug cue–elicited cocaine-seeking habits.

It is interesting to note that NAC was effective in decreasing marijuana use during an 8-week, double-blind, randomized, placebo-controlled trial for treatment-seeking cannabis-dependent adolescents.

 NAC was well tolerated and associated with minimal adverse effects. In contrast, a controlled clinical trial failed to demonstrate an ability of D-cycloserine to boost relapse prevention outcomes when combined with cognitive-behavioral therapy.

 Thus, pharmacological modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors.

The finding that noncompetitive NMDA-R antagonists such as phencyclidine and ketamine can elicit the positive, negative, and cognitive symptoms of schizophrenia in healthy individuals gave rise to the hypothesis of impaired NMDA-R functioning in psychosis. A number of compounds licensed for medical conditions, including several NMDA-R and mGluR agents, may have antipsychotic effects, but none has proved overall benefit over risks (adverse effect, tolerability).

The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) found no beneficial effect of glycine as an add-on treatment in chronic schizophrenia. Nonetheless, given a clear role for glutamate in the neurobiology of psychosis, it remains an active target for drug development.

One of the most promising therapeutic strategies for treatment-induced dyskinesias in Parkinson disease (PD) is mGluR5 antagonism.

 found an antidyskinetic effect of mGluR5 antagonism in de novo l-dopa–treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Glutamate dysregulation may also be involved in fragile X syndrome (FXS). The FXS mental retardation gene (Fmr1) encodes fragile X mental retardation protein (FMRP), which alters the cascade-regulating glutamate homeostasis in the brain.

In early clinical trials, mGluR5 antagonists have shown evidence of efficacy in treating neurobehavioral symptoms associated with FXS.

 Moreover, acute treatment with mGlu5 inhibitor in the Fmr1 knockout mouse suggests that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype.

 This glutamate-based therapeutic strategy may have important implications for management of such neuropsychiatric disorders as PD and FXS in the future.

Might targeting glutamate lead to new approved treatments in psychiatry? Understanding the pathophysiology of glutamate systems has yielded tremendous progress, which we hope will translate into novel and exciting neurotherapeutics. Increasing our understanding of biological vulnerability factors such as glutamate function in psychiatric disorders is important, but such advances should be combined with psychosocial interventions to yield optimal outcomes. The future is bright for developing neurotherapeutics based on the brain glutamate systems-so, up, up and away!

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Author | Clairélaine Ouellet-Plamondon, MD, FRCPC

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