How Stress and Bipolar Disorder Interact: Causes, Course, and Treatment

By Julie Myers, PsyD, MSCP | Point Loma Clinic

Stress and bipolar disorder (BD) interact bidirectionally. Stress, particularly in early life, appears to have lasting effects and marks for early onset of BD, although the exact mechanism is poorly understood. The relationship of stress to the onset of the disorder and its course has implications for treatment and management — and perhaps even prevention.

What is Bipolar Disorder?

Bipolar Disorder is a mood disorder, characterized by shifting states between mania or hypomania and depression. The length of time that a person spends in either the up or the down phases are not fixed in length nor in severity, although those with Bipolar I Disorder have periods of mania, while those with Bipolar II Disorder only reach hypomania. Periods may last from years to hours in rapid or ultra-rapid cycling BD. In most cases, it is a progressive disorder, with the length of time spent in the depressive stage increasing with time. Those with BD have other characteristics, such as delayed-sleep cycle and neurocognitive deficits (Correll, et al., 2007).

Mania and Hypomania

The DSM-5 (APA, 2013) characterizes those with mania as having pronounced and persistent moods of euphoria, grandiosity, or elevated self-esteem, decreased need for sleep, rapid pressure speech, racing thoughts, distractibility, increased activity or psychomotor agitation, behavior that reflects expansiveness, and poor judgment. Hypomania is the occurrence of a persistent elevated, irritable, or expansive mood for at least four days, with the presence of three additional symptoms including "inflated self-esteem or grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility, increased involvement in goal-directed activities or psychomotor agitation, and excessive involvement in pleasurable activities that have a high potential for painful consequences (p. 335.) The Mood Disorder Questionnaire (MDQ) is a well-known screening tool for BP.

Depression and Mixed States

The depressive state of BD is much like that of Major Depressive Disorder, although there is usually an increased need for sleep and psychomotor retardation rather than agitation. Other signs include depressed mood, anhedonia, fatigue, feelings of worthless, guilt, thoughts of suicide, and executive functioning difficulties such as trouble concentrating. Periods of mixed states or dysphoric mania also occur with BD. Symptoms of dysphoric mania include, marked irritability, severe agitation or anxiety, pessimism and unrelenting worry and despair, marked insomnia, and decreased need for sleep (APA, 1994). In my experience, it is these mixed states that are the most troublesome, and they appear to be marked by severe stress reactivity.

 

Why Bipolar Disorder Is So Often Misdiagnosed

Diagnosis is particularly difficult, because those with BD often do not recognize their hypomanic episodes as being abnormal and so do not report their presence; insight is state-dependent. They may also loathe to give-up these hypomanic states. Patients usually present for help during the depressive stage (Perugi, Ghaemi, & Akiskal, 2006), and when in a depressive state, patients with BD have difficulty remembering their hypomanic states, feeling that they have always felt low. "Diagnosis may only be possible retrospectively utilizing histories from patients who have distorted recollections" (Stahl, 2005, p. 14.) Because of these distorted recollections, it is important to have collaborating information from family members or close friends. The hypomania, which the client so often enjoys, is often more problematic to those close to the patient than to the patient themselves and may lead to dysfunctional family interactions and stress. In my opinion, it is the client's unwillingness to disclose these hypomanic states and the stressful events that trigger them that often leads to misdiagnosis.

Bipolar Disorder and Co-morbid Conditions

Comorbidity is common in BD, further complicating the diagnosis. In one study, a

comorbid disorder was found in all the samples, and in 59% the condition preceded the onset of BD symptoms (Kessler, Rubinow, Holmes, Abelson, & Ahao, 1997). Common among the comorbid disorders are anxiety, substance abuse, ADHD, Oppositional-Defiant Disorder, Bulimia, Social Phobia, Panic Disorder, and obsessive-compulsive disorder (Correll, et al., 2007) and (Perugi, Ghaemi, & Akiskal, 2006), many of which are stress related. Personality disorders also occur at a higher rate than the public, which may be an expression of phenotypic expression of a bipolar diathesis (Correll, et al., 2007). BD has the highest prevalence of any psychiatric disorder for alcohol and other substance use disorders, with a lifetime comorbidity estimated from 17 – 61% (Vizzarri, et al., 2007). In one large study of 500 bipolar patients, a lifetime substance use disorders was found in the entire sample (Simon, et al., 2004). In many cases, it is unclear whether these co-occurring disorders are truly biologically distinct, or simply risk markers, prodromal states, overlapping characteristics, or subtypes (Correll, et al., 2007).

Anxiety Comorbidity Is Especially Prevalent

Comorbidity of BD with anxiety disorders is particularly high. In one large study of 500 BD patients, the lifetime comorbidity with anxiety disorder occurred in over half the sample (Simon, et al., 2004); approximately 11-63% had panic disorder, 8-47% social anxiety disorder, 3-35% obsessive compulsive disorder, 7-39% posttraumatic stress disorder and 7-32% generalized anxiety disorder. Overall anxiety comorbidity was higher in Bipolar I disorder than Bipolar II disorder. The presence of anxiety predicted a lower age of onset (about 16 as opposed 20 years old) and a shorter time in the euthymic state. Presence of anxiety disorder also was associated with impaired function, poorer quality of life, decreased likelihood of recovery, greater prevalence of substance abuse, and greater likelihood of suicide attempt. In my experience, those in hypomanic states have a high reactivity to stress, often engaging in activities to relieve stress, such as compulsive shopping, sexual activity, or risk-taking. Substances are often used to "self-medicate."

Stress in Relationships Makes Things Worse

When chronic stress in family, romantic, and peer relationships is present, there is less improvement in mood symptoms in adolescents. "The association between chronic stress in peer relationships and mania symptoms is likely a recursive one in which the most impaired youths generate the highest levels of peer-related stress, which further exacerbates their mood symptomatology" (Kim, Miklowitz, Biuckians, & Mullen, 2007, p. 37). Possibly, this may create a pattern of dysfunctional reactivity to stress.

A Case Example

In one case example, Bob is an 18-year-old male, who expressed BD at the age of 5 after a family stress. Although he did not receive a diagnosis of BD until the age of 12, his symptoms where characteristic of juvenile BD. He had symptoms of obsessive-compulsive disorder, social anxiety disorder, separation anxiety, and generalized anxiety disorder. His mind was often occupied with ruminative "bad" thoughts. He developed many compensatory behaviors to relieve his stress including a shut-down depressive state, psychomotor agitation, and tics. Bob manifested psychotic symptoms and suicidal ideation during times of heightened stress. School, for example, was a continual source of stress from teachers and peers, resulting in poor performance and exacerbation of bipolar switching. This further resulted in a deterioration of peer relationships, recursively leading to a greater number of bipolar episodes.

What Causes Bipolar Disorder? The Role of Stress and Biology

The strong relationship between stress and BD generates speculation about the etiology of the disorder. The exact nature of the relationship between the two is unclear (Simon, et al., 2004). Anxiety in early life may represent a prodromal symptom, or they may both share the same biological or genetic origin. Heritability rates of BD are between 40 (a narrow definition) and 97% (a broad-spectrum definition) (Correll, et al., 2007).

Etiological Theories

Preston and colleagues (2002) summarize the etiological theories that have been proposed for BD. Several of these relate directly to the role that stress may play in the treatment of the disorder. The Deregulation Theory revolves around the homeostatic regulation of mood. Over activity outside of the bounds of homeostasis leads to associated behavioral manifestations. The Chaotic Attractor Theory hypothesizes that there is a biochemical deficit that leads to deregulation of the synthesis of neurotransmitters. The mood state depends on the physiological or environmental conditions present. It predicts a chaotic course of the illness. The HPA Axis Theory associates the overactivation of the HPA axis in mixed state and depressive states. The Kindling Theory hypothesizes that the buildup of subclinical biochemical changes in the limbic system. Eventually there is a build-up of neuronal excitability until symptoms appear. This theory explains the progressive nature of the disorder, resulting in more frequent and severe symptoms. It is the Kindling Theory that is the most relevant to the interaction of stress disorders and BD.

The Kindling Hypothesis: Two Interpretations

The Kindling hypothesis asserts that the first episode of a mood disorder "… is more likely to be associated with major psychosocial stressors than are episodes occurring later in the course of the illness" (Post, 1992, pp. 999-1000). Post further hypothesized that sensitization to stressors and episodes became encoded at the level of gene expression.

There is confusion in the literature about the Kindling Hypothesis, which may be generated primarily from the ambiguities surrounding poorly described ideas and terminology in early studies. Specifically, "do recurrent episodes become autonomous of stress, such that stress is no longer an etiological mechanism in the precipitation of recurrence? Or do individuals become sensitized to stress, such that ever more minor forms of adversity are capable of precipitating recurrence? Most generally, if minor events increase in their frequency and impact in precipitating onsets of depression across recurrence, then this would support sensitization. By contrast, if all forms of stress (major and minor) decrease in their frequency and impact in precipitating recurrences, then this would support autonomy and suggest that some other mechanism" (Monroe & Harkness, 2005, p. 442). The disruptions of the social rhythms that cause bipolar episodes gives credence to the psychobiological hypothesis of the etiology of BD (Malkoff-Schwartz, Frank, Anderson, Hlastala, Luther, & Houck, 2000).

With either interpretation, studies have shown that stress in early life predicts earlier onset of the disorder. They also agree on stress as being a precipitator to episodes in early life. Childhood abuse, for example, was reported in nearly half of one study of veterans with BD (Brown, McBride, Bauer, & Willifor, 2005). Abuse may cause a change in brain physiology, making BD more difficult to treat, with more rapid cycling, anxiety, and panic disorder (Post, 1992) and (Brown, McBride, Bauer, & Willifor, 2005). But the confusion in interpretation lies in what occurs after the initial onset.

In the first interpretation, the person with BD experience life stressors, which may be severe. These stressors precipitate a manic or depressive episode. Although the person has reacted to the stressor, it has desensitized him/her to further episodes of stress. In other words, it is not that the person no longer has bipolar episodes, but that these episodes are endogenous in nature and come independent (or at least less dependent) of the stressors. McPherson, Hervison, and Romans (1994) found life events precipitate bipolar episodes only for earlier episodes. In another study, stress levels predict relapse, although the number of previous levels did not affect the stress response, which showed that BD episodes were not increasingly independent of stressors. However, it did show that personality traits, such as introversion and obsessionality, did affect the patient's reactivity to stress (Swendsen, Hammen, Heller, & Gitlin, 1995). There are a certain number of episodes that cannot be explained be stress events (Malkoff-Schwartz, Frank, Anderson, Hlastala, Luther, & Houck, 2000).

In the second interpretation of the Kindling Theory, earlier stressors sensitize the person with BD to stress events. That is, once someone has had experienced stress preceding a bipolar episode, they become more sensitive to any future stress. In this case, even minor stressors may precipitate an episode. Hammen and Gitlin (1997), for example, found that stressors may precipitate BD episodes and more quickly, especially in those with more prior episodes. This, they say, is "inconsistent" with the Kindling Hypothesis. They confirmed the importance of stressful life events as a contributor to BD and showed that patients with prior history of episodes were more likely to have had a several stressors in the previous months.

Although the debate about the interpretation of the hypothesis has not been resolved, I believe that both interpretations may be valid. I have seen bipolar episodes that appear to be independent of life events or stressors and those triggered by very minor stressors. A bipolar client may switch into hypomania quite rapidly, without noticeable triggers, as if it is just "time to switch." What most people, even the patient, would not discern as a stress may be enough to trigger an event. The bipolar event may thus look as if it was spontaneous. This would give credence to the idea that prior stress might serve as a sensitizer, such that even minor stresses create a bipolar event. Reactivity may be a complex interaction between age, stress, onset, and new episodes (Hlastala, et al., 2000).

Treating Bipolar Disorder: Medication

The treatment of BD is complex. Psychosocial treatments are necessary but rarely sufficient for controlling relapse or acute symptoms. From my observations, the treatment of BD is as much of an art as it is a science, with different researchers and clinicians having different ideas as to what is the appropriate formulation. Critically important is the assessment of suicide throughout the treatment. Suicidal ideation and suicide completion is a very real possibility in those with BD, both in depressed and hypomanic or manic states. Suicidal acts in those with BD may be a tendency to develop pessimistic response to major life stressors (Oquendo, et al., 2004).

Comorbid anxiety disorders should be treated concurrently. Treatment of anxiety disorders may lessen the severity of the BD symptoms and possibly increase pharmacological response (Simon, Otto, & Wisneiewski, 2004). According to Simon and colleagues (2004), there is a growing awareness of the need to address comorbid anxiety disorders, which should be integrated into the treatment of high-risk bipolar patients and suicide prevention. However, few specific anxiety-targeted interventions for BD have been developed. As of 2004, there was no data showing anxiety treatment efficacy for clinical course of BD. There is also little known about how anxiety increases suicidality, although it may be that BD patients with severe anxiety are less able to tolerate negative affect and less capable of calling upon social supports or cognitive strategies.

Psychopharmacological treatment focuses on controlling current acute symptoms and maintenance to prevent relapse. Mood-stabilizers are administered for reducing episodes, anti-psychotics generally for reducing symptoms of mania, hypomania, aggression, and irritability, and anti-depressants for depressive phases (although generally only after mood-stabilizers are use.) Psychopharmacological treatment also usually involves treatment of the co-occurring disorders. However, because there is such a strong co-occurrence of substance abuse problems in those with BD, many of the anxiolytics are used with caution. Benzodiazepines, although very effective for many of the anxiety disorders, can generate rapid physical dependence and are subject to abuse. Particularly important, according to some researchers, is the discontinuation of any stimulants, even coffee.

Tracking you mood events can be a helpful part of psychotherapy of bipolar disorder

Treating Bipolar Disorder: Psychosocial Approaches

A wide array of psychosocial interventions is available including psychoeducational, cognitive-behavioral, family therapy, social rhythm therapy and interpersonal psychotherapies. All these techniques help to teach self-monitoring, identification of early warning signs of relapse, and enhance coping mechanisms (Parkikh, et al., 2007). Early warning signs are associated with life-stressors. Several studies have identified the coping mechanisms involved with prodromal states as being particularly important in controlling symptoms, including Parkikh, et al. (2007) and Koukopoulus (2006). A self-report questionnaire called the Coping Inventory for Prodroms of Mania (CIPM) has been developed to assess coping styles in the manic and hypomanic state (Wong & Lam, 1999).

Psychoeducation

Psychoeducation is universally accepted as an integral part of the psychosocial treatment protocol and includes learning aspects of healthy habits, behavioral changes, symptom management, and adherence (Colom & Vieta, 2006). Colom and colleagues (2003) designed a 21-session program, which educates patients about all aspects of their illness, such as treatment, symptoms, drug use, lifestyle, and stress management. Other common goals of psychosocial treatment include decreasing denial, challenging assumption, monitoring moods, managing environmental triggers, relapse prevention and enhancing social and occupational functioning (Miklowitz, 2006).

Cognitive-Behavioral Therapy (CBT)

Cognitive behavioral techniques are useful since bipolar patients have distinct attributional styles and cognitive distortions. Research linking stress and lowered social support to bipolar episodes suggest treatment target stress reduction, improvement of relationships, and altering perceptions, and treatment that addresses these psychosocial vulnerabilities may help alter the course of Bipolar I disorder (Cohen, Hammen, Henry, & Daley, 2004). Patients are then taught to plan for potential events and learn new ways of resolving interpersonal difficulties. This approach has shown great promise for the treatment of BD (Colom & Vieta, 2006). Combination CBT and medication has shown to delay relapse, improve symptoms, and sometimes increase social functioning (Miklowitz, 2006).

Interpersonal Social Rhythm Therapy (IPSRT)

Interpersonal Social Rhythm Therapy revolves around the notion that sleep-wake cycles are primary to symptoms and disruption of the cycles can act as a stressor. Social rhythms, such as exercise and personal habit routines, social stimulation, and work, affect the sleep cycle (Miklowitz, 2006). Social routines may entrain circadian rhythms; disruption may cause bipolar episodes, suggesting that minimization of stressful and social rhythm disruptions may prevent episodes (Malkoff-Schwartz, Frank, Anderson, Hlastala, Luther, & Houck, 2000). The client is encouraged to track mood, sleep, and events that lead to a disruption of the social rhythm, such as a lost night of sleep. Bipolar manic episodes may be more sensitive to social rhythm disruption and life events, as compared to other types of bipolar and unipolar episodes (Malkoff-Schwartz, Frank, Anderson, Hlastala, Luther, & Houck, 2000).

Family, Group, and Biofeedback Approaches

Other treatment modalities are available. Family-focused therapy focuses on family interactions and use of family members as allies in the treatment process (Miklowitz, 2006). Skill training is used to reduce negative expression of emotion, which result in stress. Group therapy is also used, which help patients learn to feel accepted and learn self-care strategies from one another.

I am personally interested in the use of biofeedback and neurofeedback to treat BD. Although there is no real "hard" evidence about its effectiveness with BD, largely due to the difficulty in replicating treatment in controlled experiments, anecdotal information from such people as Siegfried Othmer (one of the "fathers" of neurofeedback) convince me that the possibility for treating BD with neurofeedback are just beginning to emerge. The use of biofeedback techniques for stress management in those with BD are useful but must be administered with care. Over-activation of the parasympathetic or sympathetic nervous system may induce a bipolar event.

Why Early Intervention Matters

Of direct implication from the kindling hypothesis is the timing of intervention. Intervention may be much more effective at the initial stages of expression than at later stages (Monroe & Harkness, 2005, p. 442). By tackling the stressful life situations of those at risk early on, the course of the disorder may be changed. How much of the developmental process is a reaction to life course and how much is an independent psychobiological process is yet unknown but begs for further investigation. "The key implication of this study is that childhood adversity may be related to a more challenging presentation of bipolar disorder, with an earlier age at onset and greater vulnerability to experiencing recurrences of mood episodes in the face of even mild stress. Earlier onset and a more difficult course of bipolar disorder may have serious consequences for both the efficacy of treatment of bipolar disorder and for the functioning of bipolar individuals. If childhood adversity is a trigger of earlier onset and sensitizes individuals to stress, preventing stress exposure in high-risk families, or promoting coping capabilities in such youngsters might have positive consequences on the course of illness" (Dienes, Hammen, Henry, Cohen, & Daley, 2006, p. 49). Prevention of stress and early intervention may be critical in reducing the severity of the disorder in later life.

References

1.   Akiskal, H. (2006). The Scope of Bipolar Disorders. In H. Akiskal, & M. Tohen, Bipolar Psychopharmacotherapy (pp. 1-8). West Sussex, England: John Wiley & Sons Ltd.

2.   Akiskal, H., Mendlowicz, M., Jean-Louis, G., Rapaport, M., Kelsoe, J., Gillin, J., et al. (2000). TEMPS-A: validation of a short version of a self-related instrument designed to measure variations in temperament. J. of Affective Disorders , 85 (1-2), 45-52.

3.   Angst, J., & Gamma, A. (2002). Prevalence of bipolar disoders: traditional and novel approaches. Clinical Approaches in Bipolar Disorder , 1, 10-14.

4.   APA. (1994). Diagnostic and Statistical Manual of mental Disorders, 4th Edition. Washington DC: American Psychiatric Association.

5.   Berk, M., Malhi, G., Cahill, C., Carman, C., Hadzi-Pavlovic, D., Hawkins, M., et al. (2007). The Bipolar Depression Rating Scale (BDRS): its defvlopment, validation and utility. Bipolar Disorders , 9 (6), 571-579.

6.   Brown, G., McBride, L., Bauer, j., & Willifor, W. (2005). Impact of childhood abuse on the course of bipolar disorder:A replication study in U.S. veterans B. J. of Affecgtive Disorders , 89, 57-67.

7.   Brudick, K., Funke, B., Goldberg, J., Bates, J., Jaeger, J., Kucherlapati, R., et al. (2007). COMT genotype increases risk of bipolar I disorder and influences neurocontive performance. Bipolar Disorders , 9 (4), 370-376.

8.   Cohen, A., Hammen, C., Henry, R., & Daley, S. (2004). Effects of stress and social suport on recurrence in bipolar disorder. J. of Affegtive Disorders , 82, 143-47.

9.   Colom, F., & Vieta, E. (2006). The pivotal role of psychoeducation in the long-term treatment of bipolar disorder. In H. Akiskal, & M. Tohen, Bipolar Psycopharmacotherapy: Caring for the Patiens (pp. 331-345). West Sussex: John Wiley & Sons, Ltd.

10.  Colom, F., Vieta, E., Sanchez-Moreno, J., Reinares, M., Martinez-Aran, A., Torrent, C., et al. (2003). Psychoeducatio efficacy in bipolar disorders beyond compliance enhancement. J Clin Psychiatry , 6, 294-298.

11.  Correll, C., Penzner, J., Lencz, T., Auther, A., Smith, C., Malhotra, C., et al. (2007). Early identificaiton and high-risk strategies for bipolar disorder. Bipolar Disorders , 9 (4), 324-338.

12.  DelBello, M., & Geller, B. (2001). Review of studies of child and adolescent offspring of bipolar parents. Bipolar Disorders , 3, 325-334.

13.  Dienes, K., Hammen, C., Henry, R., Cohen, A., & Daley, S. (2006). The stress sensitization hypothesis: Understanding the course of bipolar disorder. Journal of affective Disorders , 95, 43-49.

14.  Faraone, S., Lasky-Su, J., Glatt, S., Van Eerdewegh, P., & Tsuang, M. (2006). Early ongset bipolar disorer: Possible linkage to chromosome 9q34. Bipolar Disorder , 8, 144-151.

15.  Gottesman, I., & Gould, T. (2003). The endophenotype concept in psychiatiry: Etymology and strategic intentions. Am J Psychiatry , 160, 636-645.

16.  Hammen, C., & Gitlin, M. (1997). Stress reactivity in bipolar patients and its relation to prior hisotry of disorder. Am J Psychiatry , 154, 856-857.

17.  Hammen, C., & Gitlin, M. (1997). Stress reactivity in bipolar patients and its relation to prior history of disorder. Am J Psychiatry , 154 (6), 856-7.

18.  Hillergers, M., Burger, H., Wals, M., Reichart, C. V., Nolen, W., & Ormel, J. (2004). Impact of stressful life events, familial loading and their interaction on the onset of mood disorders: Study in a high-risk cohort of adolescent offspring of parents with bipolar disorder. British J. of Psychiatry , 185, 97-101.

19.  Hirschfeld, R., & Vornik, L. (2004). recognition and diagnosis of bipolar disorder. J of Clinical Psychiatry , 65(Supp 15), 5-8.

20.  Hlastala, S., Frank, E., Kowlaski, J., Sherril, J., Tu, X., Anderson, B., et al. (2000). Sressful life events, bipolar disorder, and teh "kinlding model". J Abnormal Psychol , 109 (4), 777-86.

21.  Kessler, R., Rubinow, D., Holmes, C., Abelson, J., & Ahao, S. (1997). The epidemiology of DSM-III-R bipolar I disorder in a gerneal population survey. Psychol Med (27), 1079-1089.

22.  kilbourne, A., Rofey, D., McCarthy, F., Post, E., Welsh, D., & Blow, F. (2007). nutrition and exercise behavior amongh patients with bipolar disorer. Bipolar Disorders , 9 (5), 443-452.

23.  Kim, E., Miklowitz, d., Biuckians, A., & Mullen, K. (2007). Life stress and the course of early-onset bipolar disorder. J of affective Disorders , 99, 37-44.

24.  Koukopoulos, A. (2006). The Primacy of Mania. In H. Akiskal, & M. Tohen, Bipolar p2006sychopharmacotherapy: Caring for the patient (pp. 169-192). West Sussex, England: John Wiley & Sons, Ltd.

25.  Kupka, R., Altshuler, L., Nolaen, W., Suppes, T., Luckenbaugh, D., Leverich, G., et al. (2007). Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disorders , 9 (5), 531-535.

26.  Leahy, R. (. (2006). Contemporary Cognitive Therapy. New York: Guilford Press.

27.  Malkoff-Schwartz, S., Frank, E., Anderson, B., Hlastala, S., Luther, J. S., & Houck, P. K. (2000). Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodess. Psychol Med , 30 (5), 1005-6.

28.  Manji, H., & Lenox, R. (2000). The nature of bipolar disorder. J Clin Psychiatry , 61 (Supp 13), 42-57.

29.  McPherson, H., Herbison, P., & Romans, S. (1994). Life eventws and relapse in established bipolar affective disorder. Br. J Psychiatry , 164 (3), 417.

30.  Miklowitz, D. (2006). Psychosocial interventions in bipolar disorders: Rationale and effectivness. In H. Akiskal, & M. Tohen, Bipolar psychopharmacogtherapy: Caring for the Patient (pp. 313-332). West Sussex: John Wiley & Sons.

31.  Monroe, S., & Harkness, K. (2005). Life stress, te "kindling" hypothesis, and the recurrence of depression: Considerations from a life stress perspesctive. Psychological Review , 112 (2), 417-445.

32.  Newman, C., Leahy, R., Beck, A., Reilly-Harrington, N., & Gyulai, L. (2002). Bipolar disorder: A cognitive therapy approach. Washington, DC: American Psychological Association.

33.  Oquendo, M., Galfalvy, H., Russo, S., Ellis, S., Grunebaum, M., Burke, A., et al. (2004). Prospective study of clinical predictors of suicidal acts after a major depressive episode in patients with major depressive disorder or bipolar disorder. Am J Psychiatry , 161 (8), 1433-1441.

34.  Parkikh, S., Velyvis, V., Yatham, L., Beaulieu, S., Cervantes, P., MacQueen, G., et al. (2007). Coping styles in proderomes of bipolar mania. Bipolar Disorders , 9 (6), 589-595.

35.  Perugi, G., Ghaemi, N., & Akiskal, H. (2006). Diagnosis and clinical management approaches to bipolar depression, bipolar II and their comorbidities. In S. Hagop, & A. Tohen, Bipolar Psychopharmacotherapy: Caring for the Patient. John Wile & Sons, Ltd.

36.  Post, R. (1992). Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J. Psychiatry , 149, 999-1010.

37.  Post, R. (1992). Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am j. Psychiatry .

38.  Preston, J., & Johnson, J. (2004). Clinical psychopharmacology made rediculously simple. United States: MedMaster, Inc.

39.  Preston, J., O'Neal, J., & Talaga, M. (2002). Handbook of clinical psychopharmacology for therapists. Canada: New Harbinger Publications, Inc.

40.  Simon, N., Otto, M., & Wisneiewski, S. (2004). Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry , 161, 2222-2229.

41.  Simon, N., Otto, M., Wisniewski, S., Fossey, M., Sagduyu, K., Frank, E., et al. (2004). Anxiety disorder comorbidity in bipolar disorder patients: Data from the first 500 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Am J psychiatry , 161, 2222-2229.

42.  Smith, Cornelius, V., Warnock, A., Tacchi, M., & Taylor, D. (2007). Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disorders , 9 (6), 551-560.

43.  Smith, L., Cornelius, V., Warnock, A., Bell, A., & Young, A. (2007). Effectivenessof mood stabilizers and antipsychotics in the mainenanc e phase of bipolar diosrer: a systematic review of randomized controlled trials. Bipolar Disorders , 394-412.

44.  Stahl, S. (2006). Bioplar vs. difficult to treat depression. Advances in Psychopharmacology Throughout the Life Span (pp. 83-107). San Diego: U. of CA, San Diego School of Medicine.

45.  Stahl, S. (2006). Bipolar vs difficult to treat depression. Advances in Psychopharmacology Throughout the Life Span (pp. 83-107). San Diego, California: University of California, San Diego School of Medicine.

46.  Stahl, S. (2005). Diagnosis and treatment of bipolar spectrum disorders. NEI Psychopharmacology Academy 2-Day Series (pp. 37-54). United States: Neurscience Education Institute.

47.  Stahl, S. (2000). Essential psychopharmacology of depression and bipolar disorder. Cambridge, United Kingdom: Cambridge University Press.

48.  Stahl, S. (2003). Essential Psychopharmacology: Neurosceintific Basis and Practical Applications. United States: Cambridge University Press.

49.  Stahl, S. (2005). Essential Psychopharmacology: The Prescriber's Guide. Canada: Cambridge University Press.

50.  Stahl, S. (2005). Mechanisms of action of mood stabilizers and atypical antipsychotics. In S. Stahl, NEI Psychoparmacology Academy Workbook: Tratment Issues for Depressiona dn Bipolar Disorder (pp. 29-36). United States: Neuroscience Education Institute.

51.  Stahl, S. (2005). The every-evolving bipolar spectrum: From bipolar mania to mixed mania and beyond. Distinguishing the Diagnosis and Tretments for Bipolar Mania, Mixed Mania, and Difficult-to-Treat Depression within the Bipolar Spectrum (pp. 7-26). San Diego: Neuroscience Education Institute.

52.  Swendsen, J., Hammen, C., Heller, T., & Gitlin, M. (1995). Correleates of stress reactivity in patients with bipolar disorder. Am j Psychiatry , 152 (5), 795-7.

53.  Vizzarri, J., Sbrana, A., Rucci, P., Ravani, L., Massei, G., Gonnelli, C., et al. (2007). The spectrum of subtance abuse in bipolar disorder: reasons for use, sensation seekinjg and substance sensitivity. Bipolar Disorders , 9(3), 213-220.

54.  Wong, G., & Lam, D. (1999). The development and validation of the coping inventory for prodromes of mania. J Affect Disorders , 53, 57-65.

55.  Yurgelun-Todd, D., Silveri, M., Gruber, S., Rohan, M., & Pimentel, P. (2007). White matter abnormalities observed in bipolar disorder: a diffusion tensor imaging study. Bipolar Disorders , 9 (5), 504-512.