Risk Taking Behavior in Bipolar Disorder

A very rough compilation of articles and how it may be applied to animal models in our lab.

Negative Symptoms Surrounding Bipolar Disorder (BPD)During stages of mania in BPD, patients exhibit

altered processing (Roiser et al.) including behavioral symptoms of:Poor judgementHyperactivityRecklessnessAggressive behaviorIncreased goal directed/pleasurable activities

(Shaltiel et al.) (Yechiam et al.) Excessive pleasure seeking can often lead to increased

risk taking behaviors which are categorized by the negative implications involved (Yechiam et al.)

Neurocognitive ChangesEuthymic patients with BPD have been documented

to show neurocognitive impairments (Glahn et al.) Attention domainsExecutive processingDeclarative memoryPoor cognitive function has also been linked with acute

psychotic symptoms in patients with BPD (Glahn et al.)It is hypothesized that these changes may be driven by

motivational changes (increased pleasure seeking)this has also been described as increased focus on potential gains rather than losses(Yechiam et al.)

Impaired CognitionA study conducted by Glahn, et. al, found

patients with BPD had impairedSpeed of processingAttentionExecutive functioningWorking and declarative memory

These findings suggest that BPD involves and impairs multiple brain systems (Glahn et al.)

Impaired Cognition cont.

Glahn, et. al, found 75% of BPD patients performed more than 1 standard deviation below healthy volunteers on various levels of cognitionGreatest effects were seen in the speed of

processingBPD patients were also found to make

increasingly random and erratic choices compared to control patients (Yechiam et al.)

Patients with acute BPD had a low choice consistency—they made more erratic choices

Risk TakingDue to the neurocognitive changes experienced by a

patient with BPD, risk taking behaviors are increased during episodes of mania

Although these behaviors are hard to define, it has been noted that manic patients have the following risky behaviors:Increased prevalence of HIV(King et al.)Increased vulnerability to sexually transmitted

infections(King et al.)Substance abuse (Shaltiel et al.)General increased pleasure seeking (Shaltiel et al.)Belief in special physical and mental powers (Leahy)Excessive spending or gambling (Leahy)

Quantifying Increased Risk TakingIn a study examining sexual risk behaviors and

increased pleasure seeking in an outpatient psychiatry clinic, several significant relationships were found among affective disorders versus control population (King et al.)Females were found to have a high prevalence of

trichomoniasisPaitents noted having snorted/smoked cocaine

and/or heroin within the past 6 monthsPatients reported having had an STI within the

past 6 months

Quantifying Cont.Statistically significant relationships

How does this impact risk-taking behavior?

Those with a substance abuse problem (affective disorder patients), were more likely to report having exchanged sex for drugs

Increased number of sexual partners

Little STI protection was used – more than half reported no use of condoms during their last 5 sexual acts (King)

BPD patients, in some cases, have been found to express hypersexuality, which may augment their risk taking behavior (King)

The addition of drug use to hypersexuality further exploits a BPD patient’s risk-taking behavior

Sleep Deprivation (Killgore et al.)As previously mentioned,

BPD patients experience hyperactivity during episodes of mania

Sleep deprivation has been found to decrease the global brain activity and slow cognitive processes, One research article found

that cognitive processes become Slowed Effortful Inconsistent

Impaired CognitionCreative thinkingVerbal fluencyDecision makingMoral reasoningDivergent thinking

Whats the Point?“Judgement and decision making processes associated with risk taking may be impaired by sleep deprivation, along with motivation to act upon these judgments” (Killgore et al.)

In a manic patient, the sleep deprivation would not lead to decreased motivation or energy to act

Therefore, sleep deprivation augments a patient with mania to engage in risky behaviors

Gambling and SpendingDuring episodes of mania, patients demonstrate “poor

probabilistic reward learning due to oversensitivity to occasional rewards when choosing stimuli primarily associated with punishment” (Roiser et al.)

It was noted in one article, “patients in a manic state often believe they have unlimited financial resources” (Leahy)

Thus, patients with BPD are oversensitive to rewards of gambling/spending without financial means to recover from losses

This demonstrates the multi-faceted nature of risk-taking behavior in BPD

Animal models of Risk taking behavior---what does this stuff mean for our labMany of the methods used in the discussed

experiments can be modified to fit animal models

These experiments includeSleep DeprivationQuantifying RiskDietLithium TherapyValproate TherapyOther medications

Sleep DeprivationAs previously mentioned, sleep deprivation augments a manic’s ability

and desire to engage in risk taking behaviorSleep deprivation causes a decrease in cognitive processing-much like

mania, but this may not be enough for an accurate model of mania because of the decreased energy expenditures (Killgore et al.)

However, it was found that administration of dextroamphetamine most closely mimicked the high energy level, racing thoughts, increased propensity to seek out risky activities associated with mania. (Killgore et al.)

Thus, sleep deprivation with amphetamine administration will increase activity with little changes to the impaired cognition which provides a model for mania

This may help us quantify risk taking behaviors and provide us with ways to test medications for the attenuation of mania

Quantifying Risk in the Lab SettingThe elevated plus maze (EPM) is a way to

measure anxiety or risk taking behavior in mice (Shaltiel et al.).

By placing mice in the EPM, we can assess how “risky” they are being based on the amount of time in the open fields and how many times they enter the open fields.

Thus, including EPM in future experiments, we can quantify risk-taking behavior

DietIt was found that reduction in dietary tryptophan reduced

the synthesis of CNS serotonin Serotonin plays a large role in mood regulation. It was

suggested that hyperactivity of serotonin may play a role in mania and hypoactivity may play a role in depression. (Applebaum et al.)

In animals, ingestion of tryptophan free amino acid mixtures rapidly reduced plasma tryptophan levels without directly affecting other neurotransmitters (Applebaum et al.)

This study found that depressive symptoms were not exacerbated by serotonin but also tryptophan free amino acid mixtures administered with valproic acid had a strong, rapid antimanic effect (Applebaum et al.)

Medication TherapyMany medications have been found to have antimanic effectsOf these, several have been validated in animal models

LithiumValproate

Common BPD treatments in humans includeLithiumValproateOndansetronAtypical antipsychotics-rispiridoneCarbamazepineClozapine**These may all have value in animal models as their use in

humans is becoming increasingly more common**

LithiumLithium has been commonly used as a mood

stabilizer in BPD patients. (Willson)Lithium has well established efficacy for the

prevention of mania and, to some extent, depression.(Alda et al.)

In rats and mice, lithium administration has been shown to attenuate amphetamine induced hyperactivity. (Willson)

Because lithium is the standard treatment for manic patients, it serves as a cornerstone for experiments testing mania and risk taking behavior.

ValproateValproate is widely used as a mood stabilizer for BPD in

humans.(Willson)Valproate is less validated for preventing manic

symptoms than lithium.(Alda et al.)In rats and mice, Valproate has been shown to as an

effective pre-treatment for attenuation of hyperactivity (Willson).

In humans, valproate has been shown to significantly attenuate amphetamine induced energy, happiness, and alertness (Willson)

This evidence suggests that valproate may be an effective treatment for mania induced risk-taking behavior.

Atypical Antipsychotics and Other measuresOne study suggests that

olanzapine, aripiprazole, and quetiapine have mood stablilizing properties and may serve as long-term therapy options (Alda et al.)

Antipsychotics have had mixed results in terms of attenuation of amphetamine-induced mania, but should not be discounted from future studies

Because of the link between serotonin and mania, administering a tryptophan free diet may provide an alternate way to attenuate manic-like symptoms

In addition to depriving the body of serotonin precursors, serotonin receptor antagonist (such as ondansetron 5-HT3 antagonist) may also be effective for the attenuation of mania (Willson)

Works Cited Alda, Martin, Hajek, Tomas, Calkin, Cynthia and O'Donovan, Claire(2009)'Treatment of bipolar

disorder: New perspectives',Annals of Medicine,41:3,186 — 196 Applebaum, Julia, Yuly Bersudsky, and Ehud Klein. “Rapid tryptophan depletion as a treatment for

acute mania: a double-blind, pilot controlled study.” Bipolar Disorders 9 (2007): 884-887. Web. 1 Aug. 2009.

Glahn, David C., Carrie E. Bearden, Marcela Baraguil, Jennifer Barrett, Abraham Reichenberg, Charles L. Bowden, Jair C. Soares, and Dawn I. Velligan. “The Neurocognitive Signature of Psychotic Bipolar Disorder.” Society of Biological Psychiatry 62 (2007): 910-916. Web. 1 Aug. 2009. <http://www.sobp.org/journal>.

Killgore, William D.S., Nancy L. Grugle, Desiree B. Killgore, Briam P. Leavitt, George I Watlington, Shanelle McNair, and Thomas J. Balkin. “Restoration of Risk-Propensity During Sleep Deprivation: Caffeine, Dextroamphetamine, and Modafinil.” Aviation, Space, and Environmental Medicine 79.9(2008): 867-874. Web. 1 Aug. 2009

King, Cynthia, Jacqueline Feldman, Yvonne Waithaka, Inmaaculada Aban, Jianfang Hu, Sijian Zhang, Edward Hook, and Laura H. Bachmann. "Sexual Risk Behaviors and Sexually Transmitted Infection Prevalence in an Outpatient Psychiatry Clinic." American Sexually Transmitted Diseases Association 35.10 (2008): 877-82. Web.

Leahy, Robert. L. “Clinical Implications in the Treatment of Mania: Reducing Risk Behavior in Manic Patients.” Cognitive and Behavioral Practice 12 (2005):89-98. Association for Advancement of Behavior Therapy. Web. 1 Aug. 2009.

Rosier, J., A. Farmer, D. Lam, A. Burke, N. O’Neill, S. Keating, G. Powell Smith, B. Sahakian, and P. McGuffin. “The effect of positive mood induction on emotional processing in euthymic individuals with bipolar disorder and controls.” Psychological Medicine 39 (2009):785-791. Cambridge University Press 2008.

Shaltiel, G., S. Maeng, O. Malkesman, B. Pearson, R. J. Schloesser, T. Tragon, M. Rogawski, M. Gasior, D. Luckenbaugh, G. Chen, and H. K. Manji. "Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania." Molecular Psychiatry. Nature Publishing Group, 2008. Web. 1 Aug. 2009. <http://www.nature.com/mp>.

Willson, Morgan C., Emily C. Bell, Sanjay Dave, Sheila J. Asghar, Brent M. McGrath, and Peter H. Silverstone. "Valproate attenuates dextroamphetamine-induced subjective changes more than lithium." European Neuropsycopharmacology 15 (2005): 633-39. Elsevier. Web. 1 Aug. 2009. <http://www.elsevier.com/locate/euroneuro>.

Yechiam, Eldad, Elizabeth P. Hayden, Misty Bodkins, Brian F. O’Donnell, William P. Hetrick. “Decision making in bipolar disorder: A cognitive modeling approach.” Psychiatry Research 161 (2008). Elsevier. Web. 1 Aug. 2009. <http://www.sciencedirect.com>