Elsevier

Journal of Affective Disorders

Volume 241, 1 December 2018, Pages 388-401
Journal of Affective Disorders

Review article
A review of the neurobiological underpinning of comorbid substance use and mood disorders

https://doi.org/10.1016/j.jad.2018.08.041Get rights and content

Highlights

  • Neurobiological associations for comorbid affective and substance disorders are not fully elucidated.

  • Neuroimaging supports dopaminergic dysfunction in depression and tobacco use.

  • Positive association between alcohol use and hippocampal glutamate concentrations.

  • Alcohol may further reduce prefrontal glutamate concentrations in comorbid bipolar disorder.

  • Inflammation and oxidative stress biomarkers were identified in comorbid depression and tobacco use.

Abstract

Background

There is evidence that substance use disorders and other mental disorders may have shared biological mechanisms. However, the neurobiological basis of this comorbidity remains only partially explained. This review describes the historical evolution of the dual disorders concept and approach, and reviews the existing literature on neurobiological findings specifically regarding comorbid substance use and mood disorders.

Methods

Searches were conducted using PubMed and Scopus in December 2017. A Boolean search was performed using combinations of “dual diagnosis” or “dual disorder” or “depression” or “bipolar” or “affective disorder” or “mood disorder” and “substance use” or “substance abuse” and “neurobiology” or “functional neuroimaging” or “genetics” or “neurotransmitters” or “neuroendocrinology” in the title or abstract, or as keywords, using no language restriction.

Results

32 studies met the inclusion criteria. We found robust evidence for involvement of the neurotransmitters dopamine, GABA and glutamate and their receptors, as well as by the central corticotrophin-releasing hormone, hypothalamic–pituitary–adrenal axis activation, oxidative stress and inflammation. Recent studies focusing on neuroimaging and genetics have not shown consistent results.

Limitations

Only two search tools were used; most identified studies excluded the population of interest (comorbid mood and substance abuse disorders).

Conclusions

The neurobiological relevance for the occurrence of comorbid mood and substance abuse disorders has not been fully elucidated. Considering the high levels of individuals who experience comorbidity in these areas as well as the negative associated outcomes, this is clearly an area that requires further in-depth investigation. Furthermore, findings from this area can help to inform drug abuse prevention and intervention efforts, and especially how they relate to populations with psychiatric symptoms.

Introduction

There have been previous attempts to describe models that could explain the interrelationship between substance use (SUDs) and mood disorders. However, the neurobiological basis of these dual diagnoses remains unclear. Four predominant hypotheses assist in explaining the interrelationship. The self-medication hypothesis considers drug use to be the result of an attempt to alleviate pre-existing symptoms of a mental disorder (Markou et al., 1998, Khantzian, 1985); while a second hypothesis argues that repeated drug administration leads to a neuronal adaptation in brain areas mediating mental illness (Mcewen, 2000, Markou et al., 1998). A third hypothesis suggests that both disorders share neurobiological vulnerabilities (Markou et al., 1998), and a fourth hypothesis postulates that SUDs and mental illness have functionally discrete neurobiological mechanisms (Markou et al., 1998).

More recent hypotheses are focus on the construct allostatic load, cross-sensitization and kindling. Allostatic load is the cost to the organism of the attempts to re‐establish homeostasis after perturbations caused by stressors (Kapczinski et al., 2008). More stressors, mood episodes, or substance use require new adaptations, increasing allostatic load. It is believed that this can generate a potential vicious cycle which can further impact brain circuits required for mood regulation and cognition and amplify vulnerability to recurrent episodes of illness (Berk et al., 2017). Evidence also suggests that intermittent stressors, mood episodes and substance use not only show sensitisation to themselves, but cross-sensitisation to the others contributing to illness progression. (Post and Kalivas, 2013).

The approach taken towards understanding the neurobiology of addictions has evolved over the years since early research in 1954 uncovered that rodents could learn to electrically autoactivate specific brain regions. Furthermore, the researchers confirmed that there is a specific brain circuit that processes pleasant sensations and rewards, which is the same brain circuitry that processes the reward effect of natural reinforcers such as food, water or sex (Olds and Milner, 1954).

During the 1950s, it was proposed that continued drug use could be maintained to avoid or mitigate withdrawal symptoms (Rossetti et al., 1992), or as an attempt to treat pre-existing psychological or psychiatric symptoms such as anxiety, phobias, depression, etc. In the 1960s, a conceptual change took place, where addictive behaviour was explained as a process of positive reinforcement. This change was the result of a series of animal studies, which demonstrated that different substances could increase and maintain self-administration behaviours in the absence of withdrawal symptoms (Stolerman, 1992). Likewise, it was observed that laboratory animals mainly choose psychoactive substances that generate abuse and dependence in humans over other types of substances, except for the majority of hallucinogens (Di Chiara and Imperato, 1985).

Addiction is currently understood as a complex disorder. Depending on the approach, it could be considered as a disorder of the brain, memory, learning, neuronal maturation, neuroplasticity, homeostatic regulation or compulsion (Nathan et al., 2016). Similarly, different substances of abuse affect different neurobiological systems. For instance, cocaine and methamphetamine engage the catecholaminergic system, opiates signal through endogenous opioid system and nicotine acts through the nicotinic-cholinergic system. Additionally, marihuana uses the cannabinoid system while drugs such as alcohol and benzodiazepines engage the GABAergic and glutamatergic systems (Grotenhermen, 2005, Volkow and Morales, 2015). However, the fact that withdrawal syndromes from different drugs share a common symptomology (Rossetti et al., 1992) and the high comorbidity rates between different substance use disorders suggest a common neurochemical substrate (Volkow et al., 2015). Thus, various studies have consistently described the brain addiction circuit, finding that barbiturates, benzodiazepines, cannabinoids, ethanol, nicotine, and opiates act on the ventral tegmental area (VTA), while amphetamines, cannabinoids, cocaine, opiates, and ketamine act on synapses associated with the nucleus accumbens (NAc) (Gardner, 2000, O'brien and Gardner, 2005).

This intricate network is known as the reward circuit (see(Nestler, 2005) for a review). The system is composed of structures related to the mesolimbic dopaminergic (DA) system and is directly connected to other neurotransmission systems, such as the serotoninergic, the GABAergic or the endogenous opioid system, among others (Koob and Weiss, 1992).

Opiates, alcohol and cannabinoids have an inhibitory effect on the γ-aminobutyric acid (GABA) interneurons of the mesencephalic VTA, releasing the DA neurons from the tonic inhibitory action of the GABAergic neurons (Di Chiara and Imperato, 1985). The disinhibition of the VTA DA neurons produces a greater release of DA in the NAc and the said neurochemical effect would be the neurobiological substrate of the positive reinforcing effect (Joffe et al., 2014) .

Nicotine directly activates DA neurons, both in the VTA and in its NAc terminals (De Biasi and Dani, 2011). Phencyclidine, ketamine, and alcohol have an antagonist effect on glutamatergic N-methyl-d-aspartate (NMDA) receptors, which may also be related to its reinforcing effect (Lodge and Mercier, 2015). Psychostimulants block monoamine reuptake (DA, noradrenaline- NA, serotonin- 5-HT) (Sulzer, 2011) and amphetamines produce monoamine release (Robinson and Berridge, 1993, Koob et al., 2004).

The difference between natural and drug-reward stimuli is that the latter can generate sensitisation (Robinson and Berridge, 1993). The theory of sensitisation postulates that a high motivation for drug intake occurs when a sensitisation state is generated in the mesolimbic reward system (Robinson and Berridge, 1993, Robinson and Berridge, 2000, Robinson and Berridge, 2003). This system has a prominent role in the attribution of incentive, relevant to a stimulus, such that conditioned stimuli are perceived as pleasant, inducing compulsive motivation or powerful desire of substance consumption (craving) (Robinson and Berridge, 1993). However, the development of an addiction could lead to a reward system downregulation and the recruitment of stressors that contribute to negative emotional states, thereby increasing the “need” for repeated substance consumption (Koob and Le Moal, 1997) (see(Koob et al., 2004)for a review).

The relationship between addictive and other psychiatric disorders has become increasingly important to researchers. Evidence of the comorbidity can be analysed from clinical, genetic, environmental, developmental, pharmacologic and neurobiological factors, among others.

From a clinical perspective, comorbidity manifests in the overlapping symptoms, which constitutes a challenge in terms of research, diagnosis and treatment. Furthermore, different studies have shown that antidepressant treatments improve mood and reduce the consumption of some drugs (Markou et al., 1998). Thus, in case of opiates, cocaine and alcohol abuse, depressed drug users may reduce their drug consumption more than non-depressed users when treated with antidepressants (Markou et al., 1998).

Environmental factors influencing substance abuse and depression have also shown an overlap (Kendler et al., 2003), of which stress is a crucial determinant. Stress increases the risk of drug abuse and relapse (Sinha, 2001), and episodes of depression (Nemeroff, 1996). A study assessed the reactivity of the hypothalamic–pituitary–adrenal axis in nonsubstance-abusing subjects (n = 7), polysubstance-abusing subjects without depressive symptoms (n = 31), and subjects with substance abuse and depressive symptoms (n = 7), finding that polysubstance abusers with no past or current diagnosis of other Axis I disorders showed blunted adrenocorticotropic hormone and cortisol responses to ovine corticotrophin-releasing hormone administration (Contoreggi et al., 2003). This suggests an overlapping role of central corticotrophin-releasing hormone and hypothalamic–pituitary–adrenal axis activation in mood and substance use disorders (Contoreggi et al., 2003). Cross-sensitization has been described in different studies (Yap et al., 2015, Tidey and Miczek, 1997, Tidey and Miczek, 1996) and is consistent with the difficulty experienced in the management of stressful situations and emotional distress, and relapse under these conditions (O'Brien et al., 1998).

While there is ample evidence about neurobiological underpinning of substance use disorders and psychotic illness, the common neurobiological bases of substance use and mood disorders remain unclear. To illustrate the lack of recent publications, in this paper the agents involved in the neurobiology of dual disorders are reviewed and their relationship with the pathogenesis of mood and SUDs, evidence on the neurobiology of comorbid substance use and mood disorders are discussed.

Section snippets

Methods

A narrative review was performed to investigate studies showing the neurobiological underpinning of SUD and mood disorders. Searches were conducted using the electronic databases Medline (PubMed) and Scopus in December 2017. Boolean search of clinical trials was performed using combinations of “dual diagnosis” or “dual disorder” or “depression” or “bipolar” or “affective disorder” or “mood disorder” and “substance use” or “substance abuse” and “neurobiology” or “functional neuroimaging” or

Results

32 studies met the inclusion criteria and tried to elucidate the neurobiological underpinning of drug exposure and mood disorders.

Discussion

The interaction between substance use and mood disorders is complex and multifactorial. Indeed, the existing overlap of developmental, genetic, environmental and symptomatic factors is a clinical and research challenge. After initial work defining shared neurotransmitters and their receptor dysfunctions, the new studies describe genetic, neuroendocrine and neuroanatomical influences, which are reviewed in the present paper. Although the scope of this article has been the neurobiological

Conclusion

The neurobiological relevance for the occurrence of comorbid mood and substance abuse disorders has not been fully elucidated as most studies exclude comorbid patients (Busto et al., 2009). Considering the high levels of individuals who experience comorbidity in these areas as well as the negative associated outcomes, this is clearly an area that requires further in-depth investigation. Furthermore, findings from this area can help to inform drug abuse prevention and intervention efforts, and

Conflicts of interest

Nieves Gómez-Coronado has received travel grants from Janssen Cilag, Lundbeck, and Otsuka; has been a speaker for Otsuka, Lundbeck, and Pfizer and has received grant/research support from the Fundanción Española de Psiquiatría y Salud Mental. Rickinder Sethi,Chiara Cristina Bortolasci, Lauren Arancini have no conflicts of interest. Michael Berk has received grant/research support from the National Institutes of Health, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments

MB is supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (grant number 1059660).

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