Apart from socioeconomic and demographic factors, the most widely held explanation for substance use comorbidity in schizophrenia and other mental illnesses is the self-medication hypothesis (Buckley 1998; Dalack et al 1998; Krystal et al 1999). This hypothesis is based on the psychologic construct of negative reinforcement, defined here as the reinforcing property associated with the “purposeful removal of an aversive stimulus” (March 1999). Self-medication hypotheses assert that patients use drugs to alleviate aversive disease symptoms or medication side effects; however, a growing body of evidence suggests that the neuropathology of schizophrenia may contribute to the vulnerability to addiction by facilitating neural substrates that mediate positive reinforcement. This primary addiction hypothesis is based on basic and clinical neuroscience literature that supports two fundamental tenets: An inherent feature of this hypothesis is that both the schizophrenia syndrome and vulnerability to addiction are primary disease symptoms, each directly caused by common neuropathologic substrates (Figure 1). In contrast, the self-medication hypothesis asserts that vulnerability to addiction is a reaction to the schizophrenia syndrome or medication side effects, and thus represents a secondary symptom. In this scenario, drug use is dependent on the experience or manifestation of symptoms; however, the primary addiction hypothesis posits that both schizophrenia symptoms and addictive behavior occur as independent manifestations of the same disease. This latter feature may account for the failure to find a consistent association of drug addictions with alleviation of general or specific symptoms in schizophrenia as described below.

First, several studies indicate that substance use rates in schizophrenic populations are substantially higher when compared with other psychiatric populations who would be as likely to self-medicate. For example, although smoking is suggested to alleviate negative emotional states, anxiety, depression, or poor cognitive functioning, nicotine use in patients with schizophrenia is more prevalent than in nonschizophrenic patients who exhibit similar symptomatology as primary features of their disorders. Tobacco use is consistently reported in more than 70% of schizophrenic patients but in less than half of patients with major depression, anxiety disorders, panic disorders, and personality disorders (Glassman et al 1992; Hughes et al 1986; Pohl et al 1992). Even when considering the constellation of symptoms in schizophrenia, there is no consensus among studies for substance use comorbidity to be associated with any particular subset of symptoms in individual patients (Cuffel et al 1993; DeQuardo et al 1994; Lambert et al 1997; Van Ammers et al 1997). Instead, studies on large patient populations find that drug availability is a primary determinant for the type of drugs patients use (Baigent et al 1995; Lambert et al 1997). These findings may suggest an association between heterogeneous schizophrenia presentations and a facilitation of the positive reinforcing and incentive motivational properties of addictive drugs.

A second consideration is that drugs of abuse have a complex array of effects in schizophrenic patients, often producing outcomes that are inconsistent with the view that these drugs serve to medicate their symptoms. For example, although some patients report symptom relief with drug use, others report symptom exacerbation, and yet their drug use persists (Addington and Duchak 1997; Selzer and Lieberman 1993). In many cases, self-reports of symptom improvement with drug use are contradictory to concurrent objective clinical observations that clearly show symptom exacerbation (DeQuardo et al 1994; Seibyl et al 1993). Moreover, drug or alcohol use greatly increases the likelihood of rehospitalization, length of hospitalization, need for greater neuroleptic dosage, and treatment noncompliance in schizophrenic patients (Dixon 1999; Gerding et al 1999; Seibyl et al 1993). Interestingly, the term self-medication is commonly used to explain high rates of drug use in dual-diagnosis patients who are especially medication noncompliant (Agarwal et al 1998; Seibyl et al 1993). These data suggest that similar to the natural course of addictions in nonschizophrenic patients, the incentive motivational properties of drugs that produce chronic drug taking in schizophrenia outweigh motivation to abstain stemming from psychiatric, medical, and financial consequences of drug use.

Another observation indicating a dissociation of schizophrenia symptomatology from addictive behavior is the prevalence of substance abuse before clinical presentation and medication treatment in schizophrenic patients. Studies have found that both drug and alcohol abuse occurs before the onset of psychosis and neuroleptic treatment in 14 to 69% of cases of schizophrenia (Berti 1994; Buckley 1998). One study found that 77% of first-episode patients are already smokers before treatment (McEvoy and Brown 1999). In another study, smoking rates are 54% and 15% in early- versus late-onset schizophrenia respectively, despite a similar duration of neuroleptic treatment (Sandyk and Awerbuch 1993). Although it is difficult to distinguish the initiation of drug use from the onset of prodromal symptoms, in many cases addiction vulnerability may occur as a natural antecedent to onset of other frank signs and symptoms, as a primary consequence of neuropathologic brain development that will later present as schizophrenia.

A final limitation of attributing drug abuse to self-medication of symptomatology is the assignment of treatment value to the effects unique to each type of abused drug while overlooking their common ability to mediate positive reinforcement. Different drugs commonly abused by schizophrenic patients produce highly specific effects on mood, perception, and cognitive functioning, and even mutually opposing subjective experiences via activity on a great diversity of neurotransmitter systems (Ling et al 1996). These facts have lead to attempts to define independent neurobiological mechanisms for self-medication specific to each drug of abuse in association with a particular psychiatric symptom, resulting in a host of relatively disparate theories that are not generalizable to more than one drug. Furthermore, these theories do not explain why standard medication treatments, with well-known efficacy for a variety of symptoms in schizophrenia, are not alone generally effective in reducing substance abuse in dual diagnosis cases (Selzer and Lieberman 1993). The primary addiction hypothesis focuses on the common ability of the abused drugs to produce incentive-motivation and positive reinforcement while remaining unencumbered by their differential ability to worsen or ameliorate certain symptoms of schizophrenia. A pathologic facilitation of incentive-motivational processes is consistent with observations that schizophrenic patients are known to suffer from a variety of apparently “senseless” motivational disturbances in parallel to substance abuse. These include motor and behavioral stereotypies, frequent and inappropriate masturbation, polydipsia, bulimia, pacing, pica, hoarding, and pathologic gambling (Aizengerg et al 1995; Chambers and Potenza 2001; Luchins 1992; Skopec et al 1976).

The primary addiction hypothesis is based on substantial data that directly relates deficits in hippocampal-cortical function with neurochemical, neurophysiologic, and neurobehavioral alterations consistent with a facilitation of both schizophrenia and addictive behavior. Figure 3A illustrates this hypothesis by showing that hippocampal and PfC outputs normally exert inhibitory control over DA-mediated behavior via their interaction with NAc neurons. During this “resting state,” homeostasis between hippocampal-cortical inputs and low basal dopaminergic tone contribute to stability in neuronal ensembles and suppression of uncontrolled goal-directed behavior in favor of executive premotor planning. The behaviorally “activated state” is produced by phasic DA surges in response to novelty, natural or drug rewards, stressful situations, or exposure to salient cues associated with rewards (Figure 3B). These DA surges act in the PfC to dampen afferents to the NAc and in the NAc to counteract the glutamatergic influence of hippocampal and PfC inputs. The vast majority of NAc output neurons (many of which receive hippocampal and PfC input) send descending GABAergic projections to the ventral globus pallidus and other brain-stem structures involved in thalamocortical loops that regulate thought, premotor planning, motivation, and movement (Mugnaini and Ortel 1985; Yang and Mogensen 1985). Dopaminergic surges in the NAc could diminish NAc GABAergic outflow to these structures, serving to translate motivation into behavioral action (Lavin and Grace 1994). Thus, DA surge would shift NAc function toward activation of motivated behavior, either in the form of appetitive (approach) or aversive (withdrawal) responses. In schizophrenia (Figure 3C), developmental alterations in hippocampal and PfC ultra-structure impair the ability of hippocampal projections to provide excitatory drive of PfC-NAc projections and provide effective facilitation of PfC inputs to the NAc, resulting in functional hyperresponsiveness to basal and drug-stimulated DA release. Thus, the patient with schizophrenia is particularly sensitive to the reward-activated, relative hyperdopaminergic state induced by addictive drugs in the NAc, by virtue of reduced inhibitory control over DA-mediated behavior. Such cortical-hippocampal dysfunction ultimately could lead to perseveration of drug-seeking and a propensity for relapse, as well as classic schizophrenic symptomatology.