Where Does Bipolar Disorder Come From

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GENETICS, BIOLOGY, AND STRESS

Stacy, 38, had two young daughters and worked part time for an accounting firm. She had carried the bipolar I diagnosis for at least 15 years and took Depakote on a regular basis. Although she agreed that she'd had severe mood swings, her interpretations of their causes tended toward the psychological rather than the biological. She often doubted that she had bipolar disorder: She was scientifically trained and felt that the absence of a definitive biological test meant that the diagnosis should remain in doubt. Her psychiatrist frequently reminded her of her family history: Her uncle had been diagnosed with bipolar illness and alcoholism, and her mother suffered from major periods of depression. But she remained unconvinced and continued to wonder whether she really needed medication. After all, she had been feeling fine for more than a year. She toyed with the idea of discontinuing her Depakote but was talked out of it, time and time again, by her psychiatrist.

Over the course of a year, Stacy went through a series of life changes, including divorcing her husband. Other than some mild depression, she made it through the initial marital separation reasonably well. It wasn't until she and her children had to undergo a child custody evaluation that she began to show symptoms of mania. As the evaluation proceeded, she found that calls from her lawyer made her spring into action: She would rush off to the library and copy every legal precedent that was even re motely pertinent to her case, call friends all over the country to ask them to speak to lawyers they knew, and fax numerous documents to her lawyer's and doctor's offices. She often called her estranged husband and screamed threats into the phone. Her lawyer assured her that the divorce and custody agreement would be comfortable for her and her children, but his assurances did little to stop her from working harder and harder and sleeping less and less.

When her psychiatrist suggested to her that she was getting manic, she shrugged and said "probably," adding that she needed to spend every minute preparing for her upcoming court date. As her mania escalated, her doctor convinced her to try an increased dosage of Depakote and to add a major tranquilizer (Zyprexa). She reluctantly agreed to these modifications but still maintained that her problems were stress-related.

The divorce and custody arrangement were eventually settled out of court (and in Stacy's favor). Perhaps due to the additional medication and the removal of this life stressor, her mania gradually remitted and a major crisis was averted.

Two major questions plague virtually everyone diagnosed with bipolar disorder: "How did I get this?" and "What triggers an episode of mania or depression?" As you read this chapter, you'll make distinctions between factors that cause the onset of the disorder and factors that affect the course of the disorder once it is manifest. These factors are not necessarily the same. Alternatively, the same factors may carry different weight in the onset than in the course of the disorder. Specifically, the initial cause of the disorder is strongly influenced by genetic factors (having a family history of bipolar disorder or at least depressive illness). In contrast, new episodes that develop after the first one appear to be heavily influenced by environmental stress, sleep disruption, alcohol and substance abuse, noncompliance with drug treatments, and other genetic, biological, or environmental factors.

If you have had the disorder for quite some time, you may be aware that your mood swings have a strong biochemical basis. You may also be aware that bipolar disorder runs in families. You may know several other people in your family tree who have had it or versions of it. If you are learning about bipolar disorder for the first time, you may not have been told that the cycling of the disorder is influenced by disturbances in the activity of receptors on your nerve cells and the production or breakdown of certain neurotransmitters, hormones, and other chemicals in your brain. Medications are designed to correct these imbalances. In either case, it is useful to know about the genetic and biological origins of the disorder, because this knowledge will help you accept the illness and educate others close to you about what you are going through (see also Chapter 12). Also, knowing about the biological bases of your disorder will probably make taking medications feel more reasonable to you.

But genetics and biology are not going to be the whole story. As Stacy's case reflects, a major life stressor, such as going through a divorce, can serve as a catalyst for the cycling of mood states. Everybody gets mad, sad, or happy, depending on the nature of the things that happen to them. People with bipolar disorder, because of the nature of their biology, can develop extreme moodiness in reaction to events in their environment. We don't know whether stress causes people to have bipolar disorder in the first place, but we're fairly certain that it makes the course of the illness worse in people who already have it.

Vulnerability and Stress

We needn't think of bipolar disorder as "only a brain disease" or "only a psychological problem," It can be both of these things, and each influences the other. Most professionals think of the cycling of bipolar disorder—and, for that matter, the waxing and waning of most illnesses—as reflecting a complex interplay between biological agents (for example, reductions in the activity of dopamine in your brain), psycho logical agents (for example, your expectations about things), and stress agents (things that bring about changes, whether positive or negative, such as transitions in your job or living situation, financial problems, family conflicts, or a new romantic relationship). Think of it this way: You have underlying biochemical disturbances ("vulnerabilities") with which you may have been born. These disturbances can include your brain's over- or underproduction of neurotransmitters (such as norepinephrine, dopamine, or serotonin) and abnormality in the structure or function of your nerve cell receptors. Much of the time these disturbances are "dormant" and have little effect on your day-to-day functioning, though they still make you more susceptible to experiencing bipolar episodes. When stressors reach a certain level, these biological vulnerabilities or predispositions get expressed as the symptoms you're already familiar with—irritable mood, racing thoughts, paralyzing sadness, and/or sleep disturbance. In other words, your biological predispositions affect your psychological and emotional reactions to stress (and in all likelihood, vice versa). Likewise, when the stress agent is removed, your biochemical imbalances may become dormant again (as happened for Stacy).

Some psychiatrists and psychologists use a vulnerability-stress model (Zubin & Spring, 1977) to explain a person's bipolar symptoms. Look at the graph on page 76. If you are born with a great deal of genetic vulnerability— for example, the disorder is present across multiple past generations of your family—a relatively minor stressor (for example, a change in your job shift hours) may be enough to elicit your bipolar symptoms. If you have less ge-

Stress Vulnerability Model
Vulnerability

A vulnerability-stress model for understanding periods of illness and wellness. Copyright by the American Psychoiogical Association. Adapted by permission from Zubin and Spring (1977).

netic vulnerability (for example, only one extended relative, like an uncle, had bipolar disorder, or a few relatives had depression, but no one was bipolar), it may take a relatively severe stressor (for example, the death of a parent) to evoke your bipolar symptoms.

In this chapter, you'll see examples of what is meant by genetic and biological vulnerability and a way to determine whether your family tree puts you at greater or lesser risk. You'll also see examples of the kinds of stressors that have been shown in research studies to be important in triggering mood cycling. Recognizing that you may be biologically and genetically vulnerable and that certain factors are stressful for you is the first step in learning skills for managing your disorder. By the chapter's end, you should have a general idea of how genetics and biology answer the question "How did I get this?" and how these factors combine with stress to bring about new episodes (recurrences) of your bipolar disorder. Later chapters provide practical suggestions for minimizing the impact of stressful events or circumstances.

"How Did I Get This?": The Role of Genetics

We have known for many years that psychiatric disorders are genetically heritable and run in families. In the 1960s and 1970s, studies of schizophrenic patients who had been adopted away from their natural parents showed that schizophrenia occurred at higher than average rates in the biological relatives of the patients, even when these relatives had played no role in raising the patients (Heston, 1966; Kety, 1983; Rosenthal, 1970). Identical twin studies have also supported the idea that genes can predispose a person to developing schizophrenia, probably in combination with environmental triggers (Gottesman, 1991). Genetic studies of persons with bipolar disorder (reviewed in the next section) have led to similar conclusions (Gershon, 1990).

As we discussed in Chapter 3, family history is often a part of the initial diagnostic evaluation. Stacy, as it turned out, had a mother and an uncle who showed signs of mood disorder, although it was only her uncle who had bipolar disorder. It is not unusual for bipolar disorder to "co-segregate" or be associated in family trees with other kinds of mood disorders, particularly various forms of depression (Gershon, 1990, Nürnberger & Gershon, 1992) .

How do we know that bipolar disorder runs in families? Geneticists usually establish that an illness is heritable through family studies, twin studies, and adoption studies. I discuss each of these briefly and offer additional sources for reading more about these topics.

Family, Twin, and Adoption Studies

Family history studies examine people who have an illness and then find out who in their family "pedigree" or family tree also has the disorder or some form of it (recall from earlier chapters that bipolar disorder can look quite variable). We know that when one person has the disorder, often a brother, sister, parent, or aunt or uncle will also have it. We also know that some relatives of bipolar people will have other mood disorders, such as major depressive disorder or dysthymic disorder (long-term, mild depression). They may also be affected by alcoholism, drug abuse, panic or other anxiety symptoms, or an eating disorder (for example, obesity with binge eating), which, while not mood disorders themselves, are problems that co-occur with and sometimes mask underlying depressive or manic symptoms. The figure pictures Stacy's family pedigree. The circles represent women, and the squares represent men. Notice that some of her relatives had mood disorders and some did not.

The rate of mood disorder (major depression, dysthymia, or bipolar disorder) among first-degree relatives (siblings, parents, and children) of bipolar persons averages about 20%. That is, one of every five first-degree relatives of a bipolar person has a mood disorder. On average, about 8% of a person's first-degree relatives have bipolar disorder, and about 12% have major depressive episodes without mania or hypomania. These numbers are averages: Some people have many more relatives who have mood disorders and some have

Bipolar Pedigree
Stacy's family pedigree.

fewer. Also, these numbers are "age-corrected," meaning that older first-degree relatives, because they have had more time to develop a mood disorder, are given more weight in the calculations than are younger first-degree relatives. If you would like to read further about these family history studies, check out two excellent chapters authored or coauthored by Eliot Gershon (1990; Nürnberger & Gershon, 1992).

Another way to establish heritability is to ask this question: When one identical twin has the disorder, what is the probability (percentage) that the other identical twin has it also? Identical twins, as you probably know, share 100% of their genes. Fraternal twins (from two different eggs) share only 50% of their genes, just like brothers and sisters. If we think a disorder is heritable, we would expect that the identical twin pairs will have higher "concordance" or agreement rates—when one twin is bipolar, the other should be also—than fraternal twin pairs.

One review of the genetic literature found that concordance rates for bipolar disorder among identical twins averaged 57% and between fraternal twins, 14% (Alda, 1997). Stated another way, when one identical twin has bipolar disorder, there is more than a one-in-two chance that the other identical twin does also. When a fraternal twin has bipolar disorder, there is about a one-in-seven chance that his or her twin has it. This suggests that bipolar disorder has a strong genetic component. If the illness were entirely genetic, the identical twin rate would be 100%. Because it is only 57%, we know there must be nongenetic, environmental causes as well, and these are discussed later in the chapter (DeRubeis et al., 1998).

Twin studies have been criticized because identical twins tend to be treated as more alike by their parents than do fraternal twins. If environmental factors do play a role, then the differences found between identical and fraternal twins cannot necessarily be attributed to genetics. To eliminate the environmental factor, researchers look for identical twins who have been raised separately. Few studies have been done on this topic because they are very hard to do. Two such studies found that identical twins raised from birth in two different households had concordance rates for major mood disorders that were similar to the rates for identical twins raised in the same household (McGuffin & Katz, 1989; Price, 1968).

Finally, geneticists can find out if bipolar disorder runs in families through adoption studies. Adoption studies are another way to begin to separate ''nature from nurture" by examining whether the biological parents or siblings of bipolar adoptees are themselves ill, even if they never shared an environment with the bipolar adoptee. Two researchers, Mendlewicz and Rainer (1977), examined the biological relatives of bipolar people who had been adopted. These biological relatives had the same rate of mood disorder (bipolar or major depressive illness) as the biological relatives of bipolar persons who had not been adopted (about 26%). The adoptive parents of these bipolar persons did not show a higher than average rate of mood disorder. Once again, it seems that bipolar disorder runs in families, even when scientists are able to rule out, or at least limit, the influences of the person's upbringing.

What Exactly Is Inherited?

We know that inheriting bipolar disorder can't be as simple as inheriting brown hair or blue eyes. Too many people with bipolar disorder have no mood disorder in their families, or the last time it occurred in the family was several generations ago. This means that the way the disorder is inherited has to be more complicated, it may be that the tendency to become "emotionally dysregulated"—extremely moody—runs in families. It may be that people inherit a mild form of bipolar disorder (for example, bipolar II disorder) or perhaps just a moody temperament, but develop the full bipolar condition only if other predisposing conditions occur. Some of these conditions may include inheriting genes for bipolar disorder from both sides of the family, being "in utero" when the mother contracted a virus, undergoing a difficult, complicated birth, taking street drugs when growing up, sustaining a head injury, or some traumatic environmental circumstance.

The hypothesis that a person's genetic inheritance interacts with specific environmental conditions to produce bipolar disorder is just that, a hypothesis. To test this hypothesis in a research study, we would have to determine whether children born with a genetic history of bipolar disorder and affected by these predisposing environmental conditions are more likely to develop bi polar disorder in adulthood than children with a similar genetic history who have not been affected by these environmental conditions. These long-term studies, which would take many years to complete and are extremely difficult to execute, have not been done.

Current advances in modern genetics now allow researchers to examine regions of the chromosomes in an attempt to locate genes for bipolar disorder. To date, no single gene of large effect has been found, leading researchers to suspect that many genes—each with quite small effect—contribute to the genetic vulnerability to bipolar disorder. Several investigations have reported a vulnerability gene on chromosome 18 (for example, the research of MacKinnon and associates, 1998), but pinpointing the exact gene has been elusive. At this stage, there is a lot we don't know about how bipolar disorder is inherited, but scientists are working veiy hard to solve the puzzle. Once the genes are located, more accurate diagnoses and better treatments are likely to follow.

"Do f Have a Genetic Vulnerability?": Examining Your Own Pedigree

Before we get into the issue of what the genetic data might mean for your own life, let's take a look at whether bipolar disorder runs in your family. Are you genetically predisposed to the disorder? In part T of this exercise, fill out the table on page 81 to the best of your knowledge. Confine yourself to your own children, your siblings (note in the table if the person is a full sibling or a half sibling), your parents, grandparents, aunts, and uncles. Leave out cousins, nephews and nieces (the information people have on these relatives tends to be unreliable). Consult your relatives if you want more information, i have filled in the first four lines from Stacy's family as examples.

Next, place a star next to anyone you think may have had (or still has):

1. Full bipolar 1 or bipolar II disorder, or even a milder form of bipolar disorder, such as cyclothymia (mild and short depressed periods that alternate with short hypomanic periods)

2. Major depressive episodes or long-term periods of milder depression (dysthymia)

3. Any other psychiatric problem that is not a mood disorder but that may be masking changes in mood (for example, drinking or drug problems, panic attacks, or eating disorders)

Answers to the following questions will give you clues as to your relative's health or illness:

COLLECTING INFORMATION TO DRAW YOUR PEDIGREE

Age now

Name of relative

Relationship to you

(or at

How did he/she die?

death)

1, Robert

Father

66

Heart attack

2. Isabelle

Mother

64

(Still alive)*

3. Mark

Brother

41

(Still alive)

4. Valerie

Sister

34

(Still alive)

• How did the relative die (if deceased)? Was it an accident, suicide, or an illness?

• Was the person ever unable to work for a period of time, or did he or she constantly switch jobs?

• Did he or she jump from one marriage or relationship to another?

• Are there family stories about the person being drunk, hurting him- or herself or others, or having a "nervous breakdown"?

• Are there stories about how this relative was a recluse, shutting him- or herself away in a room for days at a time?

• Did he or she ever take medication? What kind?

• Was the relative ever in a psychiatric hospital?

Now assemble your information into the pedigree. Again, circles refer to female relatives and squares to males. Fill in the circle or square of any relative you think may have had bipolar disorder. Fill in only half of the circle or square if the person had major depression, dysthymia, cyclothymia, or any of the other problems mentioned that can mask a mood disorder (for example, alcoholism, drug abuse, eating disorders). Put an "S" above anyone who committed suicide. Put a question mark in the circles or squares of any relatives you're not sure about.

Next, examine the pedigree (paying particular attention to the solid and half-solid circles or squares) and ask yourself the following questions: How many of your relatives have bipolar disorder? If none, are there members in your family tree who are/were depressed, alcoholic, drug-addicted or have had

Bipolar Pedigree
Locating relatives with mood disorders in your family pedigree.

an eating disorder? If so, consider whether the alcoholism, eating problem, or panic symptoms may have hidden an underlying depressed or bipolar condition, For example, if the person had bursts of rage even when not drunk, and became withdrawn for periods of lime even when "on the wagon," he or she may have had an underlying mood disorder as well as alcoholism.

Disorders like alcoholism or drug abuse tend to affect males more than females, whereas major depressive episodes affect more females than males (for example, Kessler et al., 1994). Does this pattern help you determine whether the male versus the female relatives in your family tree had psychiatric conditions? Did any relative spend time in a psychiatric hospital or take psychiatric medications for a long period of time? Did anyone commit suicide? Although we cannot know for sure, there is a possibility that a suicidal relative had a mood disorder and/or an alcohol or substance dependence disorder.

If you have children, you may know whether one or more of them has a psychiatric disorder and can fill in those circles or squares. Of course, your children may not yet have reached an age when the disorder is recognized—-bipolar disorder can be diagnosed at any age, but most frequently starts between ages 15 and 19. Be sure to fill in any psychiatric information relevant to your children's mother {if you are their father) or father (if you are their mother), and draw in "tree branches" to any affected or unaffected relatives in his or her family of origin. As you know, it is possible that your children inherited mood disorders from the other parent's side of the family, or from both sides of the family.

"What Does the Genetic Evidence Mean for Me?" Practical Implications of Genetics

It is not yet possible to assign a number to a person's genetic vulnerability to bipolar disorder. Instead, vulnerability is usually described in general terms like "low," "medium," or "high." One way of assessing your family tree is to ask whether the number of late-teenage or adult first-degree relatives in your pedigree who have bipolar disorder exceeds the average rate of 8% (20% if you include persons with depressive disorders). If your family tree is "dotted" with people who have bipolar disorder or some other mood disorder (more people are affected than unaffected), your vulnerability is high. Likewise, if bipolar disorder or other mood disorders are present in several generations (for example, in your siblings, parents, and grandparents), then your genetic vulnerability is higher than for a person with bipolar disorder in only one generation. If only one of your first-degree relatives had a mild dysthymic depression and no one had bipolar disorder, your genetic vulnerability is probably on the low end of the continuum.

Now, what do you do with the information if you have concluded that bipolar disorder, or at least depression, runs in your family? Genetic evidence has practical implications for your life. First, the fact that the disorder runs in your family should make you feel less ashamed of having the illness. None of us can control the genes with which we come into this world. As you'll see in later chapters, there are things you can do to control the cycling of your disorder. But getting the disorder in the first place is heavily influenced by your genetic makeup. We don't know how to engineer the environment to prevent the original onset of the disorder. In other words, it isn't your fault—a fact that your family members may also need to hear (see Chapter 12). As the father of one young man with bipolar disorder put it, "For a long time we thought he was just a screw-up. He seemed able to screw up everything. But eventually we realized there was an illness, and that there was something really wrong with his brain. He had a real problem that had a chemical basis, and it was probably something he got from me or from my wife's side of the family. He wasn't doing all that stuff to hurt us. That's when we came to some understandings as a family."

Having a family history of bipolar disorder may also help confirm your diagnosis, if you still have doubts (see also Chapter 3). If bipolar disorder clearly runs in your family, this fact will sway your doctor toward a bipolar diagnosis rather than, say, attention-deficit/hyperactivity disorder, depression, or schizophrenia. A family history of bipolar disorder is not a conclusive piece of evidence, but it provides one piece of the diagnostic puzzle.

This is not to say that genetic evidence is the key to why you have mood swings. We heiieve genetics play a big role in who has bipolar disorder, but we know that genetics alone do not explain when and why your mood swings occur. Even if bipolar disorder runs in your family, you probably feel that your mood swings are a product of more than just your genes or some chemicals in your brain that have gone haywire. Stacy certainly felt this way. That's why it's very important to think of genetics as providing only a background for problems you may have in regulating your emotions, thinking, and activity levels. It's the same way with high blood pressure; It certainly runs in families, but not everyone in a genetically susceptible family ends up with high blood pressure, and certainly not everyone with a family history of heart disease ends up dying of a heart attack. What people eat, whether they smoke, their weight, their levels of stress, and a whole host of other factors come into play. Again, there is an important distinction to be made between the original causes of the disorder and triggers of episodes.

"What If I Don't Have a Family History of the Disorder?"

Some people with bipolar disorder examine their family pedigrees and see no evidence of any illness, mood or otherwise. This is unusual, but it does happen. The thing to ask yourself is whether you know enough about the people in your pedigree to say that they had no illness. Could the "exhaustion" that your mother describes about her own mother have reflected a depression? If your grandfather is described as "dominating," "angry," or "aggressive," could he have also been manic? If not, could bipolar illness have occurred in someone several generations back?

Often, your older relatives will know more about your family pedigree than you do, in which case you can enlist their help in filling out your pedigree chart. Your parents, if they are alive, will almost certainly know more about the lives of their parents, siblings, and other relatives. Consider asking your doctor to perform a family history interview with one or more of your relatives, if such an evaluation was not done as part of your initial evaluation (see Chapter 3).

Nonetheless, you may not be able to identify any relatives in your pedigree who have had mood disorders. We believe there are other triggers for the onset of bipolar disorder, but we aren't certain what these are. It's possible that prolonged drug abuse can bring on bipolar disorder in some people. An injury to the head or a neurological illness such as encephalitis or multiple sclerosis can bring on mood swings that look just like those of bipolar disorder. Perhaps we will find that the onset of bipolar disorder can be attributed in some people to complications that occurred during their birth or to viruses their mothers contracted during pregnancy, as has been found for schizophrenia (for more information about this possibility, see an excellent review of the schizophrenia literature by Barbara Cornblatt and her associates (1999). It is unlikely that environmental stress or traumatic experiences alone can make a person develop bipolar disorder if he or she has no genetic predisposition, but this topic has never been studied.

Even if your disorder doesn't have an obvious genetic basis, you may still respond to the medications that are used to treat bipolar disorder (see Chapter 6), just as environmental stress can cause a headache that aspirin can alleviate. Some studies indicate that if you have a high prevalence of bipolar disorder in your family tree, you may respond better to lithium than if you have a low prevalence (Abou-Saleh & Coppen, 1986; Alda et al., 1997; Grof et al., 1993; Maj et al., 1984; Prien et al., 1973). You may respond better to anticonvulsants (for example, Tegretol) than to lithium if you have little or no family history (Post et al., 1987). But the evidence for this is not strong enough to guide our choice of treatments. Given our current state of knowledge, your physician will probably place greater emphasis on your current and past symptoms and pattern of mood cycling in making his or her drug treatment recommendations, rather than on your family history,

"What about Having Children?"

As indicated above, if you have bipolar disorder, your chances of passing the disorder on to your kids average about 8% (20% if you include major depression). These probabilities are relatively low and are comparable to other psychiatric disorders. For example, if you have schizophrenia, your chances of passing it on to your children are about 13% (Gottesman, 1991). So, the odds are in your and your child's favor. Of course, the question of whether to have children goes well beyond statistics. Whether you are a woman or a man, your answer to this question should be based on considerations such as whether you are clinically stable enough to take care of a child, whether you are physically healthy in other ways, and, where applicable, whether you are satisfied with your relationship with your partner.

Genes Are Not Destiny

Despite the relatively small chance that bipolar disorder will be passed genetically from parent to child, many people feel doomed by the evidence that they may have those genes. They assume that having the associated genes means that they and their children have nothing to look forward to but a lot of mood cycling, doctors, medications, and hospitals.

Being genetically prone or vulnerable to a disorder means that, by means of your biology, you are more likely to get an illness than someone without the same genetic susceptibility. But being genetically vulnerable does not mean that you will necessarily get ill within a certain stretch of time; it does not tell you the probability or the timing of your recurrences. It also does not mean that there is nothing you can do to control your cycling. High blood pressure, high cholesterol, and diabetes are all heritable, but exercise, diet, and appropriate medications go a long way in controlling these diseases. Likewise, lifestyle management and medications are critical to controlling episodes of bipolar illness (see Chapters 6-10).

Being genetically susceptible doesn't mean that your first-degree relatives, including your children, will necessarily get the illness, even if they are at a higher than average statistical risk. Illnesses skip generations or can be transmitted to your children in a milder form. Nonetheless, if you do have a family history of bipolar disorder and you also have children, you may be concerned about how you can protect them. There are ways to determine whether one or more of your children are showing signs of disturbance that suggest the beginnings of bipolar disorder. These can include irritability, aggressiveness, sleep disturbance, night terrors, school problems, inappropriate sexuality, drug or alcohol abuse, extreme and rapid switches in mood, sadness, lethargy, or withdrawal from others. There are steps you can take to get your child treatment if these signs are present, even if you're not really sure that he or she has bipolar disorder. If you'd like to learn more about bipolar disorder in children, I'd suggest reading The Bipolar Child by Demitri and Janice Papolos (1999).

What Is a Biochemical Imbalance?

Stacy had been told that her illness was probably biochemical. However, no linkage had ever been made for her between her biochemistry and her medications. She understood that having a biochemical imbalance meant that her illness was not fully under her control, but she was unclear what else it meant. Was the biochemical imbalance something that could be measured? Why was there no blood test for it? Was the imbalance there only when she was manic or depressed? What were the medications doing to it? Were the medications creating a different kind of biochemical imbalance? Could the imbalance be corrected by diet? She became frustrated that her doctor didn't give clear answers to these questions, even though he seemed quite knowledgeable otherwise. She felt that she was being asked to accept a lot of things on faith, and her scientific background made her feel doubtful.

Biological Vulnerabilities

Given that genetic background so strongly influences the onset of bipolar disorder, surely anatomical and/or physiological factors play a role as well. As I discussed in the preceding sections, a biological vulnerability can be dormant and then become activated by a trigger, such as environmental stress or drug abuse. Defining the nature of this biological predisposition is much trickier, however. If you have been told that you have a "biochemical imbalance in the brain," you may feel that this explanation raises as many questions as it answers, as it did for Stacy.

You may find you're more willing to accept the necessity of a medication regime if you understand what your doctors mean by a biological vulnerability or biochemical imbalance. They are usually referring to something that is part of you even when you're not having any symptoms. To use the blood pressure analogy, people with hypertension always have a vulnerability to an attack of high blood pressure, even when they're doing fine. Their system is such that their blood pressure is above normal even when they are relatively stress-free and eating well, and stress causes their blood pressure to rise even higher. Likewise, we think that in bipolar disorder, certain chemicals or molecules in the brain—notably neurotransmitters—are produced at levels that are too high or too low. The cells' receptors for these neurotransmitters—along with various enzymes or neurohormones—may be altered in their molecular structure and function. In bipolar disorder, biological vulnerabilities involving these chemicals may be evoked by stress agents (for example, a sudden change such as loss of a job), alcohol or street drugs, or for some people, antidepressants (see Chapter 6). When a stressor brings vulnerabilities to the foreground, the symptoms of bipolar disorder are most likely to appear.

To get technical for a moment, we strongly suspect that people with bipolar disorder have disturbances in the production and catabolism (chemical breakdown) of the neurotransmitters norepinephrine, dopamine, acetylcholine, serotonin, and GABA (gamma-aminobutyric acid). We believe that some of these neurotransmitters are over- or underproduced during different phases of the illness, then not broken down quickly enough, or broken down too quickly. We also know that people with bipolar disorder and unipolar depression have an abnormal production of hormones (for example, glucocorticoids such as Cortisol) produced by the adrenal glands when a person is under stress. Long-term stress and glucocorticoid overproduction may damage or destroy cells in the hippocampus, a brain structure that is an important component of the limbic system, which regulates emotional states, sleep, and arousal (Sapolsky, 2000; Manji, 2001).

Measuring biochemical imbalances gives us incomplete information. For example, many people with bipolar disorder have low levels of the metabolite (the breakdown product) of norepinephrine when they are in the depressed phase and higher levels when in the manic phase (Manji & Potter, 1997; Manji, 2001). Generally in these studies, levels of the breakdown product in a bipolar person's urine, blood, or cerebrospinal fluid (which requires a spinal tap) are measured. Such procedures may tell us that something is wrong in the production of norepinephrine, but we don't have the precision to point to the area in the brain where this misfiring is occurring. Eventually, the "neural circuits" (brain pathways) most associated with bipolar symptoms may be identified, perhaps through brain imaging techniques such as fMRIs (functional magnetic resonance imaging). Identifying these brain circuits may help us recognize persons at risk for the disorder, even when they are symptom-free, and hopefully develop more effective treatments.

New research with bipolar persons has found problems in their second messenger systems (also known as "signal transducers"), which are molecules inside brain nerve cells. When one nerve cell "fires," it sends neurotransmitters (the "first messengers") to the next nerve cell. Then a second messenger system informs the second nerve cell that the first nerve cell has fired. In other words, second messengers help to determine whether a cell communicates messages to other parts of the same cell and to nearby cells. One part of the second messenger system, called G-proteins (guanine nucleotide-binding proteins), may be present at abnormally high levels in the blood platelets of people with bipolar disorder, even when they are free of symptoms (Mitchell et al., 1997). Lithium probably changes G-protein function (Avissar et al., 1988; Jope, 1999; Risby et al., 1991). Lithium and Depakote also slow down activity of the protein kinase C signaling cascade, an important mediator of signals within the cells when their receptors are stimulated by neurotransmitters (Manji, 2001). This exciting research suggests that changes in second messenger systems may constitute one form of biological vulnerability to bipolar disorder—one that may be partially correctable by medications.

The Lack of a Definitive Test

Despite this promising research, there is no definitive biological or genetic test for chemical imbalances in bipolar disorder. Most professionals, patients, and families wish there were, because that would make diagnosis and treatment planning much easier. Most of us believe that such a test will be found eventually, but for now it's a long way off.

The absence of a definitive test makes it easy to forget that you have a biochemical imbalance and even easier to believe that you never had one in the first place. Notice that Stacy, who had been free of symptoms for quite some time, started to wonder whether she really had a biological predisposition. It is understandable to have this question. Could your manic or depressive episodes have been one-time occurrences that were set off by unpleasant life circumstances? Many people start to believe that "I had this illness once, but now it's under my control," especially when they've been well for a while. But bipolar symptoms have a way of recurring when you least expect them. We believe this is because biological vulnerabilities are still present, even when your symptoms are controlled by medications and psychotherapy.

What Turns a Biological Vulnerability into an Episode?

Learning that you probably have a biological imbalance, although perhaps frightening, should help to arm you against recurrences of your illness. Like the diabetic who knows he or she must avoid ice cream, or the person with high blood pressure who must avoid extreme distress and be sure to exercise, you can exert a degree of control over your bipolar disorder by learning to avoid triggers that influence the expression of your chemical imbalance. When people who do not have biochemical imbalances experience these triggers (for example, they take drugs or alcohol or intentionally take on high levels of stress), they may experience changes in mood but not to the degree that characterizes a person with bipolar disorder.

Some triggers may directly impinge on a person's chemical imbalances and set them off, kind of like lighting a fuse connecting a string of firecrackers. For example, LSD stimulates the action of certain serotonin receptors in the brain, which produces other biochemical events that will increase your risk of developing a manic episode. Studies of laboratory animals as well as humans find that amphetamine (speed) stimulates the release and prolongs the activity of dopamine in the brain, which can also result in a state of high arousal, paranoid thinking, irritability, and increases in energy or motor activity. Caffeine usage blocks a receptor for the neurotransmitter adenosine, which may result in greater release of dopamine, norepinephrine, and acetylcholine. Alcohol inhibits the activity of your central nervous system (for example, it increases the effects of the inhibitory neurotransmitter GABA on its receptors) and, like caffeine and other substances, interferes with your sleep-wake rhythms. When you stop drinking, your brain circuits become more excitable, much like they do in mania.

Environmental stress can augment your biochemical imbalances, but the mechanisms by which this happens are not well understood by scientists. Stress cannot be avoided in the same way that alcohol or drugs can be avoided, but knowing what kinds of stress agents will be particularly troublesome will help you know when you are most at risk for bipolar recurrences and plan preventively in the ways that are covered in the next few chapters.

Stress and Bipolar Episodes

Can bipolar disorder be caused by environmental factors, such as a highly confiictive marriage, problems with parents, life changes, a difficult job, or being abused as a child? These are extremely important questions that are not fully answerable. As I mentioned earlier, most of us doubt that environmental factors alone can cause bipolar disorder without the contributing influences of genetics and biology. However, we are reasonably certain that stress affects the course of your illness, or increases the chances that you will have an episode of mania or depression if you already have bipolar disorder. Your level of stress may also affect how long it takes you to get over a bipolar episode. That is, the level and type of stress you experience is a "prognostic factor" that helps determine your likelihood of getting better or worse within a certain time frame. Psychiatrists and psychologists are interested in knowing about the role of stress in your life because it can help them in treatment planning, such as deciding what type of therapy to recommend to you.

What kinds of environmental stress are particularly impacting? If you have bipolar disorder, encountering a major life change-—whether positive or negative—increases your likelihood of having a bipolar recurrence. Stacy's divorce had relatively little immediate effect on her mood state, but the child custody evaluation played a major role in her manic episode. Other kinds of stress include sleep-wake cycle disruptions and conflicts with significant others. I'll be talking about each of these and giving examples, I'll also discuss some of the current thinking about mechanisms by which biochemical imbalances might be affected by stress.

Major Life Changes

Changes are a part of life, and sometimes they are quite welcome. Some of them are positive and some quite negative. Examples of positive life changes include getting married, having a child, buying a new house, making money from an investment, or getting a job promotion. Negative life changes include the death of a loved one, the loss of a relationship, the loss of a job, a car accident, or the development of a medical illness in yourself or another family member.

Manic and depressive episodes often follow major life changes, both positive and negative. Sheri Johnson, PhD, a psychology professor at the University of Miami, has written extensively about life events in bipolar disorder (for example, Johnson & Roberts, 1995). She points out that it is not always clear whether life events are a cause or an effect of the mood episode. A client with bipolar disorder, Patrick, age 36, provides an illustration. When he was cycling into mania, he would become overconfident and frequently "tell off' his employers. He often lost jobs as a result. When discussing his history, he would argue that his pattern was to lose jobs and then become manic—when the reality was probably the other way around. But even when considering only events that couldn't have been brought about by the illness itself (for example, the death of a parent; losing one's job at a plant that closed down), researchers still find that life events play a role in the onset of manic and depressive episodes (Johnson & Roberts, 1995).

All of us are emotionally affected by stress, but not everyone has the severe mood swings that bipolar people have when under stress. Are people with bipolar disorder somehow more sensitive to life events? Johnson and her colleagues (2000) point out that the kinds of events that precede manic episodes are often goal- or achievement-oriented. Examples of these kinds of events include job promotions, new romantic relationships, financial investments, and athletic successes. She and her colleagues think that these kinds of events activate a circuit in the brain known as the behavioral activation system, which regulates the activity of the brain when "cues" or stimuli indicating reward are present (for example, investments that signal the possibility of great financial gain). In contrast, other kinds of events cause people to shut down and withdraw, as they do when they get depressed. These events, which usually involve loss, grief, or rejection, may activate a different set of neural circuits, called the behavioral inhibition system. This system motivates the person to avoid stimuli that signal punishment. For example, the loss of a relationship may make a person withdraw from others as a way of avoiding further rejection.

The behavioral activation and inhibition systems probably involve dopamine and serotonin activity, which, as mentioned earlier, may be abnormal in the brains of people with bipolar disorder. People with bipolar disorder might therefore be more biologically sensitive to events that are goal-oriented or loss/rejection-oriented. Johnson's hypothesis is an intriguing one, and she has supported it in her research by showing that, among people with bipolar I disorder, manic episodes are often preceded by events that stimulate goal-directedness (Johnson et al., 2000).

Stressful Events: Examining Your History

Have stressful events played a role in your previous episodes? If you have had more than one clear-cut episode, you may find the following exercise useful. Fill out the dates of three or more of your previous manic/hypomanic or depressive episodes and see if you can determine whether life events occurred

WHAT ROLE HAS STRESS PLAYED IN YOUR ILLNESS?

Approximate date of episode Type of episode

{or your age at the (manic, hypomanic, time) depressed, mixed) Stressful events (describe)

before (or during) any or all of them. If your previous episodes have been mainly mixed, indicate this in the table so that you can keep them separate when evaluating the exercise. Currently, we don't know whether mixed episodes have different environmental stress triggers from manic or depressive episodes.

include major events (for example, a move to a new state, new romantic relationships or relationship breakups, car accidents, job changes, deaths in the family) as well as events that, by comparison, are less severe or disruptive (for example, buying a new pet, getting the flu, taking a vacation, changing your job hours). Include both positive and negative life events.

Try to take a somewhat removed stance when examining the role of life stress in your own illness. Are particular types of events consistently related to your episodes? Has an event involving loss or grief ever preceded one or more of your depressive episodes? How many of your prior manic or mixed episodes were related to romantic relationships, even if positive (such as, finding a new partner)? Do events that involve achievement (for example, an increase in your work assignments) often precede your manic or hypomanic episodes? How many of these events might have resulted in changes in when or how much you slept? More generally, do these events occur independently of your mood disorder? Or does your manic or depressive behavior play a significant role in causing these events?

Don't be disappointed if you have difficulty answering these questions. Many people with bipolar disorder have trouble recalling when their episodes started and ended and when certain stressful events occurred. If you are having trouble, try consulting a family member or your doctor if he or she has seen you through several episodes. Take him or her through the exercise and see if he or she can help jog your memory about when certain events occurred, whether these events came before or after an episode, and what type of episode you had.

The temporal relationship between a life event and a resulting mood state can be quite complicated. For example, Annie, a 27-year-old, become mildly depressed after she broke up with her live-in girlfriend but did not develop a full bipolar depression. However, when her physician started her on a regime of antidepressant medication, she developed a mixed episode. In this case, the environmental stressor (the relationship ending) was related to the outcome (the mixed episode) only through the avenue of a change in her medication.

Remember that discovering a linkage between life events and your mood disorder episodes does not mean that you are somehow at fault for causing your own illness. Many life events are unavoidable. Some of these events can become more likely to occur when you get manic or depressed, but that still doesn't mean you are fully in control of their occurrence. For example, you may have lost certain jobs once your mood cycled into irritability or depression, but that doesn't mean you should have been able to control these mood states or their effects on others, particularly without having any tools to do so.

The Role of the Sleep-Wake Cycle

We've already talked about one mechanism by which stress can affect bipolar symptoms—the behavioral activation and inhibition systems. Another mechanism is sleep. If you remember back to your first episode or any other episodes, you will probably agree that sleep played some role in them. Perhaps it is simply that when you were manic you slept less, and when you were depressed you slept more. But changes in sleeping and waking are important in another way. Researchers believe that bipolar people are very sensitive to even minor changes in sleep—wake rhythms, such as when they go to bed, when they actually fall asleep, and when they wake up (Wehr et al. 1987; Frank et al., 2000; Malkoff-Schwartz et al., 1998). If so, events that change your sleep-wake cycle will also affect your mood. Stacy became quite manic when she began the child custody proceedings, possibly because the preparations were stressful and forced her to stay up later at night. Darryl, age 24, became manic shortly after his graduate school finals, during which he had stayed up later and later. Losing even a single night's sleep can precipitate a manic episode in people with bipolar disorder who have otherwise been stable (Malkoff-Schwartz et al., 1998). In parallel, sleep deprivation can improve the mood of a person with depression, although only briefly (Barbini et al., 1998; Liebenluft & Wehr, 1992).

What Affects Our Sleep-Woke Regularity?: Social Zeitgebers and Zeitstorers

Unless you speak German, you've probably never heard these terms before— nor had I until I started reading about the social rhythm stability hypothesis of Cindy Ehlers and her associates at the University of Pittsburgh Medical Center (Ehlers et al., 1988; Ehlers et al., 1993). This model helps us understand why life events might affect bipolar people's mood cycles.

Ehlers' theory states that the core problem in bipolar disorder is one of instability. Usually, people maintain regular patterns of daily activity and social stimulation, such as when they go to bed, when they get up and go to work, how many people they ordinarily socialize with, or where they go after work. These "social rhythms" are important in maintaining our "circadian rhythms," which are the more biologically driven cycles such as when you actually fall asleep, the production of hormones like melatonin (which is produced when you are approaching sleep), or your pattern of rapid eye movement activity during sleep.

Social rhythms stay stable, in part, because of social Zeitgebers, which are persons or events that function as an external time clock to regulate your habits. Your dog can be a social Zeitgeber if she or he needs to be walked at a certain time of the morning. If you have a spouse, he or she almost certainly plays a role in organizing your eating and sleeping schedules and probably affects how much stimulation you have from other people during the day. If you were to split up with your spouse, or even if he or she were to go away for a period of time, your daily and nightly routines would be disrupted. Your job also keeps you on a regular routine.

In contrast, a social Zeitstorer (time disturber) is a person or a social demand that throws everything off balance. When you start a new relationship, your patterns of sleeping, waking, and socializing change. The same thing will happen if you have a baby. In these cases, the new romantic partner or your baby is a Zeitstorer. If you take on employment that has constantly shifting work hours or requires that you travel across different time zones, your social and circadian rhythms will be disrupted considerably.

What does all of this mean for a person with bipolar disorder? Events that bring about changes in social rhythms, either by introducing Zeitstorers or removing Zeitgebers, alter circadian rhythms. You are particularly vulnerable to a manic episode after you have experienced a social rhythm-disrupting life event (for example, Malkoff-Schwartz et al., 1998).

Let me give you an example. Debra, a 36-year-old woman with bipolar II disorder, lived with her husband, Barry. During a therapy session with the couple, Debra complained that Barry had changed the schedule for feeding their two cats. He had begun feeding them both in the morning instead of the evening, and as a result one or both of the cats were coming into the couple's room in the middle of the night, crying for food. Debra wanted to feed the cats before she and Barry went to bed, but he refused, saying it would make the cats overweight. After three consecutive nights of poor sleep, she became irritable, experienced mental confusion at work, and developed racing thoughts. Finally, Barry agreed to the new evening feeding schedule, which alleviated the problem with the cats. As Debra got back on a regular sleep-wake cycle and experienced several nights of restorative sleep, her hypomania started to settle down. In Debra's case, a major episode was averted by reestablishing routines that had been disrupted by a relatively minor event.

Miriam, a 47-year-old woman with bipolar I disorder, reported that she developed manic or mixed symptoms the moming or afternoon after drinking alcohol, even if only in small quantities. It wasn't entirely clear to me why a small amount of alcohol would make her manic until I considered her sleep cycle: alcohol was acting as a disruptive Zeitstorer. She had much more difficulty falling asleep after drinking. Once she stopped drinking (or limited herself to one beer, usually consumed early in an evening), she had less trouble sleeping and fewer shifts in her mood states.

In Chapter 8, "Practical Ways to Maintain Wellness," I'll tell you about a method for keeping your social routines regulated even wh;n events conspire to change them (the social rhythm stability method; Frank et al., 2000). This self-monitoring technique can help you keep your mood and sleep-wake cycles stable.

Conflicts with Significant Others

So far, we've talked about single life events and changes in your routine. The other major type of stress has to do with your ongoing relationships. Chapter 12 is devoted to dealing with family members, so I'll give it only brief mention here. There is no evidence that disturbances in family relationships (for example, poor parenting when you were a child) cause bipolar disorder in the first place. But high-conflict family or marital situations can increase your likelihood of having a recurrence of bipolar disorder once you have it.

I conducted my dissertation research on this topic at UCLA with my former mentor, Michael Goldstein (Miklowitz et al., 1988). In this study, we worked with bipolar I manic adults who lived primarily with their parents. We examined the level of conflict between these patients and their parents while the patients were in the hospital and once they got out. Not surprisingly, those who returned to high-conflict families had more manic and depressive episodes (recurrences) within nine months after their hospitalization than those who returned to low-conflict families. Though all of the people in our study were hospitalized, many people with bipolar disorder never enter a hospital. Nevertheless, other researchers have found similar associations between family relationships and the outcome of bipolar disorder, whether or not the patients had been hospitalized (O'Connell et al., 1991; Priebe et al., 1989; Honig et al., 1997).

We don't know exactly why conflict-ridden family environments make bipolar people more recurrence-prone (though it makes sense), but we do know that family environments affect the course of many other psychiatric disorders, including schizophrenia, depression, alcoholism, and eating disorders (Butzlaff & Hooley, 1998), We also suspect that it is not only conflicts with family members or a spouse that can affect the cycling of your disorder but also conflicts with other significant people in your life, such as your employer, coworkers, or friends, In Stacy's case, her conflicts with her ex-husband may have played a role in her escalating mania. Had she been able to sit down with him and work things out with civility, her chances of staying stable might have been better. But she really didn't have that option.

For now, let's simply recognize that family and interpersonal conflicts can be risk factors in the course of your illness. Begin thinking about what role family or marital conflict has played in your disorder. Do your episodes typically coincide with significant family or marital arguments? Do these conflicts come before the episode, after the episode has begun, or is it impossible to tell? Many of my clients say that the family conflicts came before their episodes; others say that the conflicts arise once they've become manic, mixed, or depressed—but also make it harder to get better. Some report that family conflicts that have been there all along get worse when they become ill, or that "buried" issues come out in their dealings with family members. When you are becoming ill, it can be difficult to "edit" the things you want to say to your family members, and these family members may have similar difficulties in their communication with you (see Chapter 12),

When thinking through these issues, try to avoid blaming others for their role in your illness—in most cases family members are trying their best to be helpful and often don't know what to do or say. As you'll see in Chapter 12, there are good and bad ways to deal with your family members regarding issues surrounding your disorder. Managing your family relationships is an important element of maintaining wellness.

Bipolar disorder does not have clear-cut causes, but we know enough to say that it involves biological brain imbalances that are partly under genetic control. These biological vulnerabilities can be set off by various kinds of stressors, conflicts, or life changes, whether positive or negative. Stacy's experiences with life stress, family conflict, and sleep-wake disturbances may mirror some of your own.

Medications are designed to correct the underlying biological imbalances. The next chapter describes the available medications, what we think they do, their side effects, and the role of psychotherapy as an adjunctive treatment. Later chapters describe lifestyle management techniques. Usually these techniques are recommended alongside medication as a way of improving your ability to cope with stress. As you read on, try to think of biology and environment as interacting with each other—you'll have an easier time making choices about treatments if you can keep these multiple causes of bipolar disorder in mind.

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Do Not Panic

Do Not Panic

This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.

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