doi:10.1017/S1092852912000119

Original Research

Conceptualizing Treatment Nonadherence in Patients with Bipolar Disorder and PTSD Jeffrey J. Rakofsky, MD, Steven T. Levy, MD, and Boadie W. Dunlop, MD

ABSTRACT

FOCUS POINTS

Treatment nonadherence is a concern among

• Bipolar disorder is often comorbid with postttraumatic stress disorder (PTSD) leading to a more severe course of illness for patients suffering with both illnesses. • There are various patient, illness, medication, and clinician-related risk factors associated with treatment nonadherence among patients with bipolar disorder and among those with PTSD. • There is a high likelihood of treatment nonadherence among bipolar disorder patients with PTSD, given the shared risk factors for nonadherence among primary bipolar disorder and PTSD samples and because of the psychodynamic interpretation of trauma-related meanings patients may assign to their interactions with physicians.

patients with bipolar disorder and posttraumatic stress disorder (PTSD). PTSD is common among patients with bipolar disorder and those with this comorbidity often have a more severe course of illness. While many factors have been associated with nonadherence in bipolar disorder patients and in PTSD patients, almost no research has focused on the factors associated with non-adherence in bipolar disorder patients with comorbid PTSD. Studies in primary bipolar disorder samples reveal patient, illness, drug and clinician characteristics associated with

For bipolar disorder-PTSD patients with early

nonadherence while studies in primary PTSD

childhood trauma, noncompliance may be

samples reveal a significantly shorter list of

related to the trauma-related meanings attrib-

patient, illness and drug characteristics. Shared

uted to interactions with their physicians and

risk factors between these two populations and

their prescribed medications. Given the high

the characteristics that predict noncompliance

side effect burden of bipolar disorder treatments

in only one population but often present in the

and the importance of lifelong adherence, clini-

other, suggest a high likelihood of nonadher-

cians should vigilantly monitor for nonadher-

ence in the bipolar disorder-PTSD population. Dr. Rakofsky is Psychopharmacology Research Fellow in the Mood and Anxiety Disorders Program/Bipolar Disorders Clinic at Emory University Department of Psychiatry and Behavioral Sciences in Atlanta, GA. Dr. Levy is Professor and Chair in the Emory University Department of Psychiatry and Behavioral Sciences. Dr. Dunlop is Assistant Professor in the Mood and Anxiety Disorders Program at Emory University. Faculty Disclosures: Dr. Rakosky and Dr. Levy report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Dunlop has received research support from AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Ono Pharmaceuticals, Takeda, and Wyeth; and he has received honoraria from Bristol-Myer Squibb, Digitas Health, Imedex, Pfizer and Wyeth. Submitted for publication: March 25, 2010; Accepted for publication: June 29, 2010; First published online: January 1, 2011 . Please direct all correspondence to: Jeffery J. Rakofsky, MD, Psychopharmacology Research Fellow, Mood and Anxiety Disorders Program/Bipolar Disorders Clinic at Emory University Department of Psychiatry and Behavioral Sciences, 1256 Briarcliff Rd, 3rd Floor, Atlanta, GA 30306; Tel: 404-712-5083, Fax: 404727-3700; Email: [email protected]

CNS Spectr 16:1

11

January 2011

Original Research

ence in their bipolar disorder-PTSD patients and

previous traumas, history of psychiatric illness, greater neuroticism, lower extraversion, lower social support, and lower socioeconomic status. They also describe mood state-dependent risk factors that affect bipolar disorder patients’ ability to cope with a traumatic event, including an increase in dysfunctional thinking, a decrease in problem solving skills and an increase in anxiety sensitivity. Others have underscored the role of hyperarousal combined with heightened anxiety sensitivity during manic states as a possible mediator of PTSD development.18 Compared to the general population, bipolar disorder patients may carry a unique risk for experiencing early childhood trauma because of the higher likelihood of psychiatric illness among their parents and siblings and because of the reactions that bipolar disorder patients’ early psychopathology may provoke from others.12 Bipolar disorder patients abused in childhood have a longer duration of illness and time untreated, spend a greater percentage of time ill, and have a higher lifetime prevalence of medical and psychiatric comorbidities. They have an earlier age of bipolar disorder illness onset, faster cycling frequencies, a higher family history of bipolar disorder and substance use disorders, and a higher severity of manic symptoms. 12 , 13 , 19 Childhood emotional abuse, sexual abuse, and an increasing number of forms of childhood abuse have all been associated with lifetime suicide attempts. 13 Psychotic bipolar disorder patients with either adult or childhood assault exposure report more distress on scales of general health functioning, hopelessness and less happiness at two year follow up compared to those without a history of assault exposure.10 Similarly, compared to bipolar disorder patients without PTSD, those with PTSD have greater social, occupational, and family impairment, and worse mental and physical health-related quality of life. They are more likely to have a younger age of bipolar disorder onset, a history of substance abuse, more rapid cycling, and a greater need for inpatient psychiatric services. They spend less time euthymic and have an increased history of lifetime suicide attempts. Compared to bipolar disorder patients with other anxiety disorders, bipolar disorder patients with PTSD have more “well days” lost.14,20-23 When bipolar disorder and PTSD co-occur, they tend to show separate courses relative to each other.24 However, symptoms of each illness may

be particularly aware of patient-physician psychodynamics that might contribute to this behavior.

INTRODUCTION Treatment adherence can be defined as the extent to which a patient’s behavior follows the recommendations made by a healthcare provider.1 Medication adherence may result from decisions by patients regarding their willingness versus ability to adhere1 and the felt necessity of treatment versus concerns around the prescribed treatment.2,3 Poor treatment adherence is associated with worse clinical status and is a crucial area to address in order to improve outcomes in patients with various medical and psychiatric illnesses.1,4,5 Treatment adherence is of particular concern among bipolar disorder and posttraumatic stress disorder (PTSD) patients, who may require complicated psychotropic medication regimens in order to reduce their symptom burden and maintain a reasonable quality of life. Bipolar disorder affects 4% of the population and is associated with extensive morbidity and mortality,6,7 and is highly comorbid with substance use disorders and anxiety disorders.8 PTSD is an anxiety disorder present in 16% of bipolar disorder patients.9 Many other bipolar disorder patients likely experience sub-syndromal symptoms of PTSD, given that between 36% and 51% of bipolar disorder patents have had a history of >1 lifetime traumatic event.10-13 In primary care settings, bipolar disorder patients are 2.6 times more likely to report a history of physical or sexual assault compared to those without bipolar disorder.14 Bipolar disorder patients have higher rates of childhood physical and sexual abuse than unipolar depressed patients,15,16 and similar to the general population, females with bipolar disorder have higher rates of PTSD than do males with bipolar disorder.17 States of mania involving pursuit of high reward/high risk activities, such as disinhibited sexual behaviors, dangerous driving, gregariousness with strangers, and increased aggression, all place bipolar patients at higher risk of experiencing traumatic events. Otto and colleagues9 have described risk factors associated with the development of PTSD following trauma exposure that are common among bipolar disorder patients. These factors include: greater severity of trauma and history of CNS Spectr 16:1

12

January 2011

Original Research

PTSD patients, their physician and the prescribed treatment.

exacerbate the course of the other. For example, the lack of judgment and impulse control during manic episodes can lead patients to engage in dangerous behaviors with traumatic outcomes. This may then trigger the reemergence of PTSD symptoms from earlier traumas. Depressed bipolar disorder patients may lack the motivation or energy to attend PTSD-related therapy sessions or to complete therapy-assigned homework. PTSD patients may be too fearful to leave their home to get bipolar disorder medications refilled, get mood stabilizer-related blood work completed, or follow up with their psychiatrist for continued treatment of their mood episode. Additionally, the PTSD-related nightmares, hyperarousal and sleep impairments may affect a bipolar disorder patient’s sleep-wake cycle and put him at risk for mood relapse.25,26 Given the predominant role of antidepressants in the treatment of PTSD and the risk, though controversial,27 for antidepressant-induced manic induction, cycle acceleration, or mixed episodes in bipolar disorder patients,28-30 treatment of patients with these comorbid illnesses is challenging. Though psychotherapy in the form of exposure, cognitive therapy and eye-movement desensitization and reprocessing (EMDR) are considered first line treatment options for PTSD, 31 there are no published clinical trials that have evaluated the psychotherapeutic or pharmacologic treatment of PTSD in bipolar disorder patients, 32 though Otto and colleagues9 have described a cognitive behavorial therapy-driven protocol. Given the extent of trauma and PTSD associated with bipolar disorder, the mutually-worsening impact of bipolar disorder and PTSD on patients’ quality of life, and the lack of effective pharmacologic treatments for this comorbidity, treatment nonadherence adds another layer of challenge to the psychiatric care of these patients. Prevalence and risk factors for nonadherence among bipolar disorder and among PTSD patients have been studied and much information is now known, but little regarding nonadherence has been reported for patients who are afflicted with both illnesses. We undertook a review of the treatment nonadherence literature pertaining to the separate bipolar disorder and PTSD populations in order to predict and characterize nonadherence in patients with co-occuring bipolar disorder and PTSD. This knowledge aims to inform treatment practices by directing the clinician’s attention to important, unique relational issues among bipolar disorderCNS Spectr 16:1

METHODS A literature search for all observational studies, case reports and reviews of medication nonadherence in bipolar disorder and PTSD patients published from 1950 to January 2010, was conducted via OVID’s online computerized database. The search terms used included: “patient compliance”, “medication adherence”, “posttraumatic stress disorder”, and “bipolar disorder.” Additionally, the reference lists of all publications identified from the database were hand-searched for titles that indicated an article had addressed issues of treatment adherence in these disorders. All such studies were included if they discussed aspects related to treatment adherence or compliance for either bipolar disorder or PTSD patients. Factors that were associated with nonadherence in these two patient groups were recorded and evaluated for similarities between them.

RESULTS Bipolar Disorder and Treatment Nonadherence Treatment nonadherence literature in the bipolar disorder population has focused almost exclusively on medication consumption as a marker of adherence to clinician recommendations with little attention to other aspects of adherence, including keeping appointments, completing blood work, and follow-up on psychotherapy recommendations. Because of the different Bipolar disorder samples assessed (substance abusing, euthymic, depressed, manic, inpatient, outpatient, veterans) and the different ways medication nonadherence has been defined and measured (pill counts, plasma levels, patient and caretaker interviews, medication refills), prevalences of nonadherence range from 23% to 68% with a median of 42%.33 Medication nonadherence can include taking more or less of the medicine than was prescribed by the physician34,35 and can be intentional (choosing to not take medicines) or unintentional (ie, forgetting or confusion in the setting of a mood episode, lack of finances to pay for the medicine, etc.)35 The impact of nonadherence on bipolar disorder patients can have devastating life consequences. Patient-initiated treatment discontinuation has been associated with increased hospitalization 13

January 2011

Original Research

rates, 36-41 increased relapse rates, 42,43 decreased response to previously effective mood stabilizers, 4 4 , 4 5 increased risk of committing violent acts,46 higher suicide rates47 and less life contentment.48 Patients have reported nonadherence as a source of stigma in addition to their mental illness because of the disapproving response and “noncompliant” label that these patients anticipate receiving from their providers. 49 Another potential consequence is that if the psychiatrist is unaware of a patient’s nonadherence and the patient’s symptoms persist, the psychiatrist may believe the medicine is ineffective at its current dose. As a result the psychiatrist may unwittingly increase the medication dose putting the patient at a higher, unnecessary risk for medication-related adverse events. Alternatively, the psychiatrist may discontinue an otherwise efficacious medicine, leaving available fewer treatment options for the patient. This pattern is especially likely given that most psychiatrists believe their bipolar disorder patients are more adherent than they truly are.50 Jamison and colleagues51 proposed four interacting sets of variables to explain why bipolar disorder patients stop taking lithium. Factors that have been significantly associated with nonadherence to lithium and antipsychotics can still be encompassed by these four categories. Table 1 lists these in detail organized into: Patient1,2,33,35,39,41,48,5063 ; Illness1,33,36,37,41,48,50,51,53,58-61,64; Drug1,2,33-35,50,54,56,61,65,66; and Clinician Characteristics.1,49,63 Psychodynamic interpretations of medication nonadherence, specifically to lithium, have proposed that bipolar disorder patients may be acting out their denial of having a serious lifelong illness or acting out their anger toward the therapist. 51 Some have proposed that patients discontinue lithium because they prefer mania to a difficult life situation or because their grief, feelings of abandonment and rage are too difficult to bear.67,68 Because of denial or lack of awareness of these feelings, bipolar disorder patients may rationalize their decision to discontinue treatment asserting that they no longer need the medicine, the medicine was a placebo, or they simply forgot. Others cite the provocative role of family members who miss the patient’s hypomania, and subtly or overtly encourage nonadherence.68

tial treatment program reported a 66% nonadherence rate in the year following discharge, 69 while another study of veterans reported that 54% underused, 28% overused, and 20% both overused and underused prescribed medication. 70 Measuring adherence differently, Burstein71 showed that 27% and 82% of PTSD patients who entered private practice treatment within the first nine weeks versus >40 weeks after a traumatic event, respectively, dropped out prematurely. Patients with PTSD have higher missed-appointment rates than patients with other psychiatric illnesses.72 Treatment nonadherence among PTSD patients may be related to illness characteristics, such as a sense of a foreshortened future, leaving patients less incentivized to take care of themselves (Table 2).73,74 Avoiding reminders of the traumatic event, a hallmark symptom of PTSD, can also lead to nonadherence if the medical treatments or procedures were connected to the traumatic event. This may be the case with either non-psychiatric interventions (eg, a traumatic surgery and missing follow up appointments with the surgeon)75 or with PTSD treatments that demand reliving the trauma.76 The latter has been seen in studies of exposure-based psychotherapies where compliance with symptom habituation-based homework assignments was low and associated with high depression and PTSD severity. PTSD patients may also develop feelings of detachment from others as part of their illness. As a result, trust, a sense of attachment, and a therapeutic alliance between patient and provider may never adequately form, increasing the likelihood of non-adherence.74 If a patient’s PTSD resulted from an event that included head-trauma (ie, motor vehicle accident, interpersonal violence, etc.), the cognitive deficits in memory and attention that may result could lead to missed medication doses and appointments. The desire to self-medicate and control symptoms could lead to overuse of medication, especially when treatment involves benzodiazepines.70,77 Among veterans, fewer medications and a biologic conceptualization of their psychiatric illness unexpectedly were associated with nonadherence.69,70 Taking a higher number of medications may be more often seen among adherent patients who show up to their appointments consistently while taking a fewer number of medicines may be a marker for under-treatment of illness. Neither age, presence of comorbid substance abuse, history of combat exposure nor service-connection status was related to adherence.70

PTSD and Treatment Nonadherence Researchers have directed significantly less attention to treatment adherence in PTSD patients. One study of veterans completing a PTSD residenCNS Spectr 16:1

14

January 2011

Original Research

TABLE 1.

Risk Factors Associated with Treatment Nonadherence in Patients with Bipolar Disorder Category

Risk Factors

Patient Characteristics Illness attitudes

Poor insight/denial of illness1,33,35,52-55 Denial of severity/perceived low severity of illness39,56,57 Believing medications are not needed to treat the illness1,2 Believing the condition is not controllable35 Believing they were cured58 Believing that the illness is not chronic35 Having limited knowledge about their illness33,54 Missing the euphoric high51 Having an external locus of control over their own health48,53

Medication attitudes/behaviors

Negative attitudes towards mood stabilizers/medicines53,56 Not wanting to take medicines48 Believing that pills are not helpful39,58 Fear of addiction to medicines54 Seeing medication as a symbol of their illness54 Past history of medication nonadherence56 Being bothered that moods are controlled by a medication51 Difficulty with medication routines53

Socio-bemographic features

Younger age41,50,59,60 Ethnic/racial minority status59-63 Lower educational level61,62 Unmarried marital status33,60 Previous legal history62 Homelessness59,60 Living alone33 Limited family support33 Fewer resources for coping48

Illness Characteristics Comorbidities

Personality disorders33,36,41,64 Substance use disorders1,33,41,48,50,53,58-60 PTSD60 OCD50

Symptom-related features

Grandiosity1 Persistent manic overactivity leading to missed doses/forgetting1 Cognitive impairment37,50,61,64 Greater number of affective symptoms50 Higher global psychophathology53 History of psychosis37 Feeling depressed51 Greater severity of depression61 Not being in full remission50

Bipolar Characteristics

Type I37 Recent manic episode50

Drug Characteristics

Side effects actually experienced1,33-35,50,54,61 Side effects anticipated2,35,56,65 Typical antipsychotics, risperidone, olanzapine>quetiapine66 Lithium>valproate in substance using population34

Clinician Characteristics

Lack of shared decision making between patient and provider49 Problems with the therapeutic alliance1,63

Rakofsky JJ, Levy ST, Dunlop BW. CNS Spectr. Vol 15, No 11. 2010.

CNS Spectr 16:1

15

January 2011

Original Research

DISCUSSION

depression,51 ethnic/racial minority status,59-63 and homelessness 59,60 have all been associated with nonadherence in bipolar disorder patients and are often seen among PTSD patients.78-82 These demographic and clinical markers observed frequently among patients with both disorders increase the likelihood that bipolar disorder-PTSD patients will become nonadherent to their treatment. Both bipolar disorder and PTSD frequently are characterized by a desire to avoid unpleasant emotional states. The bipolar disorder patient’s desire to avoid feeling reality-based depressed mood or grief by stopping his medicine and entering a manic state,67,68 is similar to the PTSD patient’s avoidance behaviors, such as increasing their use of medications, including benzodiazepines.70 Thus, multiple forms of treatment non-adherence may occur in bipolar disorder-PTSD patients as they strive to avoid emotional pain. Moreover, the bipolar disorder patient’s perceived lack of shared decision-making 49 and problems with the therapeutic alliance1,63 are similar to the PTSD patient’s difficulty connecting with therapists, stemming from feelings of detachment. 74 Both lead to an inability to engage in treatment and the potential for treatment nonadherence. Without trust, the bipolar disorder-PTSD patient may be less likely to take mood stabilizers and antipsychotics that have the potential for uncomfortable side effects and adverse physiologic reactions. 83 In bipolar disorder patients, experiencing an external locus of control over one’s health is associated with increased nonadherence. 48,53 This experience is similar to the sense of a foreshortened future seen in PTSD patients.73,74 In both groups, patients may believe that they have little or no control over their illness or their future and may feel disincentivized to take medications as prescribed. These feelings may be particularly strong during treatment with mood stabilizers and atypical antipsychotics, which cause a number of burdensome side effects in bipolar disorder patients who rely on these medications for lifelong treatment. Patient anger at the therapist51 and a negative attitude towards medications53,56 are risk factors for nonadherence in bipolar disorder patients and can also be observed among PTSD patients who were victims of childhood physical or sexual abuse. Josephs 84 explains that individuals who have suffered serious openbuse, particularly at the hands of authority figures come to mistrust all authority, physicians included. Mintz85 describes that in patients who have been controlled do da

Although many studies have sought to untangle factors associated with treatment non-adherence in bipolar disorder patients and in PTSD patients, none have focused specifically on bipolar disorder patients with comorbid PTSD. Additionally, none have focused on treatment adherence among bipolar disorder patients with other comorbid anxiety disorders nor on treatment adherence among unipolar depressed patients with PTSD. PTSD has been associated with non-adherence in bipolar disorder patients in primary bipolar disorder samples, but the nature of this relationship is still not understood. We explore this relationship by highlighting risk factors for nonadherence that are similar in both bipolar disorder and PTSD populations along with risk factors reported to predict nonadherence in only one patient group (bipolar disorder or PTSD) but often present in the other. Bipolar disorder related-cognitive impairments and difficulty with medication routines have frequently been associated with nonadherence in bipolar disorder patients.37,50,61,64 For PTSD patients who sustained a trauma-related head injury leading to cognitive impairment, it might be even more difficult to remember to take the complicated bipolar disorder mood stabilizer regimens and remember to get blood work completed. Thus, the bipolar disorder-PTSD patient may have multiple reasons for cognitive impairments that could ultimately interfere with following medication regimens as prescribed. Personality disorders,33,36,41,64 substance use disorders,1,33,41,48,50,53,58-60 TABLE 2.

Risk Factors Associated with Treatment Nonadherence in Patients with PTSD Category

Risk Factor

Patient characteristics

Biologic conceptualization of psychiatric illness70 Desire to self-medicate70,77

Illness characteristics

Depression severity76 PTSD severity76 A sense of foreshortened future73,74 Feelings of detachment74 Avoiding reminders of the traumatic event75,76

Drug characteristics

Fewer medications69

Rakofsky JJ, Levy ST, Dunlop BW. CNS Spectr. Vol 15, No 11. 2010.

CNS Spectr 16:1

16

January 2011

Original Research

and harmed by others in the past, ingesting a pill can lead to paranoid anxieties that lead the patient to rebel and take the medicine as they choose, in order to reestablish a sense of control. Distrust towards physicians and fear regarding future harm and control vis-a-vis medicines, provide a basis for a bipolar disorder-PTSD patient to not adhere to treatment as prescribed. In a related manner, bipolar disorder-PTSD patients may be at a higher risk of experiencing the nocebo effect, which is when a patient experiences actual harm as a result of expected harm from a medicine. Nocebo effects are conditioned by life experiences, are seen more often in patients from disadvantaged social positions, and could reflect the harm traumatized patients anticipate receiving from physician-authority figures.85 These factors are likely to lead bipolar disorder-PTSD patients to discontinue medications that they believe caused their side effects. Side effects coupled with anger towards the neglectful authority figures that allowed PTSD patients to be abused as children, can potentially become the focus of enactments between a bipolar disorder-PTSD patient and the therapist. 86 These enactments could eventually lead to treatment nonadherence or even dissolution of the therapeutic relationship, if not managed properly. Medication side effects can play an additional role in nonadherence among bipolar disorder-PTSD patients as PTSD may lead a patient to stop treatment when the side effects or the treatment itself elicits reminders of earlier trauma.75,76 Stopping treatment becomes the quickest way to avoid such frightful reminders.This phenomenon was reported in a patient with a history of sexual trauma who refused dialysis treatments because the procedure reminded her of being physically intruded upon by caregivers.87 One of our bipolar disorder-PTSD patients refused further lithium treatment because the cognitive dulling that it produced reminded her of the physical vulnerability she experienced when sexually abused by her father. Although no specific data on this topic exists, our clinical experience suggests that unwittingly, the psychiatrist may play a role in the bipolar disorder-PTSD patient’s nonadherence. As mentioned previously, pharmacologic treatment for PTSD consists of antidepressants,31 which carry a risk of destabilizing a bipolar disorder patient’s course of illness. Using an antidepressant to treat the PTSD symptoms in a bipolar disorder-PTSD patient, could induce (hypo)mania, further increasing the CNS Spectr 16:1

likelihood of noncompliance. 1 Additionally, the psychiatrist may subconsciously or overtly communicate his ambivalence about prescribing antidepressants to a bipolar disorder patient. This may create apprehension in the patient and also lead to nonadherence. Although psychotherapy is an efficacious option for treating PTSD symptoms in these bipolar disorder patients, it is not without its own risks of noncompliance, as patients may fail to complete homework assignments or miss therapy sessions in an effort to avoid reliving the trauma through the therapeutic exposure techniques.76

Recommendations Table 3 lists approaches that may improve adherence in patients with bipolar disorder comorbid with PTSD. Given the importance of trust in the patient-physician relationship, and the difficulties bipolar disorder-PTSD patients may have in forming an alliance with their psychiatrists, clinicians should put forth maximum effort to build rapport and interact in ways that support the therapeutic relationship. Although this recommendation applies to all psychiatric patients, it is of the utmost importance in treating bipolar disorder-PTSD patients. A strong therapeutic alliance between bipolar disorder patients and their physicians has been associated with less patient attrition and less time depressed88; these findings likely extend to the bipolar disorder-PTSD population as well, though no data yet exists to support this supposition. Clinicians should be forthcoming with the side effect risks and potential adverse events caused by the medications they prescribe. This openness will diminish patients’ surprise at an emerging side-effect and increase their willingness to continue on medication despite the nuisance. Medications with proven efficacy with less potential for disturbing side effects should be considered initially, eg, ziprasidone to treat mania rather than olanzapine. When patients complain about side effects, clinicians should keep in mind that many survivors of early childhood sexual and physical abuse experience ignoring and dismissive reactions from family members when initially reporting their trauma.84 To avoid re-creating a similar harmful experience for the patient, the clinician should listen empathically to his bipolar disorder-PTSD patients’ medication complaints and respond with an appropriate balance of watchful-waiting for these side effects to resolve versus medication switching. The latter option is less ideal 17

January 2011

Original Research

given the paucity of effective treatments for bipolar disorder. Patient autonomy should be encouraged by providing treatment recommendations but ultimately allowing the patients, whenever possible, to decide between medication options or rapidity of dose changes. There should be close follow-up scheduled initially, and when patients miss appointments, the clinician should call to quickly address any potential issues that may lead to nonadherence. Given the demonstrated benefits of exposure-based therapies in the treatment of PTSD, 89 psychotherapy utilizing such methods should be encouraged for the treatment of PTSD symptoms, though clinicians should also be sensitive to the risk for noncompliance generated by the exposure techniques. 76 Additionally, cognitive behavioral therapy, interpersonal group therapy, patient and family psychoeducation, and group sessions for partners of bipolar disorder-PTSD patients should be considered as these have all led to improved medication adherence in bipolar disorder patients.90 Clinicians should routinely and non-judgmentally ask their patients about missed medication doses, in a manner that allows patients to discuss the topic freely. With early detection of non-adherence and an opportunity to intervene appropriately, negative outcomes such

as hospitalization or relapse can be avoided.39,40 Clinicians should continue to reevaluate the patient-doctor dynamics throughout treatment as negative transferences based on traumatic childhood experiences may influence the likelihood of medication adherence. They should pay particular attention to the countertransference that may arise in response to a patient’s persistent failure to follow treatment recommendations. Countertransference acting out with medications may be one consequence of nonadherence when treating bipolar disorder-PTSD patients. Examples would include the tendency to over- or under-prescribe medications in response to the clinician’s feelings of frustration or defeat by the patient.91,92 Avoiding these behaviors can prevent patients from becoming entrenched in a continuing pattern of nonadherence or from ending their treatment relationship, because of side effects or the impression that their physician is less invested in their care.

CONCLUSION Bipolar disorder patients are at increased risk for trauma and developing PTSD. Bipolar disorder patients and PTSD patients have a high prevalence of nonadherence with their medication treatment, putting them at risk for worsened psychiatric outcomes. Although many factors contributing to nonadherence have been elucidated, not much attention has been focused on the unique reasons for nonadherence in bipolar disorder patients with PTSD. Given the high side effect burden of bipolar disorder treatments and the importance of lifelong adherence, clinicians should vigilantly monitor for nonadherence in their bipolar disorder-PTSD patients and be particularly aware of the traumarelated meanings these patients assign to interactions with their physicians and to their prescribed medications. ltimately, these may contribute significantly to a bipolar disorder-PTSD patient’s decision to discontinue lifesaving mood stabilizing treatments. CNS

TABLE 3.

Recommendations for Clinicians Treating Bipolar Disorder Patients with PTSD Build rapport Be forthcoming with potential medication-related side effects and adverse events Offer medications with greatest efficacy but limited side effects Make medication recommendations, but allow patient to make the final decision Schedule close follow up Check-in with patients by phone when appropriate

REFERENCES

Respond empathically to medication related complaints

1. Velligan DI, Weiden PJ, Sajatovic M, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(Suppl 4):1-46. 2. Clatworthy J, Bowskill R, Parham R, Rank T, Scott J, Horne R. Understanding medication non-adherence in bipolar disorders using a Necessity-Concerns Framework. J Affect Disord. 2009;116(1-2):51-55. 3. Dunlop BW, Dunlop AL. Counseling via analogy: improving patient adherence in major depressive disorder. Prim Care Companion J Clin Psychiatry. 2005;7(6):300-303. 4. Stephenson BJ, Rowe BH, Haynes RB, Macharia WM, Leon G. The rational clinical examination. Is this patient taking the treatment as prescribed? JAMA. 1993;269(21):2779-2781.

Encourage psychotherapy Ask about missed medication doses Continually reevaluate patient-doctor dynamics throughout treatment Rakofsky JJ, Levy ST, Dunlop BW. CNS Spectr. Vol 15, No 11. 2010.

CNS Spectr 16:1

18

January 2011

Original Research

5. Losina E, Schackman BR, Sadownik SN, et al. Racial and sex disparities in life expectancy losses among HIV-infected persons in the united states: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy. Clin Infect Dis. 2009;49(10):1570-1578. 6. Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64(5):543-552. 7. Tsuang MT, Woolson RF. Mortality in patients with schizophrenia, mania, depression and surgical conditions. A comparison with general population mortality. Br J Psychiatry. 1977;130:162-166. 8. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158(3):420-426. 9. Otto MW, Perlman CA, Wernicke R, et al. Posttraumatic stress disorder in patients with bipolar disorder: a review of prevalence, correlates, and treatment strategies. Bipolar Disord. 2004;6(6):470-479. 10. Neria Y, Bromet EJ, Carlson GA, Naz B. Assaultive trauma and illness course in psychotic bipolar disorder: findings from the Suffolk county mental health project. Acta Psychiatr Scand. 2005;111(5):380-383. 11. Goldberg JF, Garno JL. Development of posttraumatic stress disorder in adult bipolar patients with histories of severe childhood abuse. J Psychiatr Res. 2005;39(6):595-601. 12. Leverich GS, McElroy SL, Suppes T, et al. Early physical and sexual abuse associated with an adverse course of bipolar illness. Biol Psychiatry. 15 2002;51(4):288-297. 13. Garno JL, Goldberg JF, Ramirez PM, Ritzler BA. Impact of childhood abuse on the clinical course of bipolar disorder. Br J Psychiatry. 2005;186:121-125. 14. Neria Y, Olfson M, Gameroff MJ, et al. Trauma exposure and posttraumatic stress disorder among primary care patients with bipolar spectrum disorder. Bipolar Disord. 2008;10(4):503-510. 15. Hyun M, Friedman SD, Dunner DL. Relationship of childhood physical and sexual abuse to adult bipolar disorder. Bipolar Disord. 2000;2(2):131-135. 16. Levitan RD, Parikh SV, Lesage AD, et al. Major depression in individuals with a history of childhood physical or sexual abuse: relationship to neurovegetative features, mania, and gender. Am J Psychiatry. 1998;155(12):1746-1752. 17. Baldassano CF, Marangell LB, Gyulai L, et al. Gender differences in bipolar disorder: retrospective data from the first 500 STEP-Bipolar disorder participants. Bipolar Disord. 2005;7(5):465-470. 18. Pollack MH, Simon NM, Fagiolini A, et al. Persistent posttraumatic stress disorder following September 11 in patients with bipolar disorder. J Clin Psychiatry. 2006;67(3):394-399. 19. Brown GR, McBride L, Bauer MS, Williford WO. Impact of childhood abuse on the course of bipolar disorder: a replication study in U.S. veterans. J Affect Disord. 2005;89(1-3):57-67. 20. Quarantini LC, Miranda-Scippa A, Nery-Fernandes F, et al. The impact of comorbid posttraumatic stress disorder on bipolar disorder patients. J Affect Disord. 2010;123(13):71-76. 21. Thatcher JW, Marchand WR, Thatcher GW, Jacobs A, Jensen C. Clinical characteristics and health service use of veterans with comorbid bipolar disorder and PTSD. Psychiatr Serv. 2007;58(5):703-707. 22. Otto MW, Simon NM, Wisniewski SR, et al. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. Br J Psychiatry. 2006;189:20-25. 23. Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-Bipolar disorder). Am J Psychiatry. Dec 2004;161(12):2222-2229. 24. Strakowski SM, Sax KW, McElroy SL, et al. Course of psychiatric and substance abuse syndromes co-occurring with bipolar disorder after a first psychiatric hospitalization. J Clin Psychiatry. 1998;59(9):465-471. 25. Wehr TA, Sack DA, Rosenthal NE. Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry. 1987;144(2):201-204. 26. Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E. Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression. Psychiatry Res. 30 1999;86(3):267-270. 27. Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004;161(9):1537-1547. 28. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-Bipolar disorder. Am J Psychiatry. 2007;164(9):1348-1355. 29. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152(8):1130-1138. 30. Post RM, Altshuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry. 2006;189:124-131. 31. Stein DJ, Cloitre M, Nemeroff CB, et al. Cape Town consensus on posttraumatic stress disorder. CNS Spectr. 2009;14(1 Suppl 1):52-58. 32. Rakofsky J, Dunlop B. Treating non-specific anxiety and anxiety disorders in patients with bipolar disorder: A Review. J Clin Psychiatry. In press. 33. Perlick D. Medication non-adherence in bipolar disorder: A patient-centered review of

CNS Spectr 16:1

research findings. Clinical Approaches in Bipolar Disorders. 2004;3:56-64. 34. Weiss RD, Greenfield SF, Najavits LM, et al. Medication compliance among patients with bipolar disorder and substance use disorder. J Clin Psychiatry. 1998;59(4):172-174. 35. Clatworthy J, Bowskill R, Rank T, Parham R, Horne R. Adherence to medication in bipolar disorder: a qualitative study exploring the role of patients’ beliefs about the condition and its treatment. Bipolar Disord. 2007;9(6):656-664. 36. Colom F, Vieta E, Martinez-Aran A, Reinares M, Benabarre A, Gasto C. Clinical factors associated with treatment noncompliance in euthymic bipolar patients. J Clin Psychiatry. 2000;61(8):549-555. 37. Martinez-Aran A, Scott J, Colom F, et al. Treatment nonadherence and neurocognitive impairment in bipolar disorder. J Clin Psychiatry. 2009;70(7):1017-1023. 38. Scott J, Pope M. Self-reported adherence to treatment with mood stabilizers, plasma levels, and psychiatric hospitalization. Am J Psychiatry. 2002;159(11):1927-1929. 39. Schumann C, Lenz G, Berghofer A, Muller-Oerlinghausen B. Non-adherence with long-term prophylaxis: a 6-year naturalistic follow-up study of affectively ill patients. Psychiatry Res. 1999;89(3):247-257. 40. Johnson RE, McFarland BH. Lithium use and discontinuation in a health maintenance organization. Am J Psychiatry. 1996;153(8):993-1000. 41. Maarbjerg K, Aagaard J, Vestergaard P. Adherence to lithium prophylaxis: I. Clinical predictors and patient’s reasons for nonadherence. Pharmacopsychiatry. 1988;21(3):121-125. 42. Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry. 1991;48(12):1082-1088. 43. Franks MA, Macritchie KA, Mahmood T, Young AH. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol. 2008;22(4):452-456. 44. Maj M, Pirozzi R, Magliano L. Nonresponse to reinstituted lithium prophylaxis in previously responsive bipolar patients: prevalence and predictors. Am J Psychiatry. 1995;152(12):1810-1811. 45. Post RM, Leverich GS, Altshuler L, Mikalauskas K. Lithium-discontinuation-induced refractoriness: preliminary observations. Am J Psychiatry. 1992;149(12):1727-1729. 46. Swartz MS, Swanson JW, Hiday VA, Borum R, Wagner HR, Burns BJ. Violence and severe mental illness: the effects of substance abuse and nonadherence to medication. Am J Psychiatry. 1998;155(2):226-231. 47. Muller-Oerlinghausen B, Muser-Causemann B, Volk J. Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. J Affect Disord. 1992;25(4):261-269. 48. Darling CA, Olmstead SB, Lund VE, Fairclough JF. Bipolar disorder: medication adherence and life contentment. Arch Psychiatr Nurs. 2008;22(3):113-126. 49. Roe D, Goldblatt H, Baloush-Klienman V, Swarbrick M, Davidson L. Why and how people decide to stop taking prescribed psychiatric medication: exploring the subjective process of choice. Psychiatr Rehabil J. 2009;33(1):38-46. 50. Baldessarini RJ, Perry R, Pike J. Factors associated with treatment nonadherence among US bipolar disorder patients. Hum Psychopharmacol. 2008;23(2):95-105. 51. Jamison KR, Gerner RH, Goodwin FK. Patient and physician attitudes toward lithium: relationship to compliance. Arch Gen Psychiatry. 1979;36(8 Spec No):866-869. 52. Keck PE, Jr., McElroy SL, Strakowski SM, et al. Factors associated with pharmacologic noncompliance in patients with mania. J Clin Psychiatry. 1996;57(7):292-297. 53. Sajatovic M, Ignacio RV, West JA, et al. Predictors of nonadherence among individuals with bipolar disorder receiving treatment in a community mental health clinic. Compr Psychiatry. 2009;50(2):100-107. 54. Fleck DE, Keck PE, Jr., Corey KB, Strakowski SM. Factors associated with medication adherence in African American and white patients with bipolar disorder. J Clin Psychiatry. 2005;66(5):646-652. 55. Greenhouse WJ, Meyer B, Johnson SL. Coping and medication adherence in bipolar disorder. J Affect Disord. 2000;59(3):237-241. 56. Scott J, Pope M. Nonadherence with mood stabilizers: prevalence and predictors. J Clin Psychiatry. 2002;63(5):384-390. 57. Adams J, Scott J. Predicting medication adherence in severe mental disorders. Acta Psychiatr Scand. 2000;101(2):119-124. 58. Manwani SG, Szilagyi KA, Zablotsky B, Hennen J, Griffin ML, Weiss RD. Adherence to pharmacotherapy in bipolar disorder patients with and without co-occurring substance use disorders. J Clin Psychiatry. 2007;68(8):1172-1176. 59. Sajatovic M, Valenstein M, Blow FC, Ganoczy D, Ignacio RV. Treatment adherence with antipsychotic medications in bipolar disorder. Bipolar Disord. 2006;8(3):232-241. 60. Sajatovic M, Valenstein M, Blow F, Ganoczy D, Ignacio R. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv. 2007;58(6):855-863. 61. Johnson FR, Ozdemir S, Manjunath R, Hauber AB, Burch SP, Thompson TR. Factors that affect adherence to bipolar disorder treatments: a stated-preference approach. Med Care. 2007;45(6):545-552. 62. Sajatovic M, Elhaj O, Youngstrom EA, et al. Treatment adherence in individuals with rapid cycling bipolar disorder: results from a clinical-trial setting. J Clin Psychopharmacol. 2007;27(4):412-414. 63. Zeber JE, Copeland LA, Good CB, Fine MJ, Bauer MS, Kilbourne AM. Therapeutic alliance perceptions and medication adherence in patients with bipolar disorder. J Affect Disord. 2008;107(1-3):53-62. 64. Danion JM, Neunreuther C, Krieger-Finance F, Imbs JL, Singer L. Compliance with long-term lithium treatment in major affective disorders. Pharmacopsychiatry. 1987;20(5):230-231.

19

January 2011

Original Research

65. Sajatovic M, Jenkins JH, Cassidy KA, Muzina DJ. Medication treatment perceptions, concerns and expectations among depressed individuals with Type I Bipolar Disorder. J Affect Disord. 2009;115(3):360-366. 66. Gianfrancesco FD, Rajagopalan K, Sajatovic M, Wang RH. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. J Clin Psychiatry. 2006;67(2):222-232. 67. Van Putten T. Why do patients with manic-depressive illness stop their lithium? Compr Psychiatry. 1975;16(2):179-183. 68. Fitzgerald RG. Mania as a message. Treatment with family therapy and lithium carbonate. Am J Psychother. 1972;26(4):547-554. 69. Lockwood A, Steinke DT, Botts SR. Medication adherence and its effect on relapse among patients discharged from a Veterans Affairs posttraumatic stress disorder treatment program. Ann Pharmacother. 2009;43(7):1227-1232. 70. Spoont M, Sayer N, Nelson DB. PTSD and Treatment Adherence: the role of health beliefs. J Nerv Ment Dis. 2005;193(8):515-522. 71. Burstein A. Treatment noncompliance in patients with post-traumatic stress disorder. Psychosomatics. 1986;27(1):37-40. 72. Sparr LF, Moffitt MC, Ward MF. Missed psychiatric appointments: who returns and who stays away. Am J Psychiatry. 1993;150(5):801-805. 73. Cohen MA, Alfonso CA, Hoffman RG, Milau V, Carrera G. The impact of PTSD on treatment adherence in persons with HIV infection. Gen Hosp Psychiatry. 2001;23(5):294-296. 74. Ricart F, Cohen MA, Alfonso CA, et al. Understanding the psychodynamics of nonadherence to medical treatment in persons with HIV infection. Gen Hosp Psychiatry. 2002;24(3):176-180. 75. Shemesh E, Lurie S, Stuber ML, et al. A pilot study of posttraumatic stress and nonadherence in pediatric liver transplant recipients. Pediatrics. 2000;105(2):E29. 76. Scott MJ, Stradling SG. Client compliance with exposure treatments for posttraumatic stress disorder. J Trauma Stress. 1997;10(3):523-526. 77. Dunlop BW, Davis PG. Combination treatment with benzodiazepines and SSRIs for comorbid anxiety and depression: A review. Prim Care Companion J Clin Psychiatry. 2008;10(3):222-228. 78. Gomez-Beneyto M, Salazar-Fraile J, Marti-Sanjuan V, Gonzalez-Lujan L. Posttraumatic stress disorder in primary care with special reference to personality disorder comorbidity. Br J Gen Pract. 2006;56(526):349-354.

CNS Spectr 16:1

79. Mills KL, Teesson M, Ross J, Peters L. Trauma, PTSD, and substance use disorders: findings from the Australian National Survey of Mental Health and Well-Being. Am J Psychiatry. 2006;163(4):652-658. 80. Dedert EA, Green KT, Calhoun PS, et al. Association of trauma exposure with psychiatric morbidity in military veterans who have served since September 11, 2001. J Psychiatr Res. 2009;43(9):830-836. 81. Santos MR, Russo J, Aisenberg G, Uehara E, Ghesquiere A, Zatzick DF. Ethnic/Racial diversity and posttraumatic distress in the acute care medical setting. Psychiatry. 2008;71(3):234-245. 82. Taylor KM, Sharpe L. Trauma and post-traumatic stress disorder among homeless adults in Sydney. Aust N Z J Psychiatry. 2008;42(3):206-213. 83. Masand PS, Fazal FS, Patkar AA. Safety considerations in pharmacotherapy of bipolar disorder. CNS Spectr. 2004;9(11 Suppl 12):16-26. 84. Josephs L. Women and trauma: a contemporary psychodynamic approach to traumatization for patients in the OB/GYN psychological consultation clinic. Bull Menninger Clin. 1996;60(1):22-38. 85. Mintz D. Meaning and medication in the care of treatment-resistant patients. Am J Psychother. 2002;56(3):322-337. 86. Sageman S. Women with PTSD: the psychodynamic aspects of psychopharmacologic and “hands-on” psychiatric management. J Am Acad Psychoanal. 2002;30(3):415-427. 87. Krawczyk J, Raskin VD. Psychological distress related to sexual abuse in a patient undergoing hemodialysis. Am J Psychiatry. 1990;147(5):673-674. 88. Gaudiano BA, Miller IW. Patients’ expectancies, the alliance in pharmacotherapy, and treatment outcomes in bipolar disorder. J Consult Clin Psychol. Aug 2006;74(4):671-676. 89. Institute of Medicine. Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington DC: The National Academies Press; 2008. 90. Sajatovic M, Davies M, Hrouda DR. Enhancement of treatment adherence among patients with bipolar disorder. Psychiatr Serv. 2004;55(3):264-269. 91. Mintz D. Psychodynamic Trojan horses: using psychopharmacology to teach psychodynamics. J Am Acad Psychoanal Dyn Psychiatry. 2006;34(1):151-161. 92. Mintz D, Belnap B. A view from Riggs: treatment resistance and patient authority - III. What is psychodynamic psychopharmacology? An approach to pharmacologic treatment resistance. J Am Acad Psychoanal Dyn Psychiatry. 2006;34(4):581-601.

20

January 2011