COMORBID CONDITIONS: Bipolar Disorder and Cannabis Use

Adam Nelson, MD

Note: The following is a composite of actual cases. Some details have been changed to protect patient identity.

A few years ago, I received a referral for a young man who was taking Suboxone for opioid dependence. The referring physician was trying to taper the Suboxone, and other than mild anxiety, the patient had appeared to be doing well. But when his dose was reduced further, he developed worsening anxiety, insomnia, weight loss, anhedonia and panic. He felt overwhelmed, depressed, helpless and hopeless, and had begun having suicidal ideation.

The referring physician had initially diagnosed major depression and prescribed an SSRI antidepressant. When the patient failed to respond to treatment, his Suboxone dose was raised back up, and he became psychotic, with paranoid delusions of reference and guilt. He was convinced that he was possessed by an evil spirit, and that he was being targeted on the Internet.

Further history revealed several years of difficulties with anxiety, which caused social discomfort, avoidance, and episodic isolation from friends and family. At home, he sometimes retreated to his room for several days at a time, surfing the Internet and avoiding contact with others. He also engaged in reckless and impulsive “extreme” physical acts of daring, such as leaping from high walls.  

The patient had apparently turned to substance use as a means of self-medicating his anxiety. Initially, he used cannabis that he got from his older brother, who had a “cannabis card.” Then he began stealing opioid pain medications prescribed to his father for chronic back pain. During his Suboxone detox, the patient began smoking marijuana more often.

Table 1 summarizes the DSM-5 diagnostic criteria for a depressive episode.¹ Antidepressants, and SSRIs in particular, are among the most frequently prescribed medications, including for teens and children. Recently, however, the efficacy and safety of antidepressants have come under further scrutiny.² The FDA now requires a black-box warning of increased risk of suicidal thinking in adolescents and young adults in package inserts of all antidepressant medications. Some experts believe the problem of overuse or misuse of antidepressants may be due to misdiagnosis.

Many pediatric and young adult patients can present with a depressive episode that may eventually evolve into a diagnosis of bipolar disorder. Depression can present at nearly any age, ranging from childhood, to early adulthood, to late adulthood.³ Some have suggested that a history of a depressive episode in a young person, along with a family history of bipolar disorder, may be a significant risk factor for eventually developing a diagnosis of bipolar disorder.⁴ Others have suggested that a younger age of onset for an initial depressive episode may more likely predict a diagnosis of bipolar disorder, while older age of onset may predict a diagnosis of major depression.⁵ There are exceptions, of course, so when evaluating a patient with depression, it is essential to inquire about current or previous episodes of depression, mania or hypomania, especially if the patient is under 40 or has had a poor initial treatment response (see tables 2a and 2b).  

In the young man’s case, previous history of hypomanic or possibly manic episodes suggested a differential diagnosis of bipolar 1 disorder (depressed, with psychotic features) or bipolar 2 disorder (depressed, with substance- or medication-induced mood and/or psychotic disorder).

The DSM-5 specifies three bipolar disorder types and requires the clinician to exclude other possible conditions that can present with similar symptoms (see Table 3). These include PTSD, anxiety disorders, adjustment disorders, personality disorders, mood disorders due to a medical condition, as well as substance- or medication-induced disorders.

Substance use is highly comorbid with mood and anxiety disorders.6 The prevalence of these comorbid disorders has been increasing rapidly among teens and young adults.⁷ In the young man’s case, he did not appear to become severely depressed or psychotic until very late in his Suboxone taper, without any evidence of delirium or physical withdrawal symptoms. He did, however, report a significant increase in cannabis use over the preceding several weeks.

The use of medical marijuana is legal in California, and it continues to gain legal status, both medicinally and recreationally, in several other states. Cannabis exerts much of its effect via the endocannabinoid CB1 receptor found in many regions of the brain. Studies have shown that cannabis can affect mood and memory formation (hippocampus, amygdala and thalamus), and motor skills and coordination (basal ganglia and cerebellum, and brainstem).⁸

Because of increasing public interest, several professional groups, including the AMA and the American and California psychiatric associations, have extensively reviewed the currently available literature on the neuropsychiatric effects of marijuana. They and others have released several papers and position statements regarding potential difficulties with marijuana use.  

Perhaps the most significant position statement comes from the American Academy of Child and Adolescent Psychiatry.⁹ The statement warns about the immediate and long-term harmful consequences of cannabis use on the developing brain of a minor or young adult. Several research studies seem to support this concern, demonstrating significantly deleterious physiological and clinical effects of cannabis on areas of the frontal and prefrontal cortex.¹⁰ These areas are responsible for memory formation, attention, executive function, decision making, and motivation. In adults, these areas are not fully developed until age 25.

Another growing body of evidence has linked marijuana use to psychiatric problems and to increased severity of psychopathology in patients with genetic and epigenetic predisposition and risk of mental illness, including schizophrenia-spectrum disorders and bipolar disorders.¹¹ One study suggests that ongoing cannabis use can significantly prolong the acute symptoms of mood disorder and psychosis and can substantially delay recovery.¹²  

In some cases, the response to treatment of cannabis-induced psychiatric disorders may require several months, or even years. By comparison, the natural history of treatment response for other acute mood disorders tends to be considerably shorter. Perhaps the prolonged treatment latency may correlate with the detection of cannabinoids in the serum of chronic heavy users (see Figure 1).⁸  

The risk of cannabis provoking or exacerbating symptoms of severe mental illness has been known for decades, but the frequency of such problems used to be relatively low. In the past decade, however, the frequency has jumped. One possible cause is that the THC content of marijuana has been increasing significantly over the past 20 years, to a level that is estimated to be several times the potency available during the 1960s and 70s (see Figure 2).¹³

I prescribed risperidone for the young man and switched the SSRI to lamotrigine, slowly titrating to 200 mg daily. In addition, he agreed to stop using cannabis for 90 days. Over the next several months, his symptoms began to improve and eventually remitted. After six months, his risperidone was successfully tapered and discontinued. After six more months, his lamotrigine was discontinued. Six months later, he was discharged from care.

Two years later, however, he had a relapse of symptoms similar to his previous presentation, again preceded by several months of gradually increasing cannabis use. This time, I prescribed lurasidone, and he immediately halted his use of cannabis. It was unclear in the telling if any mood or anxiety disorder symptoms may have preceded his brief return to cannabis. Again, his symptoms responded to treatment and were in remission within six months. He remains on a lower daily dose of lurasidone.

What is the final diagnosis? For now, the answer is uncertain. The natural history of mood disorders may include several months or years of quiescence between acute episodes. The natural history of substance-induced disorders typically relates to the pattern of substance use. At this point, only time will tell.

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Dr. Nelson is a Mill Valley psychiatrist with a special medical interest in bipolar disorder.
Email: apnelsonmd@gmail.com

References
1. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 5th ed, APA (2013).
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4. Miklowitz D, Chang K, “Prevention of bipolar disorder in at-risk children,” Development & Psychopathology, 20:881-897 (2008).
5. Benazzi F, “Does age at onset support a dimensional relationship between Bipolar II disorder and major depressive disorder?” World J Biol Psych, 8:105–111 (2007).
6. Merikangas K, et al, “Comorbidity of substance use disorders with mood and anxiety disorders,” Addictive Behaviors, 23:893–907 (1998).
7. Kandel D, et al, “Psychiatric comorbidity among adolescents with substance use disorders,” J AACAP, 38:693-699 (1999).
8. Ashton CH, ”Pharmacology and effects of cannabis,” Brit J Psych, 178:101–106 (2001).
9. AACAP, “AACAP marijuana legalization policy statement,” www.aacap.org (2014).
10. Filbey F, et al, “Long-term effects of marijuana use on the brain,” Proceedings of Nat Acad Sci, 111:16913-18 (2014).
11. Regier D, “Comorbidity of mental disorders with alcohol and other drug abuse,” JAMA, 264:2511–18 (1990).
12. Kuepper R, et al, “Continued cannabis use and risk of incidence and persistence of psychotic symptoms,” BMJ, 342 (2011).
13. Mehmedic Z, et al, “Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008,” J Forensic Sci, 55:1209–17 (2010).