Developmental Neurobiology of Bipolar Disorder and Substance Use Disorder

August 1, 2006

A discussion of the development of the brain and whether neurobiology of the brain can play a role in predicting risk for future bipolar disorders and substance use disorders SUDs.

August 2006, Vol. XXIII, No. 9

The apparent strong association between bipolar disorder and substance use disorders (SUDs) could be explained in several ways. Bipolar disorder may be causing SUD, SUD may be causing bipolar disorder, or both disorders may share common origins. As discussed by Brown,1 however, it is not likely that any of these explanations is correct.

Since both of these disorders often have their onset in adolescence, it might be important to look at the effects that bipolar disorder and SUD have on the developing brain. Perhaps either or both of these disorders disrupt the normal development of the brain in such a way that the brain never reaches full maturity; this, in turn, could make the brain vulnerable to a more insidious course of illness than if the disorders had occurred after the brain was mature. If this is true, then medical interventions may not be as effective as they would have been had the brain reached full maturity. This article will look at the development of the brain and whether neurobiology of the brain can play a role in predicting risk for future bipolar disorders and SUDs.

Larson and colleagues2 have shown that patients with either manic or euthymic bipolar disorder (aged 17 to 45 years) and healthy controls performed similarly on the delayed response test (which measures spatial working memory and involves the dorsolateral prefrontal cortex [DLPFC]). However, patients with euthymic and manic bipolar disorder performed significantly more poorly than controls on the Object Alternation Test (which measures inhibitory control and involves the orbitofrontal cortex [OFC], the part of the brain that influences inhibition). This suggests that adults with bipolar disorder may have a deficit in the OFC.

Inhibitory control may be involved in inhibiting manic symptoms, such as hypersexuality. Inhibitory control also plays a part in SUD. Since bipolar disorder and SUD may have their onset during adolescence, the question is whether the OFC deficit occurs because these disorders prevent the brain from fully maturing as it normally would (by the end of early adulthood or about age 22) or whether these disorders damage the OFC no matter when they occur. Because earlier onset of these disorders usually results in a poorer prognosis, the first explanation may account for the influence an immature brain has on a disease state compared with the influence a mature brain would have when the disease state occurs later in life.


In order to understand how brain development may be disrupted by the emergence of bipolar disorder or SUD during adolescence, it is important to understand the normal development of the brain during this period. Much research is beginning to emerge on the development of the adolescent brain. Chambers and colleagues3 have summarized some of the findings in terms of 3 important events: (1) pruning neurons, (2) the role of hormones, and (3) maturation of the prefrontal cortex (PFC).


First, the adolescent brain begins the process of pruning. During pruning, adolescents lose 20% to 40% of their total neurons. One of the neurons involved is associated with serotonin. When serotonin neurons are lost, impulsivity increases, which may be the reason adolescents are less able to carry on cognitive processes. In a study of adolescent decision making, Baird and colleagues4 showed that, compared to adults, adolescents took significantly longer to decide whether a presented scenario was “not a good idea.” The adults were able to quickly elicit mental images of possible outcomes that steered their decision- making process by recruiting greater activation of the insula and the right fusiform face area. Adolescents may impulsively act before they take time to decide whether their choice is a good one, and they are not as likely to use mental images when making a choice.

Effect of hormones

Second, when hormones come on board, they influence the primary motivational circuitry, cortical-striatal (including the nucleus accumbens)-thalamic-cortical, which increases sensitivity to pleasurable experiences. The seeking out of pleasurable experiences, some of which may be risky, may be caused not only by an increased sensitivity to these experiences but also by the inability to distinguish which events are motivationally relevant or irrelevant.

In a study comparing adolescents to young adults, Bjork and colleagues5 showed that there were no differences in brain activity while performing a task for monetary gain. However, the adolescents had less recruitment of the right amygdala and the right ventral striatum than adults while anticipating response for such gain.

The amygdala establishes learned associations between motivationally relevant events.6 This inability to anticipate what events are motivationally relevant or irrelevant may be why adolescents seek out risky behaviors more than adults.

Maturation of the prefrontal cortex

Third, the PFC does not mature until about age 22. This means the PFC in adolescents is immature (will not have proper connections to other parts of the brain that would allow inhibition to occur quickly, especially in emotionally charged situations).

The inability to inhibit responses has been elaborated by Casey and colleagues, 7 who studied children aged 7 through 12 years and adults aged 21 through 24 years, and by Tamm and coauthors,8 who studied participants aged 8 through 20 years, on a go/no-go task with corresponding functional MRI studies. These studies showed that children used the DLPFC and had more errors than adults, who used the ventral PFC or the OFC.

Another separate process that occurs during adolescence is myelination. This can influence the speed with which one processes and the speed with which one inhibits responses. In 2006, Luna and Sweeney9 showed that the changes in the brain during adolescence occur in order to move from a brain that requires much more energy to process information to a more efficient brain as an adult. These processes can explain why experimentation may be more likely to occur in adolescence. For instance, if children do not have anything they are passionate about, such as athletics, music, or academics, they may be more likely to seek out other means of feeling pleasure (eg, risky behaviors), which puts them at increased risk for substance abuse. In fact, academic and social failure by age 7 through 9 can predict substance abuse by age 14 through 15.10

If the adolescent does not succumb to substance abuse, or other psychiatric disorders that may influence normal development, the brain will continue to undergo these changes. In particular, the PFC and the corresponding inhibitory response will mature.

Therefore, one can assume that if the brain is allowed to develop normally, the mature PFC can help to control or inhibit the disease state more effectively if bipolar disorder emerges after adolescence than it could if the disorder emerges earlier. One might wonder what would occur if bipolar disorder begins in adolescence.

Chang and associates11 looked at adolescents who were treated for bipolar disorder and found that they had significantly lower levels of N-acetylaspartate (which measures neuronal density) in the right DLPFC when compared with controls. Because N-acetylaspartate serves as a “brake control” during adolescence, reduced levels may translate into reduced effectiveness in inhibiting mania in subcortical structures.

On the other hand, neither Gallelli and colleagues12 nor Chang and colleagues13 found a significant difference between N-acetylaspartate levels in adolescents with early onset bipolar disorder (most were taking medication) and in healthy controls. This may indicate that the longer the disorder progresses, the greater the effect on the DLPFC. What remains to be understood is whether certain medications or combinations of medications can decrease the effect of bipolar disorder on the DLPFC by indirectly regulating a number of factors involved in cell survival pathways.14


What is the effect of SUD in the developing brain? The ventral tegmentumnucleus accumbens (VTA-NA) tract is important to acute drug use disorder. Kalivas and Volkow6 have shown that when substances like cocaine are used, dopamine increases in the shell of the nucleus accumbens. Increased levels of dopamine in the shell direct the brain to experiences that are more salient and pleasurable; because dopamine levels are increased with cocaine, this results in an increase in the magnitude of pleasurable effect. During withdrawal, less dopamine is released and there is a decrease in D2 receptors. When D2 receptors decrease in the shell of the nucleus accumbens, natural reinforcers are no longer salient, but drugs are.6,15 As D2 receptors decline, more drugs are needed to get the same effect.

Thanos and associates16 have studied the effects of administering adenovirus to mice to increase D2 receptors by 50%. Results showed that the mice decreased alcohol intake by 70%. While the role of the VTA-NA tract and increased dopamine in the shell of the nucleus accumbens is important in acute drug use, dopamine in the PFC and the amygdala, and glutamate release in the core of the nucleus accumbens play a key role in the reinstatement of drug seeking after chronic drug use disorder.

During chronic drug use, dopamine is released between the VTA-PFC tract and the VTA and amygdala. During chronic drug use and withdrawal periods, there is also an increase of G protein binding--protein AGS3--in the PFC. Increased AGS3 levels inhibit D2 receptor signaling and correspondingly increase D1 receptor signaling, which causes increased activity of projections from the PFC (in this case, the anterior cingulate and the OFC) to the core of the nucleus accumbens. When cues or stimuli occur that are associated with drug seeking, increased activation of projections from the PFC occurs, which, in turn, increases release of glutamate in the core of the nucleus accumbens. This increase in glutamate causes an increase in drug seeking and intake. Such stimuli might include a cue previously associated with drug use, a mild stressor, or a single dose of the drug

The release of dopamine in the PFC and the amygdala is necessary for the amygdala to recognize cue-associations with drug use (motivationally relevant events) and for the PFC to exert its effect on the nucleus accumbens (to mediate behavior). In this scenario, the PFC would not be able to restrict the compulsion to seek out stimuli that have cueassociations with drug use. Hence, this process may correlate with addiction or the loss of control, with the addict continuing to use the drug even though there is no longer pleasure in its use.

The changes that occur after chronic drug use are more permanent than changes that occur during acute drug use and may be a reason why relapse occurs in addicts. Since adolescents may not be able to differentiate between motivationally relevant and irrelevant events (as previously discussed), when addiction occurs, the PFC may increase the tendency to seek out risky behaviors whether they are relevant or not. Alternatively, addiction may tune the otherwise less sensitive amygdala found in adolescents into a more sensitive adultlike amygdala that seeks out only drugassociated relevant events.

Although patients may use substances to self-medicate their manic symptoms, it is clear that the use of multiple substances, such as marijuana and alcohol, may, in reality, make the neurobiologic effect even worse. When patients (aged 18 to 65 years) presented with active marijuana and alcohol use in the manic phase, the marijuana did not decrease the level of the manic state.17 Thus, although the sensation of feeling calmer with marijuana may have been experienced by bipolar substance abusers who were manic and using alcohol, the mania symptoms were actually worse in those who presented with bipolar disorder and marijuana and alcohol use than in those with bipolar disorder and alcohol use alone.

Use of multiple substances may be a sign of a more progressive addiction, which would likely decrease the ability to inhibit compulsive behavior and the level of mania. Moreover, the type of treatment used may have greater effect on those who are actively using marijuana during their presentation with mania and alcohol. Those who were treated with lithium and psychosocial therapy in this study (compared with those treated with lithium, valproic acid, or psychosocial treatment alone), had the highest percentage of heavy drinking days.

One might wonder whether valproic acid may have reduced craving and the urge to use drugs because of its antiglutaminergic effect on the projections from the PFC to the nucleus accumbens that occurs with chronic drug use. The individuals who used alcohol and marijuana were younger than the other study participants; because alcohol and marijuana are the most frequent substances of abuse in children and adolescents with bipolar disorder, early onset of bipolar disorder and multiple substance abuse disorders may have a greater neurobiologic effect on the immature brain if the disorders go undetected and untreated.18

How else might bipolar disorder and SUD influence each other when they occur during adolescence? As noted, teens are more likely to experiment if they have had little academic or other success before adolescence. If they have a family history of substance abuse, they are also more likely to have a genetic predisposition to tolerance.19 Since a family history of substance abuse is more likely to result in progressing from initiation to dependence, these adolescents may do so without becoming fully aware that they have a problem because their tolerance allows them to use drugs without feeling the effects as strongly as nontolerant adolescents. They may have been born with lower D2 levels or reduced D2 levels may have developed secondary to drug use.15 Whatever the reason, they are more likely to become chronic abusers and hence, become addicted.

If substance abuse occurs before the development of bipolar disorder, there may be a more rapid onset of mania because there is less ability to control or inhibit symptoms of mania (eg, hypersexuality) or mood associated with subcortical structures20 because of the effect of addiction on the OFC, as noted by Goldstein and Volkow.21 If the bipolar disorder occurs before the substance abuse, the effect on the OFC may strengthen the compulsion to use drugs.2 In addition, the addiction process changes the way the OFC normally performs (by forming different connections); thus, the OFC may not function as it normally would have before the addiction.

One may also wonder whether this reorganization of connections prevents the OFC from ever fully developing. If normal functioning or maturation of the OFC does not occur in adolescence, this may lead to less control of symptoms of mania in adulthood. This could explain why early onset of mania has a higher risk for a worse prognosis. On the other hand, if all adolescents must rely more on the less efficient DLPFC for inhibitory control during adolescence, the adolescent with bipolar disorder, who has a less mature DLPFC, may have more difficulty throughout this period. Decreases in N-acetylaspartate levels in the DLPFC (used primarily during adolescence for inhibition) were found in euthymic bipolar patients and manic patients compared with healthy adolescents. We would hope that earlier detection and treatment of bipolar disorder and SUD (presenting separately or together) would increase the likelihood that the OFC would be able to fully mature.


Early detection and treatment of SUD and bipolar disorder is extremely important to neurobiologic development in adolescents. If the developmental processes discussed above are proved true, not treating adolescents with SUD and bipolar disorder may prevent normal development of the brain and decrease the ability of the child to function at his or her fullest potential as an adult. Just as important, not treating the disorders early may decrease the responsiveness of a mature brain to medication interventions. Neurobiology is in its infancy. More research is needed to more accurately understand the underlying causes of bipolar disorder and SUD on the developing brain. New research should also concentrate on finding treatments that may allow normal development of the brain to occur despite the onset of psychiatric disorders.

Dr Simkin is clinical assistant professor at the Florida State University College of Medicine in Tallahassee, Florida. She reports that she is a speaker for Abbott Laboratories.


1. Brown ES. Bipolar disorder and substance abuse. Psychiatr Clin North Am. 2005;28:415-425.
2. Larson ER, Shear PK, Krikorian R, et al. Working memory and inhibitory control among manic and euthymic patients with bipolar disorder. J Int Neuropsychol Soc. 2005;11:163-172.
3. Chambers RA, Taylor JR, Potenza MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry. 2003;160:1041-1052.
4. Baird A, Fugelsang J, Bennett C. What you were thinking: an fMRI study of adolescent decisionmaking. Poster presented at: Cognitive Neuroscience Society Meeting; April 2005; New York.
5. Bjork JM, Knutson B, Fong GW, et al. Incentiveelicited brain activation in adolescents: similarities and differences from young adults. J Neurosci. 2004; 24:1793-1802.
6. Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162:1403-1413.
7. Casey BJ, Trainor RJ, Orendi JL, et al. A developmental functional MRI study of prefrontal activation during a performance of a go-no-go task. J Cogn Neurosci. 1997;9:835-847.
8. Tamm L, Menon V, Reiss AL. Maturation of brain function associated with response inhibition. J Am Acad Child Adolesc Psychiatry. 2002;41:1231-1238.
9. Luna B, Sweeney JA. The emergence of collaborative brain function: fMRI studies of the development of response inhibition. Ann N Y Acad Sci. 2004;1021: 296-309.
10. Hops H, Davis B, Lewin LM. The development of alcohol and other substance use: a gender study of family and peer context. J Stud Alcohol Suppl. 1999; 13:22-31.
11. Chang K, Adelman N, Dienes K, et al. Decreased N-acetylaspartate in children with familial bipolar disorder. Biol Psychiatry. 2003;53:1059-1065.
12. Gallelli KA, Wagner CM, Karchemskiy A, et al. Nacetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder. Bipolar Disord. 2005; 7:589-597.
13. Chang K, Karchemskiy A, Barnea-Goraly N, et al. Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Adad Child Adolesc Psychiatry. 2005;44:565-573.
14. Carlson PJ, Singh JB, Zarate CA Jr, et al. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx. 2006; 3:22-41.
15. Volkow ND, Fowler JS, Wang GJ. Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol. 2002;13:355-366.
16. Thanos PK, Volkow ND, Freimuth P, et al. Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem. 2001;78: 1094-1103.
17. Salloum IM, Cornelius JR, Douaihy A, et al. Patient characteristics and treatment implications of marijuana abuse among bipolar alcoholics: results from a double blind, placebo-controlled study. Addict Behav. 2005;30:1702-1708.
18. Geller B, Cooper TB, Sun K, et al. Double-blind a nd placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry. 1999; 37:171-178.
19. Schuckit MA. Reaction to alcohol in sons of alcoholics and controls. Alcohol Clin Exp Res. 1988;12: 465-70
20. Chang K, Adelman NE, Dienes K, et al. Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation. Arch Gen Psychiatry. 2004;61: 781-792.
21. Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159:1642-1652.