Co-Occurring Mental and Substance Use Disorders: The Neurobiological Effects of Chronic Stress


Part 1

Major Depression and Substance use Disorder

The implications of comorbidity are far-reaching and raise important questions that are unlikely to have simple answers.

One of the overarching issues is the question of why substance use and other mental disorders so often co-occur. Are there genetic mediators and/or neurobiological connections between these disorders that drive the comorbidity? Do different psychiatric disorders have differing relationships with various substances of abuse? Better understanding of the connection between substance use disorder and mental illness could have a profound effect on both prevention and treatment.

In next two blogs, we focus on …psychiatric disorders— depression/mood disorders, posttraumatic stress disorder (PTSD)…

In this article (a) from a decade ago but still very relevant to the “co-morbidity” debate today, the authors …”… conceptualize chronic distress as a central construct underlying the association of each of these four psychiatric disorders with substance use disorders…

…Epidemiological surveys in the 1990s emphasized the prevalence of comorbid psychiatric and substance use disorders in community samples of adults (1, 3, 4). In the Epidemiologic Catchment Area study (3), an estimated 45% of individuals with alcohol use disorders and 72% of individuals with drug use disorders had at least one co-occurring psychiatric disorder. In the National Comorbidity Study (1), approximately 78% of alcohol-dependent men and 86% of alcohol-dependent women met the criteria for a lifetime diagnosis of another psychiatric disorder, including drug dependence. The risk relationship appears to be reciprocal, with psychiatric disorder predicting increased risk of later substance use and vice versa…

…Because acute intoxication and withdrawal from drugs of abuse can mimic symptoms of psychiatric disorders, the overlap of symptoms can be problematic in making an accurate diagnosis of a psychiatric disorder in an individual with a substance use disorder. This difficulty may account for some of the high comorbidity rates reported in epidemiological studies, which are not generally designed to tease apart substance-related and independent psychiatric symptoms. Despite this caveat, even conservative estimates suggest a high rate of comorbidity between psychiatric disorders and substance use disorders…

…A growing body of evidence from basic science and translational studies implicates common neurobiological pathways and abnormalities involved in addiction and a number of psychiatric disorders. Within a neurobiological framework, at least two hypotheses can be postulated to explain comorbidity: 1) addiction and other psychiatric disorders are different symptomatic expressions of similar preexisting neurobiological abnormalities, and 2) repeated drug administration, through neuroadaptation, leads to biological changes that have common elements with the abnormalities mediating certain psychiatric disorders (13)…

..One of the bridging constructs between psychiatric and substance use disorders is the role of stress in the development and relapse of substance use disorders and other psychiatric disorders…

…various genetic and environmental vulnerability factors contribute to the development of the distress states…

Corticotropin-releasing factor (CRF), one of the key hormones involved in the stress response, has been implicated in the pathophysiology of anxiety, affective, and addictive disorders (8, 14). Preclinical evidence suggests that CRF and noradrenergic pathways are involved in stressinduced reinstatement of drug-seeking behavior in drugdependent laboratory animals (15). Stress stimuli that activate CRF circuits are also known to potentiate mesolimbic dopaminergic reward pathways in laboratory animals (16). Similarly, human laboratory studies have shown that emotional stress and negative affect states increase drug craving in drug-dependent individuals (17, 18).

Evidence of an association between severity of depressive symptoms in patients with major depression and the subjective reinforcing effect of an acute dose of dextroamphetamine (19) suggests dysregulation of reward systems with increasing levels of distress in major depression. In animal models, early life stress and chronic stress result in longterm changes in stress responses (20). Such changes can alter the sensitivity of the dopamine system to stress and can increase susceptibility to self-administration of substances of abuse (16, 21, 22)…

..In the following sections, we review emerging data that shed light on the neurobiological connections between various substance use disorders and the psychiatric disorders considered here (depression/mood disorders and PTSD)

Depression and Substance Use Disorders

Epidemiological studies reported rates of comorbidity of major depression with nicotine, alcohol, and illicit drug abuse ranging from 32% to 54% (1, 27, 28). Individuals with major depression are more likely to develop substance use disorders, and individuals with substance use disorders are at greater risk for the development of major depression, compared to the general population (27–29). Clinical similarities exist between major depression and substance use disorders. Depressive symptoms are commonly reported during acute and chronic withdrawal from drugs of abuse. Irritability, sleep difficulties, anxiety, and trouble with attention/concentration are associated with both protracted withdrawal states and major depression.

Neurobiological similarities between major depression and substance use disorders likely contribute to both symptom overlap and high rates of comorbidity (13). Substantial data indicate that extrahypothalamic CRF and HPA axis abnormalities (8) and alterations in catecholamine, serotonin, GABA, and glutamate systems are associated with major depression (30, 31). Neuroadaptations associated with chronic drug abuse are associated with alterations in these neurotransmitter systems, especially during acute withdrawal states (13). CRF/HPA response during acute drug withdrawal has a positive association with withdrawal-related distress and with depressive symptoms (32, 33).

Evidence of altered neuroendocrine response to stress challenges in substance use disorders is consistent with clinical observations that individuals with substance use disorder have difficulty managing stressful situations and emotional distress states and often relapse in the face of stressful situations (12, 38). In laboratory studies, stress and negative affect states increase drug craving and emotional distress in abstinent substance-dependent individuals (17, 39–41). These changes are accompanied by physiological arousal (18), and this finding suggests that drug craving states that are marked by increased levels of anxiety and distress are accompanied by biological stress responses. Increased distress-related drug craving is associated with vulnerability to continued drug use and relapse (12, 42), and this association suggests a mechanistic connection between depressive symptoms and substance use disorders…

… Recent findings from neuroimaging studies implicate similar alterations in frontal-limbic brain circuitry in substance use disorders and major depression. Reduced frontal metabolism and hypoactivity of the anterior cingulate have been reported in individuals with substance use disorders (45, 46). Significant reduction in dopamine D2 receptors, particularly in frontal-striatal regions, has been noted in cocaine- and alcohol-dependent individuals, compared to healthy subjects (45).

Reduced frontal-limbic metabolism has also been found in subjects with major depression, relative to healthy subjects (47). Such findings are consistent with postmortem studies showing reduced cell density and gray matter volume in individuals with a diagnosis of major depression (48). Furthermore, amygdala hyperactivity and anterior cingulate hypoactivity are associated with major depression (47), and studies of individuals with substance use disorders indicate activation in the amygdala associated with cue-induced drug craving (49, 50).

Under conditions of distress, cocaine-dependent subjects exhibited decreased activity in frontal regions such as the medial prefrontal cortex and the anterior cingulate, similar to that seen with negative mood in subjects with major depression (51, 52). Similarly, a recent study (53) reported lower levels of glucose metabolism in the anterior cingulate and insula, but higher levels in the orbitofrontal region, amygdala, middle and posterior cingulate, and ventral striatum in methamphetamine abusers with severe mood and anxiety symptoms, compared to healthy subjects…

In conclusion, neuroendocrine and neuroimaging studies indicate dysregulation in frontal-limbic systems associated with stress and reward pathways in both major depression and substance use disorders. This common dysregulation is likely to contribute to the high rate of comorbidity of these illnesses. Evidence concerning negative affect and stress-related drug seeking/craving provides additional insight into emotional distress states and drug use in drug-experienced individuals. A better understanding of these connections will contribute to the development of new treatments for major depression, substance use disorders, and the comorbidity of these disorders.

PTSD is considered in our next blog.


a. Brady, K. T., & Sinha, R. (2014). Co-occurring mental and substance use disorders: the neurobiological effects of chronic stress. American Journal of Psychiatry.

4 replies »

    • Hi Caroline, thanks for commenting. I agree diagnosis is better done in recovery – this blog also explains how many manifest symptoms of so-called co-morbidities can also dissipate in recovery – Are most co-morbidities really substance-induced disorders? – Paul

  1. I don’t think they are no but I know several people who’ve been diagnosed with schizophrenia while using who are not schizophrenic at all they have drug induced psychosis. Also people who are alcoholics are diagnosed with depression when it is really the alcohol that is making them depressed. With me alcohol and drugs dampened down my mental health problems so it wasn’t till I got clean that they burst into the light and I was accurately diagnosed. I really think being in recovery from substances is crucial for a proper diagnosis.

  2. I think that one must keep an open mind – the article I wrote on Substance Induced Disorders does however say something different – that the incidence of depression and GAD in recovering people is similar to the distribution in a normal population – – if this is the case a misdiagnosis of e.g. depression can be an obstacle to full recovery from addictive behaviours – also we have to aware of what disorders are commonly co-morbid like PTSD which is quite high I believe and has a similar effect on brain mechanisms as addiction thus can plausibly make addiction more severe in its manifestation.

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