People are said to have co-occurring disorders or conditions if they have a combination of any mental health conditions, or any substance use or addictive behavior and physical disease (Dinwiddie, 2017). Historically, individuals with co-occurring disorders (COD) experienced limited success in healing, wasted a lot of finance and time in treatment programs. That was because the wrong approach was employed by mental health specialists; they used to handle each condition separately. Currently, individuals with symptoms of mental health or addiction can be screened for COD in any psychiatric health facility. The high incidences of substance use disorders (SUDs) and other psychiatric disorders are well recognized. The group of people with COD is diverse, and the frequency of comorbidity varies by a diagnostic group (Pettinati, O’Brien, & Dundon, 2013). The consequences of comorbidity are extensive and pose challenging questions yet to be answered. For instance, why are substance use and other psychiatric diseases so frequently co-occur? Are there genetic influences or neurobiological links between these conditions that drive comorbidity? Do various mental disorders have different associations with several types of substances of abuse? Knowledge of the association between SUDs and psychiatric illness is essential for effective prevention and treatment. The rapid progress of technical innovations in neurosciences has demystified signal transduction mechanisms, neural circuitry, and neurotransmitter systems participating in SUDs and psychiatric illness (Sadock, Sadock, & Ruiz 2014). This paper focuses on co-occurrence between substance use and depression/mood disorders because research concerning neurobiology and the mechanistic association between these conditions is predominantly active. A case study is also presented. Background Information SUDs are quite frequent among young people in the US, with incidence rates ranging from ~ 8 – 35% (Dinwiddie, 2017). Frequently, they co-occur with additional mental ailments. The 2010 national statistics on drug use and health revealed that 21.1% of teenagers 12-17 years old with a profile of drug abuse or dependence had a major depressive attack in the same timespan (SAMHSA, 2017). Around 8.9 million people out of the total US population suffer from depression and substance use dependence (SAMHSA, 2017). Among the adults who at one time used injectable drugs, evidence disclose a higher rate of lifetime major depressive disorder in women than in men (SAMHSA, 2017). The average age of occurrence is 40 years. The economic burden of drug abuse has been estimated at $180.9 billion, while the overall cost of alcohol and drug abuse summed around $246 billion (SAMHSA, 2017). These comprise healthcare expenses, crime costs, and productivity losses. Although there is convincing evidence confirming a secure connection between depression and SUDs, the nature of this association is complex and varies depending on the substance used (Stubbs et al., 2017). Depression may predispose a person to SUDs or may exacerbate the effects of SUDs (Stubbs et al., 2017). Drugs and their psychotropic features are used to manage emotional distress.