Substance addiction, like any other type of addiction, is a form of mental illness, also known as Substance Use Disorder (SUD). Substance addiction comorbidity occurs when an addiction to one substance (ie. cocaine) co-occur with addiction with another substance (ie. opiods). However, SUD can also co-occur with other psychiatric disorders due to significantly similar symptoms. Addiction comorbidity is highly prevalent and can greatly affect treatment for psychiatric disorders and addiction . Studies show that over 50% of individuals with mental illness abuse drugs or alcohol, which is relatively high compared to 15% of the general population . In some cases, drug addiction develops from abuse of or dependence on prescription drugs  or as a form of self-medication for psychiatric disorders .
Psychiatric disorders comorbid with addiction commonly involves Affective, Anxiety and Mood Disorders. Comorbid disorders can worsen the progression of both disorders.
Comorbidity is the co-occurrence of two or more independent disorders simultaneously or one after another. There is an implied interaction between disorders which can affect the progression and prognosis of the disorders . Comorbidity is the vulnerability and predisposition for another disorder due to a pre-existing one, or the onset of both, and the neuroanatomical correlations of comorbid disorders. Comorbidity of a mental illness and substance abuse/dependence is more commonly known as dual diagnosis or concurrent disorders . Addiction and psychiatric disorders commonly co-occur due to overlapping genetic vulnerabilities, similar environmental triggers like stress or trauma, involvement of common brain regions (hippocampus, amygdala), and that both are developmental disorders . Substance abuse can be a trigger to bring out or enhance symptoms of other psychiatric disorders, pertaining mainly on Anxiety and Mood Disorders. Treatment of addiction disorder can greatly be affected by undiagnosed comorbidity with other psychiatric disorders. In most cases, comorbidity can result to poorer psychological, functional and treatment outcomes than either disorder alone .
Substance Use Disorder
DSM-IV recognizes four substance-related conditions: substance intoxication, substance withdrawal, substance abuse, and substance dependence. Substance Use Disorder is described to be the presence of both conditions of substance abuse and dependence causing detrimental effects on the individual and others.
Addiction-inducing substances fall into different categories:
- Central Nervous System depressants
- CNS stimulants
- Hallucinogens and PCP
Addictive substances do not only include recreational drugs but can also include prescription drugs and over-the-counter drugs which include pain-relief medication, vitamins and analgesics. Substances that commonly induce SUD include, but not limited to: alcohol, barbiturates, benzodiazepines, inhalants, cocaine, amphetamines, caffeine, opioids, heroin, morphine, hallucinogens, phencyclidine, cannabis and nicotine. 
Anxiety and Mood Disorders
|Figure 1 DSM-IV Classification of Anxiety and Mood Disorders (click to enlarge)|
Many anxiety and mood disorders (Figure 1) are comorbid with substance addiction, however the main psychiatric disorders are Bipolar Disorder (BPD), Major Depression (MD) and Post-traumatic stress disorder (PTSD). Studies on BPD-SUD mainly focus on brain structure abnormalities and its corresponding overlap. Studies on PTSD-SUD and MD-SUD mainly focus on biological mechanisms potentially involved in the development and maintenance of comorbidity. These studies will also involve treatment-related aspects as SUD develops mainly to self-alleviate symptoms of psychiatric disorders like PTSD and MD. These disorders also show high rates of comorbidity among each other.
Bipolar Disorder, under DSM-IV Mood Disorder classification is also known as manic-depression mental illness. Individuals with bipolar disorders have episodes of mania and depression with varying degree. In severe cases of BPD, especially Bipolar II disorder, the degree of depression episodes meet the criteria for major depression . (see bipolar-neuroscience)
Bipolar Disorder is commonly affected by high rates of SUD comorbidity especially during adolescence, which progressively increases during adulthood . The common co-occurrence of BPD and SUD has been the subject of many studies but still remains to be poorly understood. Previous studies suggested that the development of comorbidity may be related to specific neurological impairments . Both disorders are known to affect common structures of the brain, mainly affecting regions for motivational and emotional processing. In most cases, both BPD and SUD have shown to greatly affect portions of the prefrontal cortex as well as the medial temporal and subcortical regions of the brain (see reward-pathway-and-behavior-in-addiction). These overlapping neuroanatomical abnormalities are thought to increase the risk of an individual to develop both BPD and SUD.
|Figure 2. Brain comparison of the gray matter volume (A) and density (B)
of bipolar patients with and without comorbid CUD.  (click to enlarge)
In a comparative study by Jarvis et al (2008) of bipolar patients with and without comorbid cannabis use disorder, the gray matter volume in the left fusiform gyrus was shown to be decreased in comorbid patients than in bipolar patients alone. Furthermore, in comorbid patients, the gray matter volume in the right caudate and precentral gyrus, and gray matter density in the right middle occipital gyrus, right fusiform gyrus, and cerebellar vermis were shown to be increased (Figure 2). It was also demonstrated that there was low degree of overlap in gray matter volume and density between bipolar patients with and without CUD. These findings explain that greater abnormalities in areas affecting motivation and reward can predispose bipolar patients to development of CUD. Moreover, greater changes in areas of mood regulation (ie. anterior limbic network) can ease the development of CUD in bipolar patients. 
The genetics of bipolar comorbidity with Alcohol Use Disorder (AUD) was also studied and linkage studies have found several candidate genes in the dopaminergic and serotonergic pathways (see reward-pathway-and-behavior-in-addiction). Yasseen et al (2010) investigated any relation of BPD-AUD comorbidity with polymorphisms on dopamine and serotonin receptor and transporter genes . In female bipolar patients, they found that the Ser23Cys SNP (rs6318) in the 5HT2C gene (see genetics-of-addiction) was significantly different in genotype frequency between comorbid and non-comorbid patients. However, their results are still not enough to indicate a significant association of the dopamine and serotonin pathway with comorbidity development. Polymorphisms within candidate genes in the dopamine and serotonin pathways have been intensively studied due to implications of similar genes in either disorder alone.
DSM-IV-TR recognizes two forms of Depression, Major Depression and Dysthymic Disorder. Major depression is characterized by experiences of depressed mood or loss of interest in usual activities in which the severity interferes with the individual’s everyday life .
Because of its high prevalence, MD-SUD comorbidity has garnered great interest and has been strongly studied in the last few decades. There have been numerous studies highlighting the strong associations between two of the most common disorders. Possible explanations for the causal linkage of MD and SUD include consequences of alcohol exposure are triggers for MD, genetic factors, reciprocal enhancement of disorders, and similar brain regions and pathways affected .
Alcohol exposure can affect one’s metabolism and gene expression, increasing the risk of developing MD. McEachin et al (2008) found that excessive ethanol exposure can suppress TNFα converting enzyme activity which then reduces MTHFR expression, thus reducing folate levels. Decreased folate levels have been greatly associated with increased susceptibility to depression . Alcohol can also affect the circadian rhythms generated in the suprachiasmatic nucleus, and it was found that circadian rhythm alterations are common in MD . Sjoholm et al (2010) showed an association between the CLOCK gene and MD-AUD comorbidity. There is an increased risk for comorbidity in individuals with the CLOCK haplotype TTGC formed by four different SNPs. They argued that alcohol-induced alterations in the circadian rhythm can lead to increased susceptibility to MD.
|Figure 3 Brain imaging of areas affected by alcohol stimuli between
comorbid patients and healthy individuals.  (click to enlarge)
MD and SUD comorbidity involves the corticostriatal-limbic circuitry which includes the preforontal cortex, anterior cingulate, hippocampus, amygdala and straitum. Tremblay et al (2005) suggested that MD patients also have deficits in reward circuitry. There are evidences of altered brain activation (hypersensitivity) in the ventrolateral prefrontal and orbitofrontal cortices and the caudate and putamen in depressed patients . Disruptions in these areas are associated with alcohol craving. Due to the shared role of corticostraital circuitry in MD and AUD, Han et al (2013) studied the treatment effect of escitalopram with aripiprazole (see treatment-of-addiction). Besides showing that the aripiprazole + excitalopram treatment reduced alcohol craving in comorbid patients, they also showed changes in brain activity in comorbid patients compared to healthy individuals (Figure 3). In comorbid patients, there is decreased activity in the anterior cingulate cortex. Following treatment, brain activity in the anterior cingulate was shown to increase, thus reducing craving in MD patients. This suggests that the anterior cingulate plays an important role in AUD-MD comorbidity .
Post-traumatic stress Disorder
According to the Canadian Mental Health Association (CMHA), post-traumatic stress disorder affects 1 in 10 people, and is one of the most common mental health problems. PTSD is caused by a wide range of traumatic events that is relieved by an individual long after the actual experience (see post-traumatic-stress-disorder-PTSD. Traumatic event can be a firsthand experience wherein the individual directly experiences the event (ie. near-death experience or abuse), but it can also be a second-hand experience where the individual witnesses a traumatic event (ie. seeing a loved one die). According to DSM-IV, symptoms of PTSD are categorized into three: re-experiencing of traumatic event, emotional numbing and detachment, and hypervigilance and chronic arousal. There are numerous known contributors to PTSD including social factors (severity, duration and proximity of trauma), psychological factors (pre-existing distress), and biological factors (physiological hyperreactivity and genetics) . In fact, many studies have shown that the amygdala appears to be hyperreactive to trauma-stimuli in PTSD patients, as well as shrinkage of the hippocampus . These contributors may explain why PTSD is highly comorbid to many disorders, including SUD.
Comorbidity of SUD and PTSD has been studied intensively for the past 20 years due to its high prevalence. A multisite longitudinal study of 1000 individuals showed that individuals with a history of PTSD are at higher risk for drug abuse and dependence . Most cases of comorbidity show that the development of PTSD precedes the onset of SUD , where the overall rate of PTSD in individuals with SUD is 10 times higher than those without SUD .
In a review article by Norman et al (2012) of different peer reviewed articles, biological mechanisms involved in SUD-PTSD comorbidity were outlined. They listed the following biological mechanisms: neurotransmitter and hypothalamic-pituitary-adrenal dysregulation, structural differences in the brain, and shared genetic risk factors .
Independent studies of PTSD or AUD have shown three main neurotransmitters involved in both disorders: dopamine, norepinephrine and serotonin. These neurotransmitters are involved in mechanisms regulating reward, impulsivity, arousal and anxiety.
|Figure 4 PET scan on comorbid patients showing higher rCBF at
amygdala and parahippocampal gyrus.  (click to enlarge)
- Brain structures
In both PTSD and AUD, the hippocampus and amygdala have been known to be greatly affected. Reduced hippocampal volume was found in PTSD subjects, which is also known to be related to alcohol use. Many different studies have shown that although PTSD hippocampal volume deficits exist independently of alcoholism, alcoholism can further increase hippocampal volume deficits in PTSD . Semple et al (2000) examined regional cerebral blood flow (rCBF) in PTSD-C/AUD comorbid patients vs patients without either disorders . They found that comorbid patients had significantly higher rCBF in the right amygdala and the left parahippocampal gyrus (Figure 4). This suggests that there is a strong relationship between amygdala and frontal cortex attention systems for both addiction and PTSD.
- Hypothalamic-pituitary-adrenal (HPA) axis
Comorbidity of PTSD AND SUD may be affected by the corticotropin-releasing hormone (CRH) which activates the HPA axis. Elevated CRH levels are known to increase the drug-seeking behaviour . Consequently, elevated CRH levels are also known to strengthen fear-related behaviours as seen in PTSD patients. Therefore, PTSD patients with elevated CRH levels are at higher risk of developing SUD because of the increased hyperarousal symptoms and drug-seeking behaviour reinforcement. Likewise, SUD patients with increased CRH levels may develop PTSD symptoms increasing one’s susceptibility to develop PTSD.
Another important proposed mechanism by which PTSD and SUD co-occur is the theory of self-medication. This theory can be applied to other psychiatric disorders comorbid with SUD.
PTSD or other anxiety disorders co-develop with SUD after abusing the use of alcohol or drugs to relieve symptoms of PTSD or to generally reduce negative emotions (ie. to feel numb) . Saladin et al (2003) have shown that in comorbid individuals the severity of PTSD can predict craving behaviour when exposed to trauma and substance cues. This study further shows that negative emotions and behaviour are strongly associated with craving and addictive behaviour response to cues . In Canada, over 20% of adults age 60 or older abuse their medications or are continuously using pain-relief medication or prescribed drugs . Patients with different anxiety disorders commonly abuse their medications in order to relieve the symptoms of their disorders. This abuse of medication can progress to using other substances like alcohol and recreational drugs, which puts patients with anxiety disorders at greater risk to develop addiction.