Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications
Dr. Camacho is a research fellow with the International Mood Center in the Department of Psychiatry at the University of California in San Diego, and is attending psychiatrist at Imperial County Behavioral Health in El Centro, California.
Disclosure: The author reports no financial, academic, or other support of this work.
Please direct all correspondence to: Alvaro Camacho, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 9500 Gilman Dr, Mail Code 0603, La Jolla, CA 92037-0603; Tel: 619-252-0428; Fax: 619-497-6686; E-mail: email@example.com.
• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
The use of addictive substances is prevalent among individuals with bipolar disorder (the so-called “dual diagnosis” phenomenon). New studies have led to the proposal that the two groups of disorders exist on a continuum. The Akiskal-Pinto bipolar spectrum schema describes this continuum as bipolar type III 1/2. This review explores the possibility that some forms of substance abuse, especially stimulant abuse, can belong to the bipolar spectrum. These forms of substance abuse respond to anticonvulsant medications used as mood stabilizers. The review is divided into the following sections: neurobiology of addictive disorders, epidemiology of bipolar illness and comorbid substance abuse (particularly stimulant abuse), and clinical correlation with proposed treatment options. The proposed spectrum, with emphasis on stimulant use and bipolar disorder, provides an alternative understanding to a phenomenon that otherwise remains a diagnostic dilemma and therapeutic quagmire. Anticonvulsant medications appear to be a viable joint option for a proportion of patients with this condition.
Patients with comorbid mental illness and substance abuse disorders (SUD) frequently present for treatment with a confusing array of psychiatric and physical findings. The importance of identifying the association between mental illness and SUD in these patients was recognized as early as 1979 by McLellan and colleagues.1 Assessment of comorbid mental illness and SUD can be difficult; it begins with an open mind to avoid premature closure of diagnostic possibilities, lest the patient be left without adequate treatment.2 Given the high frequency of substance abuse among patients with mental disorders, clinicians should use a probing diagnostic approach.2-4 In order to clarify the relationship between SUD and mental illness it is recommended that they assess: when the initial mental symptoms began, and, in the case of an exacerbation, under which circumstances the symptoms began again; when the SUD started and whether the symptoms preceded the development of substance abuse; which subjective effects the substance has on the psychiatric symptoms (relief, exacerbation or cessation); and whether or not patterns of substance use alleviate the underlying psychiatric phenomena.
Of all Axis I mental disorders, mood disturbances—especially bipolar disorder—are most likely to co-occur with SUD. Studies5,6 have described that an earlier onset of bipolar disorder is seen in patients who develop SUD compared to those who do not, suggesting that an earlier age at onset of mood symptoms may put individuals at risk for developing an addiction disorder.
This review attempts to inform the clinician about the increasing evidence of comorbidity between bipolar disorder and substance use, with a particular emphasis on stimulant use disorders. The article will review the neurobiology of addiction and then the epidemiology of bipolar disorder and addictions, both of which should aid in building clinical correlations, especially with regard to emerging treatments. Stimulant abuse will again be the main focus of the model of bipolar disorder proposed in this article.
Neurobiology of Addiction
Addiction can be viewed as a form of drug-induced neuronal plasticity. Many studies identifying possible transcription factors that could contribute to the developing of tolerance and eventual dependence on addictive substances are currently underway. Two of the most studied transcription factors are the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the ΔFosB. These transcription factors are responsible for the autoregulation of intracellular transmission, which promotes the biosynthesis of certain neurotransmitters, such as norepinephrine, dopamine, glutamate, and γ-aminobutyric acid, among others, that are responsible for stable adaptations of neuronal function and the reward effects of addictive substances.7
Research has shown that the upregulation of the cAMP pathway and the eventual activation of CREB occurs in response to the administration of several drugs of abuse, including opiates, stimulants, and ethanol. The same has been described for the ΔFosB transcription factor.8-10 Thus, these transcription factors play a role in the acute and chronic administration of addictive substances. The activation of CREB is the result of the upregulation of the second messenger pathway of cAMP, which has been described as an adaption to chronic exposure to drugs of abuse, leading to tolerance and dependence. On the other hand, ΔFosB has been implicated in the acute adaptations of addictive substances or sensitization, which refers to the enhanced response to the substance use.7-11
CREB and ΔFosB seem to balance each other. CREB has been implicated in drug inhibition and states of withdrawal, depression, and dysphoria, whereas the Fos family of transcription factors has been associated with euphoria, increased locomotor responses to drugs, and rewarding responses to drugs, especially morphine and cocaine.7,8,12 These features bear some resemblance to the biphasic cyclothymic phenomenology of the bipolar spectrum.13 However, whether these underlying mechanisms are similar is speculative at this point.
Data from the Epidemiological Catchment Area study14 reported that the lifetime prevalence of any substance abuse or dependence among individuals with bipolar disorder types I and II is 56.1%, and is 60.7% in patients with only bipolar I disorder.2,14 Patients with more complicated forms of bipolar disorder (eg, mixed or rapid-cycling) are also more likely to have SUD.5,15 Antisocial personality disorder is the only psychiatric condition with a reported higher rate of comorbid SUD.2,16,17
A recent study done by Copeland and Sorensen18 found that mood disorders accounted for 71% of the diagnoses among individuals with methamphetamine use disorders. A previous study by Winokur and colleagues19 found that individuals with bipolar disorder not only have a higher incidence of alcoholism but also a considerable tendency toward stimulant abuse and dependence. Additionally, these investigators postulated the hypothesis between a common familial-genetic diathesis for a subtype of bipolar disorder and stimulant abuse. This was corroborated in another study,20 which reported that 72% of individuals with a history of alcohol use disorder had a lifetime prevalence of stimulant use (26% with powder cocaine and 46% with crack cocaine). McElroy and colleagues21 described a cohort of 288 bipolar patients in which 33% had lifetime prevalence of alcohol use disorder, followed by an 18% lifetime prevalence of stimulant (including cocaine) use disorder. Moreover, there was no significant difference between patients with bipolar I and bipolar II disorder and their comorbid substance use.
Dalton and colleagues22 reported a lifetime rate of 40% of suicide attempts in a cohort of 336 subjects with bipolar I disorder, bipolar II disorder, schizoaffective disorder, and comorbid substance abuse. The authors described that the use of drugs among this cohort was a significant predictor for suicide attempts (P=.037); they described cannabis as the most frequently used substance (74%), followed by hallucinogens (18%), sedatives (18%), and cocaine (18%).
The question that many clinicians face on a daily basis is which disorder accounts for the symptomatology that the patient is experiencing. Based on the literature reviewed, and building on the Akiskal-Pinto formulation,23 Camacho and Akiskal24 hypothesized the existence of a bipolar-stimulant spectrum. Just as in some depressives with familial-genetic permission for bipolarity who manifest hypomania upon antidepressant challenge,25,26 they suggested that in another group of potential bipolar depressives, stimulant use can bring about the first overt hypomanic or manic episode. They also suggested that anticonvulsants can stabilize the underlying bipolar dysregulation, treat the withdrawal phenomena from substances of abuse, and reduce the craving for the substance.
Emerging Treatment Approaches
Treatment with Mood Stabilizers
The use of divalproex sodium has provided promising results not only in the treatment of patients with comorbid bipolar and SUD, but also as an aid for preventing further relapse. It can be used as an adjunctive agent for detoxification, as well. Starting doses can be 500 mg at night, increased up to 2,000 mg in divided doses. It is important to monitor liver function, pancreatic function, and serum levels when using divalproex.27-29 More longitudinal studies are needed to assess the length of abstinence in these patients.
A preclinical study using carbamazepine posed interesting questions about the utility of this mood stabilizer in treating methamphetamine-related bipolar symptoms and in reducing associated methamphetamine cravings.30 Brady and colleagues31 postulated the utility of this mood stabilizer in patients with cocaine dependence and comorbid affective disorders, and found a trend toward fewer positive urine drug tests. Another study32 demonstrated improvement on self-ratings of depression and irritability. Doses of carbamazepine start at 300 mg BID, and can be increased up to 1,600 mg/day. Patients on carbamazepine should be monitored for hyponatremia and thrombocytopenia.
Lithium has shown some efficacy in reducing amphetamine-related locomotor activation.33 Larger epidemiological trials are needed to validate this finding. Lithium has also been used safely in the treatment of bipolar adolescents with secondary substance dependence.34,35 A recent study36 demonstrated that bipolar patients treated with lithium have a lower risk for suicide than those treated with divalproex (after controlling for comorbid medical and psychiatric conditions). Usual starting doses of lithium are 300 mg twice daily, with doses up to 1,200 mg/day or higher. It is important to monitor lithium levels (usually between 0.6–1.2 mEq/L), and thyroid and renal function. Future studies need to address this medication specifically in those patients with comorbid bipolarity and some types of substance abuse.
Gabapentin has been extremely useful for treatment of comorbid bipolar, anxiety, and substance abuse disorders.37 A recent study reported that gabapentin appeared to be safe and efficacious in reducing the use of cocaine in a group of psychiatric patients.38
Since oxcarbazepine may be considered a prodrug,39 it may be less likely to cause drug-drug interactions. Treatment with oxcarbazepine is started at 600 mg BID, with doses up to 2,400 mg/day. Current consensus states that the dose of oxcarbazepine should be 50% higher than that of carbamazepine. Oxcarbazepine does not have the same well-established record as carbamazepine in the treatment of comorbid substance abuse with bipolar disorder, although the literature has reported its promising use.40,41
Dosing for topiramate ranges from 300–800 mg. It has been reported that this medication has minimal drug interactions, and may cause weight loss (a potential “virtue”); however, it can cause cognitive dulling.42 This agent can potentially be used for the augmentation treatment bipolar disorder.43 Additionally, it has been reported that topiramate might help as an adjunct treatment in diminishing the impulsive cravings in patients with alcohol use disorders.44,45
Brown and colleagues46 described the potential benefit of lamotrogine in the treatment of patients with bipolar disorder and comorbid cocaine use. This finding is important, since lamotrigine appears to possess antidepressant properties that may be beneficial for patients who are experiencing protracted dysphoria from stimulant withdrawal and who have a comorbid bipolar diathesis.46,47
This newer anticonvulsant differs mainly from the others because of its beneficial side-effect profile and reduced risk of drug-drug interactions.41 Studies have reported some benefit of zonisamide in the treatment of bipolar disorder and other psychiatric conditions.48,49 However, as reported by McElroy and Keck,50 it is necessary to guide clinical practice on evidence-based medicine, leaving enough flexibility to tailor the appropriate treatment to each individual patient. Although the medications described above, including zonisamide and the other mood stabilizers, are helpful in treating patients that fall into the substance abuse bipolar spectrum, there is a need for more studies that will further validate the importance of adequately treating this complicated disorder.
Other Potential Treatments
Several short-term trials using antidepressants demonstrated some reduction in the consumption of stimulants, and showed potential in achieving abstinence.51 These trials have been performed using imipramine, desipramine, fluoxetine, and pramipexole.52-55
However, it is generally best to avoid antidepressants in stimulant abuse patients, since these patients could be switched to a mixed or manic state. Treatment of these patients with an anticonvulsant first to control their increased irritability, dysphoria, racing thoughts, insomnia, and agitation beyond the expected phase of a withdrawal episode is therefore recommended.
New-generation antipsychotics have also been also used for the treatment of the proposed spectrum of bipolar and addictive disorders. Brown and colleagues56 reported that quetiapine could be used to stabilize patients with bipolar disorder and to reduce their cocaine use. Recently, a pilot trial showed that olanzapine was not effective in the treatment of primary cocaine dependence without baseline mood disorder.57 Future clinical trials need to elucidate the use of these medications in patients with comorbid bipolar disorder and substance abuse, especially stimulant use.
This review has presented information about two conditions, bipolar disorder and SUD, which could be considered as a continuum of a bipolar spectrum. This model of a continuum of bipolar and substance abuse disorders was exemplified using stimulant abuse as a case in point.24
A similar hypothesis involving the heroin-bipolar connection has been proposed by Maremmani and colleagues.58 Additionally, the proposed hypothesis by Khantzian and colleagues59 on “self-medication” in individuals with stimulant use disorders has raised several questions regarding possible associations between temperament and stimulant addiction. Aharonovich and colleagues60 recently tested a similar hypothesis: the investigators used the State-Trait Anger Expression Inventory in 60 individuals with SUD, including cocaine, heroin, and marijuana use disorders, and found that individuals with cocaine use disorders reported a trend toward more angry temperament compared with individuals with opioid addiction. Studies done by Helfrich and colleagues61 and Craig62 found that patients with cocaine abuse problems had increased problems with impulsive behavior, acting out, and authority figures, according to patients’ scores on the Minnesota Multiphasic Personality Inventory.61,62
When prescribing for such conditions, the clinician should keep in mind the possibility of increased side effects associated with the concomitant use of medications and addictive substances, especially stimulants,63,64 although it is also important to provide the care necessary to avoid devastating behavioral consequences of substance-related mood and psychotic disorders, particularly if there are stimulants involved. It is also important to treat comorbid bipolar disorder and substance abuse as a continuum and not as isolated disorders.24,65
Furthermore, experts in the field of addiction have emphasized the importance of a detailed lifetime evaluation for independent psychiatric problems and SUD. In this process, careful attention should be placed on patients with bipolar disorder, as they may not provide a reliable information about their comorbid substance abuse.66-68
Increasing training in the early identification of individuals with a bipolar-addiction diathesis could avoid problems, such as overprescribing stimulants or antidepressants in susceptible individuals whose initial presentation is depression.69 Despite reported stabilization of bipolar-related electroencephalographic changes with methylphenidate, the clinician should be cautious in prescribing stimulants to bipolar patients.70 With documented attention-deficit/hyperactivity disorder history preceding and/or co-existing with bipolar and substance abuse, mood-stabilizing anticonvulsants should be the mainstay of a treatment regimen; the difficult clinical judgment to add a stimulant to this regimen should be deferred to experts with a great deal of experience in this area.
Prospective studies on this subject should assess the risks and benefits of long-term use of stimulants for conditions such as attention-deficit disorder, which could be the initial presentation of a bipolar diathesis.71-74 Adequate follow-up and constant review of the working diagnosis is important to prevent the possible development of a complicated bipolar-stimulant use diathesis.75-78 The use of standardized questionnaires to estimate levels of cravings for substances and early identification of a bipolar spectrum could also possibly prevent devastating outcomes in these individuals.79,80
To summarize, this article presents co-occurring SUD and bipolar disorder as part of the bipolar spectrum, although it recognizes that knowledge on this subject is still limited. Understanding and identifying the different faces of the bipolar spectrum is necessary in order to offer prompt treatment, avoid suicide episodes, and educate patients about the detrimental effect of addictive substances.81,82 This clinically heuristic model to reconceptualize the relationship between bipolar spectrum and substance abuse disorders opens therapeutic opportunities to co-occurring bipolar and substance abuse disorders in both psychiatric and general medical settings. PP
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