Comorbidity between drug abuse and mental illness is very common. It reflects both a high risk for drug use in subjects with mental illness and a high frequency of psychopathology triggered by drug use. However, the significance of this comorbidity in regard to the mechanisms underling psychopathology and drug abuse, the influence that drug addiction has on the course of mental illness and vice versa, and the implications for treatment are poorly understood. Four papers published in this issue address some of these topics.
The high rate of comorbidity between mental illness and substance abuse is likely to reflect common contributing factors and brain substrates. A common contributing factor is stress, which plays an important role in substance abuse and in mental illness. The role of stress is particularly prominent in posttraumatic stress disorder (PTSD), since a "stressor" triggers the disorder. Jacobsen’s review paper discusses how the accentuated "stress" responses in PTSD could explain the abuse of drugs, particularly sedative-hypnotics such as alcohol, as a means to relieve PTSD symptoms temporarily. The abnormal response to stress in PTSD is believed to be mediated in part by enhanced noradrenergic function, which is disrupted during drug withdrawal. Drug abuse, like PTSD, is also associated with greater activation of stress circuits in the brain (1).
In addition to stress, drug abuse and PTSD share other processes such as sensitization and conditioned responses. In PTSD, sensitization makes the patient more sensitive to the "stressor," and in substance abuse sensitization makes the abuser more sensitive to the "drug." Whereas in PTSD the individual is conditioned to an aversive stimuli (the stressor), in drug abuse the individual is conditioned to a rewarding stimuli (the drug). Both sensitization and conditioning are mediated in part by the amygdala, which is also involved in the aversive effects of stress. This suggests that, in addition to the hypothalamopituitary axis, which modulates stress responses in the brain, the amygdala is another common substrate underlying comorbidity between PTSD and drug abuse.
An unresolved question in clinical psychiatry has been the role that drugs of abuse have on triggering psychosis in individuals with no previous psychiatric histories. Although it is believed that stimulant drugs induce psychosis because they increase extracellular dopamine concentration in the brain, this mechanism does not explain why psychosis can persist after the stimulant drug is no longer present in the brain. The study by Sekine and colleagues, which reports an association between the loss of dopamine transporters and positive symptoms in methamphetamine abusers with histories of methamphetamine-induced psychosis, provides some plausible explanations. Since dopamine transporters are the main mechanisms for removing extracellular dopamine concentration, their loss in methamphetamine abusers could result in high levels of extracellular dopamine even when methamphetamine is no longer present. This could explain the persistence of psychosis after methamphetamine discontinuation. Note that this explanation assumes that dopamine transporter losses in methamphetamine abusers are not due to dopamine terminal degeneration. However, if dopamine transporter losses reflect dopamine terminal degeneration, then alternative explanations are required (i.e., postsynaptic changes, overadaptation of nondamaged dopamine terminals, or improper rewiring of recovering dopamine terminals).
The results from the study of Sekine et al. are in contrast to those my associates and I previously reported (2) showing an association between dopamine transporter losses in methamphetamine abusers and psychomotor impairment compatible with "decreased" brain dopamine activity. These discrepancies are likely to reflect differences in the subjects studied, since we excluded methamphetamine abusers with histories of psychosis. A pertinent question is why some methamphetamine abusers develop psychosis and others do not.
Substance abuse is associated with a high risk for suicidal behavior, which is likely to reflect common precipitating factors as well as the effects of drugs on mood. The study reported by Roy addresses this association for cocaine abuse. This study shows that cocaine abusers with a history of suicidal behavior have a higher rate of family history of suicide and childhood trauma and are more introverted, neurotic, and hostile than cocaine abusers without a history of suicidal behavior. Since these factors were similar to those previously reported in subjects with suicidal behavior who were not drug abusers, one cannot determine whether the association reflects common contributing factors rather than cocaine’s role in exacerbating suicidal behavior. A contributing role of cocaine to suicidal behavior is plausible because chronic cocaine use affects mood negatively, as evidenced by the high frequency of dysphoria and depression in cocaine abusers. Cocaine abusers also have reductions in brain dopamine D2 receptors and in dopamine release (3). Since dopamine, in part by means of dopamine D2 receptors, regulates reward and motivational circuits (4), these reductions could result in improper activation of these circuits, leading to dysphoria and anhedonia. These changes in an individual with "predisposing factors" for suicidal behavior, which are likely to facilitate drug abuse as well, could further increase their risk for suicidal behavior.
Of considerable general interest is whether drugs of abuse damage the brain. The study by Johnson and colleagues addresses this issue in terms of the effects of cocaine on cerebrovascular pathology and stroke. Although the cerebrovascular changes associated with cocaine use are not linked with specific psychopathology, cocaine, by jeopardizing the brain circulation, induces cerebral dysfunction that is dependent on the magnitude of the disruption and on its location in the brain (5). The Johnson et al. study highlights the importance of treating adverse effects of drugs on the brain, since improving brain function in the drug abuser is likely to increase the success of detoxification and rehabilitation therapies. These therapeutic implications can be extended to other drugs of abuse, since vasoactive effects have been reported for most drugs of abuse, and to the development of therapies to prevent brain damage from drug use.
The high rate of substance abuse in patients with psychiatric diseases and its negative impact on the patient’s clinical outcome and social adaptation highlight the importance of further research in comorbidity. Such research is likely to have a direct effect on the management and treatment of psychiatric patients and drug abusers and to shed light on the mechanisms underlying these disorders.
Address reprint requests to Dr. Volkow, Brookhaven National Laboratory, Upton, NY 11973; email@example.com (e-mail).