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Organizing Your Prescriptions When You’re Managing a Mental Health Condition

Posted on August 20, 2016 by JmaC

Make Sure You Have a Consolidated View of Your Medications

Are You Having a Midlife Crisis?

Posted on August 20, 2016 by JmaC

Reaching middle age can be satisfying to some and more worrying for others. Find out the signs of a midlife crisis.

Midlife crises are the subject of many jokes — middle-aged men buying sports cars, hanging out at bars, and generally acting half their age. The unfortunate reality is that most midlife crises are anything but funny, and midlife crisis symptoms can be felt by women as well as men.

A midlife crisis can tear a family, a marriage, or an individual apart and leave a lot of victims in its wake. “A person often makes an impulsive decision uncharacteristically or changes their lifestyle dramatically,” says Sheila K. Collins, PhD, a psychotherapist and author of Stillpoint: The Dance of Self-Caring and Self-Healing. “I’ve seen men come to their wives and say without any warning, ‘I’ve decided I don’t want to be married anymore.’”

What You Might Experience During a Midlife Crisis

To the outside observer, the actions taken during a midlife crisis may seem rash or even foolish. But under the surface, a lot of emotions and experiences have been going on for a long time to lead to this moment. A midlife crisis “doesn’t just ‘occur,’” says Penny B. Donnenfeld, PhD, a psychologist in private practice in New York City. “We are talking about the development over time of negative self-assessments — feelings of being limited and burdened by life responsibilities, having limited choices, or of having missed opportunities for choices that are no longer available.”

When it comes to men and midlife crisis, their professional life is often thought to play an important role. “For men, it often happens when they begin to plateau in their careers,” says Dr. Collins. “There begins to be a realization of the limitations of time, talent, and resources on people’s lives. Some questions they ask are, ‘Is this where I was going?’ or, ‘Is this all there is?’”

While people often think of men having a midlife crisis, women can be affected in the same way, adds Collins. “Often, because women more frequently have taken their child-rearing roles into account in their lives, this may have put them 8 to 10 years behind their male peers on the career track,” she says. “Their midlife crisis, if they have one, occurs later.”

Of course, a career is not the only factor when it comes to a midlife crisis. “A midlife crisis could happen when the last child leaves home, or when someone experiences grief over a significant loss — a parent’s death, a career reversal or job loss, or a challenge to their health,” says Collins.

Navigating a Midlife Crisis

If any symptoms of a midlife crisis affect you or your partner, there are options for getting through these challenging circumstances. Here is advice that can help:

Look on the bright side. “A midlife re-evaluation can be a positive thing,” says Collins. “In fact, it’s probably a good idea for married couples, business partners, and individuals to take time to re-evaluate their lives from time to time throughout their life cycles.”
Be proactive. Once you have this discussion, it’s time to act on these possibilities and see what new and exciting directions they lead you in. A few options include taking a class, going on a trip, reconnecting with people from the past, or training for a new career, says Donnenfeld.
Avoid rash decisions. By evaluating things from time to time, people can make gradual, measured changes, as opposed to rash ones that can damage a career, a family, or a life unnecessarily, adds Collins. “Remember, this may be the time to just stand there and do nothing. Let the dust settle until your direction becomes clear,” she advises.
Be a good listener. If your partner is the one experiencing the crisis, try to really hear and to understand what your loved one is going through. Says Donnenfeld, “Don’t deny their feelings or try to ‘fix’ it immediately.” In the process of talking about the problem, many possible solutions to the midlife crisis may begin to surface. “You may figure out some things that he or she would like to do to help life feel more meaningful,” she says.
Seek outside help. Finally, remember that there is absolutely no shame in seeing a therapist to talk out issues. Midlife can be a time of great, overpowering emotions, and many a strong man or woman has needed help working their way through these feelings.

It is possible to navigate safely through a midlife crisis. Recognizing the signs and exploring your options are key to moving forward into the next phase of your life.

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Mental Health and the Heart

Posted on August 20, 2016 by JmaC

We have long known that there are strong connections between heart health and mental health. And the connection goes both ways.

Depression commonly develops in patients after they have had a heart attack. In fact, major depression affects as many as 15-20% of patients in the hospital with a heart attack, and milder forms of depression likely occur in many more individuals. Women are most likely to be affected, especially younger women. Having depression after a heart attack makes recovery harder. People with depression may find it harder to take medications regularly, follow up with their care providers, and take care of themselves. Depression clearly increases the risk of being re-hospitalized.

We also know that people with depression develop heart disease at higher rates than people without depression. A study released this week in the Journal of the American College of Cardiology gives us new information about the links between another important mental health issue, PTSD (post-traumatic stress disorder) and heart disease. A group of researchers at Emory University in Atlanta followed 562 twins from the Vietnam Era Twin Registry. Of the 177 individuals who had PTSD, nearly 1 in 4 developed heart disease. Of the other 425 without PTSD, less than 1 in 10 developed heart disease. The study also compared ‘twin sets,’ particularly those where one twin developed PTSD and the other did not. In such cases, the risk of having heart disease was nearly double the twin with PTSD.

Post-traumatic stress disorder affects as many as 7 million adults in the US alone. It can develop after someone has experienced a traumatic event. In fact, PTSD can even develop after having a major health issue, like a stroke. People with PTSD continue to feel stressed and afraid even when they are no longer in danger or in the stressful situation. You can read more information about the symptoms and treatment of PTSD here.

As a medical community, we need to be more aware of the risks that mental health conditions pose for our patients. Depression and other mental health concerns affect recovery and treatment of heart disease. But this research also adds to the information that mental health issues may have a direct effect on the heart.

Much work is yet to be done on improving our care of patients with mental health issues. We need better ways to help identify patients who are at risk and we need better methods to treat them. Doing so will no doubt be good for both the mind and the heart.

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How Do Thoughts & Emotions Impact Health?

Posted on August 20, 2016 by JmaC

Emotions that are freely experienced and expressed without judgment or attachment tend to flow fluidly. On the other hand, repressed emotions (especially fearful or negative ones) can zap mental energy and hope and lead to health problems, such as high blood pressure or digestive disorders.

Therefore, it’s important for us to recognize and identify our thoughts and emotions, and to be aware of the impact they have—not only on each other, but also on our bodies, behavior, and relationships. As our awareness increases, we find it easier to recognize what we are thinking, how we are feeling, and our attitude towards the experience. We can then choose to adjust our thoughts and emotional responses.

Negativity and physical health

Chronic stress from negative attitudes and feelings of helplessness and hopelessness can upset the body’s hormone balance and deplete the brain chemicals required for feelings of happiness, as well as have a damaging impact on the immune system. New scientific understandings have also identified the process by which chronic stress can actually decrease our lifespan by shortening our telomeres (the “end caps” of our DNA strands, which play a big role in aging).

Poorly managed or repressed anger (hostility) is also related to a slew of health conditions, such as hypertension, cardiovascular disease, digestive disorders, and infection.

The importance of positivity

Scientist Barbara Fredrickson has shown that positive emotions have two important effects: theybroaden our perspective of the world (thus inspiring more creativity, wonder, and options), and they build up over time, creating lasting emotional resilience and flourishing.

Dr. Fredrickson has spent years researching and publishing the physical and emotional benefits of positivity, including faster recovery from cardiovascular stress, better sleep, fewer colds, and a greater sense of overall happiness. The good news is not only that positive attitudes—such as playfulness, gratitude, awe, love, interest, serenity, and feeling connected to others—have a direct impact on health and wellbeing, but that we can develop them ourselves with practice.

However, in our wish to defend against threat and loss in life, we tend to prioritize bad overgood. While this is a tidy survival mechanism for someone who needs to stay hyper vigilant in a dangerous environment, the truth is that for most of us, this “negativity bias” means that we spend time ruminating over the minor frustrations we experience—bad traffic, a disagreement with a loved one—and ignoring the many chances we have to experience wonder, awe, and gratitude throughout the day.

Fredrickson has calculated that in order to offset the negativity bias and experience a harmonious emotional state, we need to experience three positive emotions for every negative one. This, she claims, can be done intentionally for those of us less “wired” to positivity. These positive emotions literally reverse the physical effects of negativity and build up psychological resources that contribute to a flourishing life.

Forgiveness

The attitude of forgiveness—fully accepting that a negative circumstance has occurred and relinquishing negative feelings surrounding the event—can be learned and can lead us to experience better mental, emotional and physical health. The Stanford Forgiveness Project trained 260 adults in forgiveness in a 6-week course.

70% reported a decrease in their feelings of hurt
13% experienced reduced anger
27% experienced fewer physical complaints (for example, pain, gastrointestinal upset, dizziness, etc.)

The practice of forgiveness has also been linked to better immune function and a longer lifespan. Other studies have shown that forgiveness has more than just a metaphorical effect on the heart: it can actually lower our blood pressure and improve cardiovascular health as well.

Gratitude

Acknowledging the good aspects of life and giving thanks have a powerful impact on emotional wellbeing. In a landmark study, people who were asked to count their blessings felt happier, exercised more, had fewer physical complaints, and slept better than those who created lists of hassles.

Brené Brown has found that there is a relationship between joy and gratitude, but with a surprising twist: it’s not joy that makes us grateful, but gratitude that makes us joyful.

Emotional resilience

Dr. Andrew Weil describes resilience as being like a rubber band—no matter how far a resilient person is stretched or pulled by negative emotions, he or she has the ability to bounce back to his or her original state. Resilient people are able to experience tough emotions like pain, sorrow, frustration, and grief without falling apart—in fact, some people are able to look at challenging times with optimism and hope, knowing that their hardships will lead to personal growth and an expanded outlook on life.

Resilient people do not deny the pain or suffering they are experiencing; rather, they retain a sense of positivity that helps them overcome the negative effects of their situation. Positive emotions have a scientific purpose—to help the body recover from the ill effects of negative emotions. Thus cultivating positivity over time can help us become more resilient in the face of crisis or stress.

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2003 S&P Award Winner Creating True Peace

Posted on August 20, 2016 by JmaC

Book Review by Frederic and Mary Ann Brussat

“True peace is always possible,” declares Thich Nhat Hanh in this watershed work. “Yet it requires strength and practice, particularly in times of great difficulty. To some, peace and nonviolence are synonymous with passivity and weakness. In truth, practicing peace and nonviolence is far from passive. To practice peace, to make peace alive in us, is to actively cultivate understanding, love, and compassion, even in the face of misperception and conflict. Practicing peace, especially in times of war, requires courage.”

This peacemaker knows of what he writes. He has survived three wars, persecution, and more than 30 years of exile from his native country, Vietnam. This book has grown out of his experiences as a Buddhist monk, a retreat leader on the art of mindful living, the author of more than 100 books of teachings and poetry, and a world leader in the nonviolence movement. In addition, he has offered spiritual advice to American Vietnam War veterans, Israeli and Palestinian activists, psychotherapists, artists, environmental activists, children, and others.

Thich Nhat Hanh’s teaching has a very practical quality to it. In this volume he writes about creating peace in our personal lives, families, neighborhoods, spiritual communities, society, and world. Many of the practices have been honed in the monastic community he founded in France, Plum Village, as well as two centers in the United States, the Green Mountain Dharma Center in Vermont and Deer Park Monastery in California. Throughout his years of service, Thich Nhat Hanh has been a pioneer in “engaged Buddhism” which views meditation practices and social activism as being of one piece.

Both war and peace reside within each of us. Thich Nhat Hanh uses the image of the many seeds that are in our minds: seeds of understanding, wisdom, and forgiveness; as well as seeds of ignorance, anger, fear, and hatred. Peace and nonviolence start with us when we refuse to water the seeds of war by our actions. The spiritual teachings of all traditions challenge us to cultivate the seeds of compassion, love, kindness, nonviolence, openness, and reconciliation. Practices, guided meditations, and other exercises included here help us calm our emotions, acknowledge our interbeing with others, and extend the circle of compassion.

The author makes it clear that “the daily wars that occur within our thoughts and within our families have everything to do with the wars fought between peoples and nations throughout the world. The conviction that we know the truth and that those who do not share our beliefs are wrong has caused a lot of harm. When we believe something to be the absolute truth, we have become caught in our own views.” Knowing this to be true, we yearn for more practices that will nourish the seeds of peace.

We were heartened to read that Thich Nhat Hanh sees the spiritual practice of openness — the willingness to accept diversity and to approach others with a receptive heart and mind — as essential to the practice of nonviolence. “Exclusion, getting caught in our views, is a deep-seated habit that arises from fear and misunderstanding of others. To transform our habit of excluding others, we must practice and develop understanding and compassion in all parts of our life.” This is a deep teaching since when we are resisting nonviolently, we still may be excluding our opponents from our care and concern. War at home and abroad comes from our attachment to certain ideas and ideals that separates us from others and quite naturally brings out their enmity.

Those familiar with Thich Nhat Hanh’s work will recognize one of his core themes in the discussion of practicing peace toward our own pain, anger, or despair. Here, for example, is the practice of acknowledging our fear and not going to war against it. Bringing our awareness to it, we say, “Hello fear, I know you are there.” Eventually, this emotion will pass through us, and other emotions come to the fore. This is a particularly good practice to teach children so they don’t wind up acting in self-destructive ways. Thich Nhat Hanh also presents concrete examples of “peace treaties” we can make with ourselves: beginning anew, a practice of reconciliation and renewal, a peace treaty for couples, a wonderful wallet reminder practice to keep love and compassion alive in our relationships, and much more.

“The war stops and starts with you and me,” notes the author. The seeds of peace, compassion, and kindness are encouraged to bloom in the following meditation for embracing and nourishing positive emotions:

“1. Breathing in, I experience calm in me. Breathing out, I smile to the calm in me.
“2. Breathing in, I experience joy in me. Breathing out, I smile to the joy in me.
“3. Breathing in, I experience equanimity in me. Breathing out, I smile to the equanimity in me.
“4. Breathing in, I experience openness in me. Breathing out, I smile to the openness in me.
“5. Breathing in, I experience happiness in me. Breathing out, I smile to the happiness in me.”

When the war starts on one channel in your mind, switch the channel. The Buddha called this practice “changing pegs,” replacing one emotion with another. There are plenty of examples of how to do this in Creating True Peace. In the closing chapters, Thich Nhat Hanh has some healing words for the violent and aggressive actions of the United States along with some suggestions for a Council of Sages to listen to people who feel they are “victims of discrimination, exploitation and social injustice.” He ends with a manifesto circulated by the United Nations that presents guidelines for peacemaking in a global community where “each of us depends on the well-being of the entire human population.” This is in conjunction with the UN declaration of the decade 2001-2010 as the International Decade for the Culture of Peace and Nonviolence for the Children of the World.

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Borderline Personality Disorder and Abandonment

Posted on August 20, 2016 by JmaC

People with borderline personality disorder (BPD) often have issues with abandonment (Common Borderline Personality Disorder Symptoms). Last week I terminated therapy with my therapist. I struggled with the decision, as I know that those of us with BPD sometimes blame others for our emotional pain. Therapists are frequently used, in acute stages of BPD, as the reason for all of our emotions, both pleasant and unpleasant. This can bring up abandonment issues for those with BPD.My therapist felt annoyed with me for cancelling too many appointments. He was so angry that he refused to communicate with me about it, not even to say, “We can talk about this in our next session.”

I knew he had a valid reason to feel angry, but since he had never mentioned feeling annoyed with me about anything before, I was surprised and hurt by his refusal to talk to me.

Borderlines Often Have Intense Feelings of Abandonment

Fear of abandonment is a symptom of borderline personality disorder. Learn how one person with BPD handled abandonment successfully. Read this.

I asked myself, “Have I ever felt abandoned like this before?”

Many scenes flashed through my memory. Abandonment is usually a key issue with borderlines. I knew that I was feeling the pain of every time I had ever felt abandoned, not just the one instance with my therapist. He was not to blame for my intense feelings (Fear of Abandonment Due to Mental Illness).

I waited four days for him to communicate with me, hurting all the while. I finally decided that I did not want to work with a therapist who would abandon me when he felt angry with me. It was not the anger that bothered me. It was his refusal to talk. I cry when I think of all the good work I did with this therapist. He knows things about me that no one else knows, but it is time to move on.

Fighting Against Emotions Is a Way of Abandoning Ourselves

Though I think I made the best decision for me, I still feel a great deal of loss. Instead of fighting the grief and pain, I allow myself to feel whatever is there to feel. I have learned, in my 52 years of life, that avoiding emotional pain is what causes suffering. Sometimes I have hurt so badly that it felt like the pain might kill me, but it never does. I would rather let myself cry than fight against the tears, which hurts even more. I am not saying we should dwell on our pain, but that we should allow ourselves to feel whatever is there to feel, andlove ourselves through it all. Let’s not abandon ourselves.

Abandonment and Borderline Personality Disorder — No One Is Perfect

We’re all learning how to manage this thing called life. Therapists are not perfect. They laugh and cry just like we do. I know my therapist didn’t intend to hurt me. I evidently did something that pushed one of his emotional buttons, and he temporarily lost touch with his therapist role. That’s okay. I’m not mad at him, but I must take care of myself.

Have you ever felt abandoned? Do you fight against your emotional pain? What are some difficult things you have done to take care of yourself? Let’s talk.

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Different Moods of Anxiety and How to Tame Them

Posted on August 20, 2016 by JmaC

Anxiety has many different moods; frustratingly, anxiety isn’t a single, simple concept. No one can count on it to be anything other than disruptive and erratic. Perhaps you’ve experienced an all-too-common situation. You’re working hard to manage anxiety. Youranxiety symptoms have lessened and your life feels less restricted. Then, seemingly without warning, bam. Anxiety strikes again, and this time it feels worse somehow. This is a normal experience for people living with anxiety because anxiety has different moods. What are the different moods of anxiety and how can you tame them?

Different Moods of Anxiety

Anxiety has many different moods that sometimes appear out of nowhere. These tips will help you tame the different moods of anxiety. Take a look. Anxiety is moody. It varies in intensity, and it varies in symptoms, sometimes from one day to the next. Among the different moods of anxiety:

My-body-is-falling-apart mood – Anxiety can mimic heart attacks. It can act like asthma. Anxiety interferes with digestion and elimination. It can make us tired or wired–or both at once. Anxiety can interfere in every system of the human body (Anxiety in the Body: Physical Side-Effects of Anxiety). We treat it and feel better, until it is in the mood to make another appearance.

I’m-worthless-and-incompetent mood – Anxiety creates severe self-doubt and makes us incredibly hard on ourselves. We tend to beat ourselves up, repeatedly and relentlessly, for so many things. Just when we start to feel confident, anxiety rears up and knocks us back down.

Bad-things-are-going-to-happen mood – Anxiety causes fear and excessive worry. Fears can be addressed and reduced successfully. When anxiety gets moody, however, fear can flare and we find ourselves uneasy, worried, and anxious.

Taming Anxiety’s Moods

The different moods of anxiety and the way they can seem to appear out of nowhere when we’re feeling good, actually puts anxiety at a huge disadvantage. When anxiety is moody, it’s unstable. When it’s unstable, it can be tamed.

You can tame anxiety’s moods by being what anxiety can never be: reliable, consistent, and calm. These suggestions can help:

Don’t impose rules and timelines – Berating yourself because you think you “shouldn’t” be anxious or rushing the healing process puts a lot of pressure on you. It also keeps your focus on your anxiety. Use the rest of these suggestions daily without rules and deadlines.

Choose mindfulness as a lifestyle – Mindfulness can calm anxiety because with mindfulness, you’re living right now, in the present moment. By focusing on your senses and taking action in the moment, you’re turning away from anxiety. When anxiety suddenly appears out of nowhere, maintain your state of mindfulness you’ve cultivated for your life, and you’ll tame any of anxiety’s moods.

Know what you want and why you want it – What is your passion? What is important to you? What do you want your life to be like, and how do you want to be? Spend time answering these questions and use them as your guide in your daily life. When you know your values and live intentionally for them, it’s possible to be true to yourself no matter what anxiety is doing at the moment.

Develop a wellness routine, and live by it – Incorporating regular exercise, proper nutrition, balanced sleep, and deep breathing into your everyday routine will positively affect your brain and the rest of your body. This consistent sense of calm and inner strength will tame anxiety when it flares unexpectedly.

Anxiety has many different moods that can seemingly appear out of nowhere. Incorporate the above suggestions to tame anxiety’s moods.

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Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder

Posted on August 20, 2016 by JmaC

Abstract

There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant.

Key words: family studies, twin, adoption, GWAS, copy number variants

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Introduction

Evidence accumulated during the 20th century for a substantial genetic contribution to the etiology of both schizophrenia and bipolar disorder,^¹ with the genetic influences initially appearing to be largely distinct for each disorder. This reinforced the traditional concept of the Kraepelinian dichotomy,^² in which the 2 disorders were viewed as etiologically independent. The picture has now significantly changed to one of partial overlap in genetic influences, although many of the details about what is shared and independent remain to be elucidated. The dichotomy concept has thus been severely weakened^³,⁴ but persists in diagnostic classification systems^⁵,⁶ due to its conceptual simplicity and notable differences between the disorders in, eg, risk factors, associations with indices of neurodevelopmental impairment, clinical course, and treatment response.^{^7–9}

In this article, we will discuss how evidence regarding the genetic relationship between schizophrenia and bipolar disorder has evolved, both in quantitative genetics—based on family, twin, and adoption studies—and in molecular genetics, particularly through genetic association studies focusing on common risk variants and studies of rarer chromosomal structural variants. We will also discuss the controversial nosological status of schizoaffective disorder, and its subtypes, in relation to schizophrenia and bipolar disorder. We will not discuss genetic relationships with other psychotic disorders, such as depressive psychosis, delusional disorder, and brief psychotic disorder, because much less is currently known about the extent of genetic influences on these disorders.^{⁵,¹⁰,¹¹}

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Defining Disorders for Genetic Research

The way in which schizophrenia, bipolar disorder, and schizoaffective disorder are defined can have a substantial effect on the patterns of genetic relationships between them. The most common approach in psychiatric genetics research is to assign a single main-lifetime diagnosis to each individual using the relevant version of the Diagnostic and Statistical Manual of Mental Disorders (DSM)^⁶ or another operational diagnostic classification system, based on the predominant clinical picture during a person’s lifetime. A notable exception is the large-scale Scandinavian population register-based family studies, which usually employ International Classification of Diseases (ICD)^⁵ clinical diagnoses. These tend to have lower interrater reliability than operational research diagnoses,^¹² but this is mitigated by the high-quality epidemiological foundations and large sample sizes of the register-based studies.

Main-lifetime diagnoses generally incorporate a diagnostic hierarchy in which schizophrenia is placed above bipolar disorder, so that, eg, a person with one or several manic episodes at one stage of their clinical history and predominantly schizophrenic symptoms at another stage will usually have a main-lifetime diagnosis of schizophrenia. This approach has the advantage of being relatively simple, but it means that a sample of people diagnosed as having schizophrenia includes those with virtually no mood symptoms and also those with notable manic or depressive symptoms at some time during their lifetime (but not substantial enough to warrant a diagnosis of schizoaffective or mood disorder). Also, a sample of people with a diagnosis of bipolar disorder (mostly bipolar I in genetic studies due to recruitment via mental health services) includes those with no psychotic symptoms, those with purely mood-congruent psychotic symptoms (such as grandiose delusions with mania), and also those with mood-incongruent psychotic symptoms that are less obviously linked with the predominant mood state and more like symptoms characteristic of schizophrenia (but not substantial enough to qualify for a diagnosis of schizoaffective disorder or schizophrenia). The most common solution to this issue is to perform secondary analyses, further dissecting phenotypes, after an initial association is found using standard main-lifetime diagnoses.

An alternative is to employ a nonhierarchical lifetime-ever approach.^¹³,¹⁴ Here, if a person has, eg, a manic episode at one time and a schizophrenic episode at another, both are counted as being present, and the person is regarded as being comorbid for manic and schizophrenic episodes. This approach retains more information about symptoms, but the relative prominence of different types of symptom is less clear, and the groups are still clinically heterogeneous: eg, a sample of people with a manic episode includes those who have only ever had manic episodes and those who have also had schizophrenic episodes at some time. This could be an issue if genetic influences on manic symptoms are notably different in these 2 subgroups, and again further dissection of phenotypes could help to resolve these issues, where there is sufficient phenotypic information and large enough samples.

Genetic studies of both schizophrenia and bipolar disorder often include people with schizoaffective disorder, or some of its subtypes, in addition to the core disorder being investigated, and the proportion of people with schizoaffective disorder might be expected to have an impact on investigations of genetic relationships between schizophrenia and bipolar disorder. Debate continues over whether schizoaffective disorder, and its subtypes, are best regarded as subtypes of schizophrenia or psychotic mood disorders; as mixtures of cases, some of whom have schizophrenia and others psychotic mood disorders; as lying between these disorders on a single liability continuum; as due to the co-occurrence of elevated liabilities to these disorders; or as partly independent disorders in their own right.^{^15–22} Additionally, investigations of schizoaffective disorder have to contend with its relatively low interrater reliability,^²³ which could potentially cause genetic overlap between disorders to be overestimated,^²⁴ and high diagnostic instability over time.^²⁵,²⁶

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Quantitative Genetics

Genetic Influences on the Individual Disorders

Prior to consideration of genetic relationships between schizophrenia, bipolar, and schizoaffective disorders, it is relevant to summarize the evidence for genetic influences on the individual disorders.

Results of family, twin, and adoption studies show a notably similar pattern for each disorder. Traditional family studies conducted during the 20th century based on clinically ascertained samples show substantial familial aggregation, with sibling relative risks of around 8–10 for schizophrenia,^{^27–29} bipolar disorder,^{^30–34}and schizoaffective disorder.^{¹⁷,¹⁸,³⁵} More recently, considerably larger studies, based on Scandinavian national population registers, have substantiated the results of the earlier family studies.^{¹⁴,²⁶,^36–38} Results from the largest study,^¹⁴ based on over 2 million families, are shown in table 1.

Table 1.

Relative Risks for Schizophrenia and Bipolar Disorder in the Family and Adoption Study of Lichtenstein et al¹⁴

Twin studies show concordances of around 40%–45% in monozygotic (MZ) and 0%–10% in dizygotic twin pairs for schizophrenia,^³⁹ mania/bipolar disorder,^{¹⁰,⁴⁰,⁴¹} and schizoaffective disorder^¹⁰ and its manic and depressive subtypes,^¹⁰ consistent with a genetic contribution to the familial aggregation seen in these disorders, while MZ concordance of considerably less than 100% indicates that noninherited risk factors are also likely to be important.

Adoption studies during the 20th century show familial aggregation of schizophrenia in biological relatives who were separated by adoption early in life,^{^42–47} consistent with genetic influences. Bipolar disorder was studied less but also showed evidence of familial aggregation.^⁴⁸ Subsequently, a large-scale population register-based study in Sweden has further substantiated these results by showing significant familial aggregation for schizophrenia and bipolar disorder in the adopted-away offspring of affected biological parents^¹⁴ (table 1). However, there is still a lack of substantive adoption study data for schizoaffective disorder.

Heritability estimates based on twin study data are around 80% for schizophrenia,^³⁹,⁴⁹ mania/bipolar disorder,^⁴⁰ and schizoaffective disorder^¹⁰ and its manic and depressive subtypes.^¹⁰ The heritability of schizophrenia and bipolar disorder has also been estimated from Scandinavian national population family and adoption data and found to be somewhat lower at around 60%.^¹⁴,⁵⁰ The reasons for the difference are not clear, eg, how much due to differences in the types of relatives included or ascertainment methods, but it can still be concluded that the heritabilities of schizophrenia and bipolar disorder are substantial and similar, and in the region of 60%–80%.

Data from risks of disorders in relatives have also been used to model the most likely mode of inheritance of schizophrenia^⁵¹,⁵² and bipolar disorder.^⁵³,⁵⁴ For both disorders, this is likely to be multifactorial in most or all cases, with many genetic and environmental risk factors, each insufficient to cause the disorder on their own, but having a cumulative effect on risk when they occur together in the same individual.

Relationship Between Schizophrenia and Bipolar Disorder

Traditional clinically ascertained family studies during the 20th century, employing main-lifetime diagnoses, generally did not find a significant excess of bipolar disorder among the relatives of individuals with schizophrenia, or vice versa,^{³²,³⁴,⁵⁵,⁵⁶} supporting the concept of an etiological dichotomy between the 2 disorders. However, these studies could not exclude a degree of familial coaggregation due to sample size limitations.^⁵⁷

Consistent with this, a twin study, based on the Maudsley twin register in London,^¹³ found no co-occurrence of schizophrenia and bipolar disorder in MZ twin pairs when a hierarchical main-lifetime diagnosis was employed, again with the caveat of sample size limitations. However, when a nonhierarchical lifetime-ever approach was taken, significant coaggregation was seen between schizophrenic and manic episodes in twin pairs, and model-fitting showed a significant genetic correlation of 0.68 between lifetime-ever schizophrenia and mania.

Subsequently, the Swedish national population register-based family/adoption study,^¹⁴ also using a nonhierarchical diagnostic approach, showed significant familial coaggregation between schizophrenia and bipolar disorder in parent–offspring, sibling–sibling, and biological parent–adopted-away offspring pairs (table 1). The cross-disorder relative risks were lower than the same-disorder relative risks, consistent with partial sharing of genetic influences, and there was a very similar genetic correlation of 0.60. For hierarchical diagnoses, the genetic correlation was 0.46 (B. Yip, personal communication). This study also found a significantly elevated risk of bipolar disorder in siblings of probands with schizophrenia (relative risk: 2.7, 95% CI: 2.3–3.1), when individuals who had both schizophrenia and bipolar disorder were excluded, showing that in the primary nonhierarchical diagnostic analysis, the familial coaggregation of schizophrenia and bipolar disorder was not solely due to individuals who had both disorders diagnosed.

Further evidence for partial overlap in familial influences on schizophrenia and bipolar disorder has come from studies based on Danish national population registers. In one study,^³⁷ the relative risk of schizophrenia for a person whose mother had schizophrenia was 8.97 (95% CI: 6.93–11.62), while the relative risk of schizophrenia if their mother had bipolar disorder was 2.41 (95% CI: 1.59–3.65). The corresponding risks for affected fathers were 6.63 (95% CI: 4.83–9.09) and 3.15 (95% CI: 2.11–4.69). A similar pattern was also seen for the relative risk of bipolar disorder when parents or siblings had schizophrenia.^³⁶ In another study,^³⁸focusing on families with 2 affected parents, where both parents had schizophrenia the absolute risk of bipolar disorder in their offspring was 10.8% (95% CI: 2.6–19.0), about 10 times higher than the general population risk of bipolar disorder.

Additionally, a meta-analysis of family studies published between 1980 and 2006 found evidence of familial overlap, with the first-degree relatives of probands who had schizophrenia showing a significantly elevated risk of bipolar disorder compared with relatives of controls (OR = 2.08, P = .01).^⁵⁸

Schizoaffective Disorder

Traditional family studies during the 20th century found evidence of familial overlap between schizoaffective disorder and both schizophrenia and bipolar disorder,^{³²,³⁴,³⁵,⁵⁵,⁵⁹} and again this has been substantiated by more recent Scandinavian population register-based studies.^²⁶,³⁶

An investigation in the Maudsley twin series,^¹³ based on nonhierarchical diagnoses, found significant genetic correlations between schizoaffective disorder and both schizophrenia and mania (correlations of 0.77 and 0.88, respectively). Model-fitting of the 3 syndromes together was consistent with all of the genetic influences on schizoaffective disorder being shared with schizophrenia and mania. Caveats included limited sample size and only moderate interrater reliability for schizoaffective disorder.

Schizoaffective Subtypes.

Investigations that have subdivided schizoaffective disorder have most commonly used manic/bipolar and depressive subtypes. In family studies, relatives of probands with both subtypes have shown elevated risks of schizophrenia.^³⁴,³⁵ The manic/bipolar subtype has been associated with a relatively high familial risk of mania/bipolar disorder in some studies,^³⁴,⁵³ supporting the value of focusing on the subtypes, while other studies have also found the depressive subtype to be associated with elevated familial risk of bipolar disorder,^{¹⁸,³⁵,⁵⁵} supporting a focus on schizoaffective disorder as a unitary entity.

An investigation of manic/bipolar and depressive subtypes of schizoaffective disorder in the Maudsley twin series,^²¹ using both hierarchical and nonhierarchical diagnostic approaches, found a marked degree of familial overlap in MZ twin pairs between all of the syndromes investigated—Research Diagnostic Criteria (RDC) schizoaffective mania, schizoaffective depression, schizophrenia, and mania/bipolar disorder,^⁶⁰ with a trend toward schizoaffective mania and mania/bipolar disorder having the highest degree of overlap. The pattern of results was consistent with the schizoaffective mania/bipolar subtype being due to co-occurring elevated liability to schizophrenia, mania/bipolar disorder, and probably also depressive disorder, while the results for the schizoaffective depressive subtype were also consistent with co-occurring elevated liability to schizophrenia, mania/bipolar disorder, and depressive disorder but probably with a lesser degree of elevated liability to mania/bipolar disorder than the schizoaffective mania/bipolar subtype. Again there was the caveat of only moderate interrater reliability for schizoaffective subtypes; also, sample size limitations prevented formal model-fitting for individual syndromes.

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Molecular Genetic Studies

During the 20th century, genome-wide genetic linkage studies produced a range of chromosomal regions of potential interest, and genetic association studies, focusing on specific genes with limited a priori evidence and/or with limited sample sizes, found a range of significant associations,^⁶¹ but these have been difficult to replicate consistently. More recently, the focus has turned to large-scale genome-wide association studies (GWAS), as these have become technically feasible, which are geared to detect commonly occurring genetic variants that individually have a small effect on risk, and studies of large chromosomal structural variants, particularly copy number variants (CNVs), that are rarer but have a larger effect on risk when they occur.

Genome-Wide Association Studies

Analysis of Individual Genetic Markers.

GWAS typically investigate a million or more measured or imputed genetic markers spread along each chromosome, with sample sizes rising in recent years to tens of thousands of cases and controls.^{^62–64} The genetic markers are usually single-nucleotide polymorphisms (SNPs) where, at a particular point in the DNA sequence, the nucleotide base varies in the population, eg, individuals may carry either a C or an A allele. The study investigates whether one of the variants occurs more frequently than expected in cases than controls. If so, this statistical association may indicate the presence of a causal genetic variant nearby (in linkage disequilibrium) or, less commonly, that the genetic marker variant itself may have a causal effect. False positive associations are also likely, particularly due to the large numbers of markers being tested, so a very high degree of statistical significance is required (so-called genome-wide significance is usually P < 5 × 10⁻⁸).

The first substantive GWAS result in schizophrenia was for a marker in the zinc finger–binding protein 804A gene (ZNF804A) on chromosome 2q32.^⁶⁵ In order to investigate whether this association might involve a genetic variant that influenced risk of both schizophrenia and bipolar disorder, a bipolar disorder sample was added to the analysis. The effect size remained similar (OR = 1.12), while the P value became notably more significant (P = 9.96 × 10⁻ ⁹), consistent with the presence of a genetic variant that has a small effect on the risk of both disorders. These findings have been further substantiated by larger meta-analysis (schizophrenia:P = 2.5 × 10⁻ ¹¹, OR = 1.10; schizophrenia and bipolar disorder combined: P = 4.1 × 10⁻ ¹³, OR = 1.11).^⁶⁶

As GWAS sample sizes increased, thanks to large-scale international collaborations, genome-wide significant associations were found with markers in or near the major histocompatibility complex region on chromosome 6^⁶⁷ and the genes encoding neurogranin (NRGN) (11q24) and transcription factor 4 (TCF4) (18q21).^⁶⁸

Concurrently, collaborative GWAS of bipolar disorder identified genome-wide significant associations with markers in the genes encoding the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) (12p13) and ankyrin 3 (ANK3) (10q21).^⁶⁹ Subsequently, the Psychiatric Genomics Consortium (PGC) published the largest GWAS “mega-analysis” of bipolar disorder to date, involving over 60 000 participants.^⁶⁴ The CACNA1C association was further substantiated and there was a new genome-wide significant association with a marker in ODZ4 (11q14).

At the same time, a GWAS mega-analysis of schizophrenia, also from the PGC and involving over 50 000 participants,^⁶² found genome-wide significant associations at 7 loci, 5 of which were new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and 2 of which had been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest of the new findings was for a marker in the gene encoding microRNA 137 (MIR137), which has a role in the regulation of neuronal development. The study also reported analyses of combined schizophrenia and bipolar disorder samples, with associations at 3 loci, CACNA1C, ANK3, andITIH3-ITIH4, being genome-wide significant and showing increased levels of statistical significance in the combined analysis, consistent with genetic variants in these regions influencing risk of both disorders.

A subsequent review summarized the strongest published GWAS findings for schizophrenia, bipolar disorder, and both disorders combined^⁷⁰ (table 2). In keeping with the focus of GWAS, the associations each involve a small effect on risk (ORs around 1.1) and are consistent with a partial overlap in genetic influences from commonly occurring genetic variants on the 2 disorders. There is also evidence that most of these associations occur in and around genes.^⁷¹,⁷²

Table 2.

Genome-Wide Association Study Findings for Schizophrenia and Bipolar Disorder From the Review by Sullivan et al⁷⁰

Recently, the PGC Cross-Disorder Group has published a broader investigation encompassing 5 psychiatric disorders: schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder (ADHD).^⁷³ In the primary analysis of all 5 disorders combined, markers in 4 regions achieved genome-wide statistical significance. In 2 cases (on chromosomes 3p21 and 10q24), the causal variant behind the marker association could be located in or between a number of genes within the region, while in the other 2 cases, the associations were in calcium channel signaling genes (CACNA1C on chromosome 12 and CACNB2 on chromosome 10), and additional pathway analysis further supported the role of calcium channel activity genes influencing all 5 disorders.

The study also investigated the diagnostic specificity of genome-wide significant associations for schizophrenia and bipolar disorder found in previous PGC analyses. In keeping with previous findings, the results ranged from associations confined to one disorder to associations encompassing all 5 disorders (table 3).

Table 3.

Disorder Specificity of Genome-Wide Association Study Findings for Schizophrenia and Bipolar Disorder in the Psychiatric Genomics Consortium Cross-Disorder Group Study of 5 Psychiatric Disorders (2013)⁷³

GWAS continue to increase in sample size.^{⁶³,^74–77} For example, in studies of schizophrenia, this has included the addition of substantial numbers of patients treated with clozapine^⁷⁴ and a Swedish national sample,^⁶³which has resulted in 22 genome-wide significant loci being identified. Further analysis of these loci across disorders is awaited. There has also been an initial GWAS directly comparing cases of schizophrenia and bipolar disorder, with a view to identifying genetic differences between the 2 disorders.^⁷⁷ The study was underpowered to achieve genome-wide significant results, but further larger studies are likely to follow soon.

Combined Analysis of Genetic Markers Using Polygenic Scores.

An alternative to analyzing each genetic marker individually is to combine markers that show some evidence of association, taking a low statistical threshold, eg, P < .5, which aims to include many associations with variants that are probably causal but have not yet achieved genome-wide statistically significant association, eg, as sample sizes are not yet large enough, and accepting a degree of noise from markers that show trends toward association by chance. Scores are assigned to each individual based on the number of markers where they carry the putative risk variant, weighted by the effect size for each marker. These are known as polygenic scores, the term relating to the focus on investigating the cumulative effect of many commonly occurring genetic risk variants.

In the first such analysis for schizophrenia,^⁷⁸ polygenic scores calculated in an initial (discovery) sample significantly distinguished between cases and controls in an independent (test) schizophrenia sample (with higher scores in cases), and further modeling was consistent with the effect coming from a large number of common risk variants. The variance in the test sample explained by the polygenic score was modest (3%), but further analysis, eg, accounting for attenuation of associations based on markers rather than the actual causal variants, suggested that at least one-third of the variance in risk could be explained by polygenic effects. These findings have been substantiated in larger samples^⁶²,⁶³ and by further analysis^⁷⁹ and have also been found to apply to bipolar disorder.^⁶⁴

In the original study,^⁷⁸ the polygenic scores in the initial schizophrenia discovery sample also significantly distinguished between bipolar disorder cases and controls in 2 independent samples, but with the variance explained dropping from 3% to 1.9% and 1.4%, consistent with partial overlap in the polygenic contribution to risk of schizophrenia and bipolar disorder. In contrast, the schizophrenia polygenic scores did not significantly distinguish between cases and controls in samples with 6 nonpsychiatric medical conditions, including coronary artery disease, rheumatoid arthritis, and type I and type II diabetes.

The recent PGC cross-disorder study,^⁷³ and a further study,^⁸⁰ using different analytic approaches, further substantiated the partial overlap in polygenic influences on schizophrenia and bipolar disorder, with a genetic correlation due to common SNP markers of 0.68.^⁸¹

CNV Studies

While GWAS results are showing evidence for notable genetic overlap between schizophrenia and bipolar disorder, studies of larger (>100 kb) chromosomal structural variants, particularly CNVs, are showing differences between the 2 disorders.

CNVs involve deletions or duplications of sections of chromosomes, between 1 kilobase and several megabases in length. An early identified CNV is the microdeletion on chromosome 22q11, which causes velocardiofacial, or DiGeorge, syndrome,^⁸² and which is associated with a relatively high risk of developing psychotic disorders.^⁸³ Subsequently, many more CNVs have been identified in the human genome.^{^84–86}

Some studies have focused on the frequency of CNVs overall,^{⁸⁷,⁸⁸} while others have focused on CNVs at particular chromosomal locations.^{⁸⁷,⁸⁹,⁹⁰} Both approaches have shown an elevation of large, rare (frequency < 0.01) CNVs in individuals with schizophrenia compared with controls. The list of specific CNVs associated with schizophrenia is gradually increasing and currently includes chromosomal deletions and/or duplications on chromosomes 1q21, 2p16 (NRXN1), 3p26, 3q29, 5p13, 7q11, 7q22, 7q36 (VIPR2), 15q11, 15q13, 16q11, 16p13, 17p12, 17q12 and 22q11.^{⁷⁰,^91–93} Frequencies are typically in the order of 0.2% in cases and 10 times rarer in controls, with ORs of 2.1–20.3.^⁷⁰ Thus, CNVs are considerably rarer than the variants that are the focus of GWAS but have a considerably greater effect on risk of schizophrenia when they occur.

Large CNVs, including those associated with schizophrenia, are also associated with other neurodevelopmental disorders such as mental retardation/intellectual disability, autism spectrum disorder, ADHD, and generalized epilepsy.^{⁷⁰,⁹¹,^94–96} Interestingly, most of the CNVs associated with schizophrenia are associated with even greater risk of earlier onset disorders such as congenital malformation, developmental delay, and autism spectrum disorder, with the overall penetrance, including schizophrenia, ranging between 10% and 100%.^⁹⁷ This means that pathogenic CNVs tend to be associated with markedly reduced fecundity and, in consequence, are selected out of the population a few generations after occurring de novo. They continue to be seen because of relatively high mutation rates at these loci.^⁹⁸

In contrast to findings in schizophrenia, studies of bipolar disorder have tended to find no evidence for increased burden of large, rare CNVs and moreover point to the possibility that such events might be even less common than in controls.^{^99–101} There is also some evidence that such CNVs are enriched in bipolar disorder cases with early age at onset,^{¹⁰²,¹⁰³} although not all studies have observed this.^¹⁰¹ Given that large CNVs have adverse consequences on brain development and cognition,^¹⁰⁴ these findings are consistent with the view that a diagnosis of bipolar disorder is unlikely to be made in the presence of cognitive and other sequelae of neurodevelopmental impairment and that what we refer to as schizophrenia has a stronger neurodevelopmental component than bipolar disorder.^⁴,⁹⁵

Molecular Genetic Studies of Schizoaffective Disorder

As discussed above, most studies include schizoaffective disorder or its subtypes as adjunctive phenotypes, when the main focus of the study is schizophrenia or bipolar disorder. However, some studies have focused on individuals with schizoaffective disorder within these samples.

For example, a study of RDC schizoaffective disorder, bipolar subtype (which has a broader definition of the disorder than DSM-IV), found an association with markers in γ-aminobutyric acid A (GABA_A) receptor genes, but no significant association with schizophrenia or bipolar disorder.^¹⁰⁵ This finding was replicated in an independent sample.^¹⁰⁶ If further investigation confirms this as a true association, it remains to be seen whether it is specific to the bipolar subtype of schizoaffective disorder or whether associations with schizophrenia and bipolar disorder become more evident, eg, with larger sample sizes.

Polygenic score analysis has also been applied to the RDC schizoaffective disorder bipolar subtype. Polygenic scores from schizophrenia^⁷⁸ were used to test differences between subphenotypes in 2 bipolar disorder samples.^¹⁰⁷ This study found that individuals with schizoaffective disorder bipolar subtype had higher scores than individuals with bipolar disorder, consistent with the polygenic influences on schizophrenia having a greater overlap with those for schizoaffective disorder bipolar subtype than with those for bipolar disorder.

It has also been noted that RDC schizoaffective disorder, bipolar subtype, may have particular utility for picking up association signals in GWAS studies,^¹⁰⁸ so it may be worthy of more research attention if the problems with interrater reliability can be overcome.

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Conclusions and Future Directions

In summary, there is now strong evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with a genetic correlation of around 0.6. It is likely that part of the overlap is due to commonly occurring genetic variants, as detected by GWAS, that have a small effect on risk individually, but where a person’s risk increases as they carry more risk alleles. It is also likely that there are common risk variants that are not shared between the 2 disorders. Additionally, current evidence suggests that large, rare CNVs are likely to have a greater influence on the risk of schizophrenia than bipolar disorder. Evidence from twin analysis is consistent with all genetic risk factors for schizoaffective episodes also being risk factors for schizophrenic and manic episodes, while association studies hint at the possibility of some relatively specific genetic risk factors for the bipolar subtype of schizoaffective disorder.

In addition to the balance of genetic and environmental risk factors with varying specificity for disorders, the clinical presentation may also be influenced by the overall quantitative burden of risk factors^¹⁰⁹ and by additional modifying factors that do not influence the risk of developing a disorder but influence the clinical picture among individuals with a disorder.^{¹¹⁰,¹¹¹}

In terms of future research developments, as GWAS continue to increase in sample size, to include more samples with ancestries other than European, and to be analyzed in more sophisticated ways,^¹¹² it is expected that many more commonly occurring risk variants will emerge. This is most likely to further substantiate the current pattern of partial genetic overlap between schizophrenia and bipolar disorder, and further dissection of the clinical phenotypes may show more substantive evidence of graded relationships,^²⁰ eg, bipolar disorder with mood-incongruent psychotic symptoms and the bipolar subtype of schizoaffective disorder having progressively closer genetic relationships with schizophrenia compared with more clinically pure forms of bipolar disorder.

At the same time, further CNVs associated with schizophrenia are likely to be identified. It will be interesting to see whether any associations with bipolar disorder tend to be predominantly with more schizophrenia-like subforms, eg, where there are mood-incongruent psychotic symptoms or cognitive impairment, and also the effect of CNVs on schizoaffective disorder.

Between the commonly occurring variants detectable by GWAS and rarer CNVs, there are likely to be genetic risk variants of intermediate frequency and effect size, and also rare single-nucleotide mutations.^⁷⁰High-throughput next-generation genetic sequencing studies are underway, aimed at uncovering both inherited and de novo genetic variants in these ranges.^{^113–116} It is an open question at present how much or little these will show associations in common between disorders.

In order to understand how candidate genetic risk variants play a causal role, it is necessary to elucidate their functional consequences, eg, at the level of RNA expression^{⁶⁶,¹¹⁷} and in animal models,^{^118–120} to consider effects at the level of biological systems,^{⁴,⁷⁰,¹²¹} and to incorporate environmental effects, including those acting via epigenetic mechanisms.^¹²² Investigations in each domain have the potential to further elucidate relationships between clinical disorders. It is hoped that such investigations will lead to the development of improved treatments, which again could have shared or relatively specific effects on different disorders.

In addition to diagnosis-based phenotypes, other clinical phenotypes, such as quantitative symptom dimensions of psychotic and mood symptoms,^{⁷⁷,¹⁰⁹,¹²³,¹²⁴} illness history variables, such as age at onset and illness course, and endophenotypes, eg, based on cognitive profiles and neuroimaging,^{^125–131} that have common and relatively distinct associations with clinical disorders, are likely to be valuable in providing further insights into genetic relationships.^{¹¹²,^132–134} Initiatives include the NIMH Research Domain Criteria (RDoC) project, which focuses on research integrating dimensions of behavior and neurobiology.^¹³⁵ Also, longitudinal studies, eg, following up large cohorts of twins from early childhood through adult life, have potential to give further insights into how genetic and environmental influences on development link with the emergence of clinical disorders, and also the etiological relationships between clinical disorders and the occurrence of subclinical psychotic and mood symptoms in the general population.^{^136–140}

As part of this process, the predominant use of current main-lifetime diagnostic categories may change to a more flexible approach^¹⁴¹ in which categorical or dimensional syndromes, networks of correlated symptoms, and/or endophenotypes are increasingly employed according to particular research or clinical requirements.

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The Diagnosis and Treatment of Bipolar Disorder: Decision-Making in Primary Care

Posted on August 20, 2016 by JmaC

Abstract

Bipolar disorder is a chronic episodic illness, characterized by recurrent episodes of manic or depressive symptoms. Patients with bipolar disorder frequently present first to primary care, but the diversity of the potential symptoms and a low index of suspicion among physicians can lead to misdiagnosis in many patients. Frequently, co-occurring psychiatric and medical conditions further complicate the differential diagnosis. A thorough diagnostic evaluation at clinical interview, combined with supportive case-finding tools, is essential to reach an accurate diagnosis. When treating bipolar patients, the primary care physician has an integral role in coordinating the multidisciplinary network. Pharmacologic treatment underpins both short- and long-term management of bipolar disorder. Maintenance treatment to prevent relapse is frequently founded on the same pharmacologic approaches that were effective in treating the acute symptoms. Regardless of the treatment approach that is selected, monitoring over the long term is essential to ensure continued symptom relief, functioning, safety, adherence, and general medical health. This article describes key decision-making steps in the management of bipolar disorder from the primary care perspective: from initial clinical suspicion to confirmation of the diagnosis to decision-making in acute and longer-term management and the importance of patient monitoring.

Clinical Points

■ Patients with bipolar disorder frequently present to primary care, but the diversity of the potential symptoms and a low index of suspicion can lead to misdiagnosis in many patients.
■ A thorough diagnostic evaluation at clinical interview, combined with supportive case-finding tools, is essential to reach an accurate diagnosis.
■ Pharmacologic treatment underpins both the short- and long-term management of bipolar disorder. Whichever treatment approach is selected, monitoring over the long-term is essential to ensure continued symptom relief, functioning, safety, adherence, and general medical health.

Primary care physicians are the first point of contact for many patients with bipolar disorder, and they have a fundamental role in the diagnosis and treatment of this lifelong condition.¹ The diversity of the potential symptoms in bipolar disorder may mean that the condition will remain unrecognized in many patients for several years. Making an inaccurate diagnosis—often of major depressive disorder (MDD)—also may be problematic, as it leads potentially to initiation of inappropriate treatment and a deterioration in symptoms.

Bipolar disorder is a chronic illness that is typically experienced first in early adulthood, although onset in childhood or in older age may also occur. Bipolar disorder can be divided into subtypes, including bipolar I and bipolar II disorder. Bipolar I disorder is distinguished by full-blown manic episodes that are more impairing than the hypomanic episodes that characterize bipolar II disorder. Depression, which is the presenting symptom of bipolar disorder in most patients, may impose a greater disease burden, in terms of both duration and impact, than manic symptoms. Depressive symptoms may be of similar severity in bipolar I and II disorder, and, therefore, bipolar II disorder should not be considered a “milder” illness than bipolar I. The form of the disease that individuals experience tends to be stable over their lifetime. For patients with either condition, the primary care physician can play an important role, often working with psychiatric consultants, in both managing treatment and monitoring the bipolar disorder and ensuring that other health care needs are met, including preventive care and managing chronic comorbid medical conditions.

Either a manic episode or a depressive episode may be the first presentation of bipolar disorder. The subsequent disease course is characterized by repeated manic or depressive episodes, which are separated by periods during which symptoms do not meet diagnostic criteria.² Even during these “euthymic” periods, patients may continue to experience some symptoms and decreased functioning,³ and brain function continues to be abnormal on functional magnetic resonance imaging (MRI).⁴ The timing of the recurrent mood episodes and their polarity (whether manic or depressive), duration, and severity are highly variable between patients and can also vary in the same patient over time. The symptoms typically have a severely debilitating impact on the patient’s functioning, employment or educational prospects, and quality of life, and they can substantially elevate the risk of suicide, particularly during depressive episodes with or without mixed features.²^,⁵^–⁷

Early, accurate diagnosis can substantially reduce the burden of bipolar disorder and improve the long-term outcome for patients.⁸^,⁹ Establishing the diagnosis can, however, be problematic, given the diversity of symptoms that can suggest a number of alternative diagnoses. A high index of suspicion that the symptoms may indicate bipolar disorder is essential.

This review recommends key decision-making steps in the management of patients with bipolar disorder—from the initial stages of clinical suspicion, to confirmation of the diagnosis, through acute and longer-term management and monitoring (Figure 1).

Figure 1

Decision-Making Steps in Bipolar Disorder Diagnosis and Management

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MAKING THE DIAGNOSIS OF BIPOLAR DISORDER

Decision steps in the diagnosis of bipolar disorder are summarized in Table 1.

Table 1

Clinical Decision Steps in Bipolar Diagnosis

When to Suspect Bipolar Disorder

Patients who first present to primary care with bipolar disorder may show a wide range of mood-related symptoms, including depression, anxiety, mood swings, irritability, fatigue, difficulty in sleeping, and inability to focus and concentrate. Certain psychiatric and medical comorbidities are also extremely common and, by their presence, raise a suspicion of bipolar disorder. The patient’s social history will often show characteristic sequelae of the illness, such as relationship and marital problems, erratic occupational histories, financial troubles, and recurrent legal issues.

Diagnosing bipolar disorder in the face of the diverse symptoms and sequelae is a challenge that requires a high index of suspicion.

Suspicion of a manic episode.

A full-blown manic episode that includes the cardinal symptoms may be readily identifiable in most patients with bipolar I disorder, but the symptomatology can be variable (Table 2). Particular attention should be paid to the symptomatology of mania in patients with comorbidities (eg, anxiety, panic disorder, substance abuse), as these symptoms can further complicate or mask the diagnosis. Patients experiencing a manic episode should receive urgent specialist investigation and treatment because of the high risk of harm to self or others. Manic episodes frequently require intensive outpatient treatment or admission to a psychiatric facility (including involuntary admission) to provide a safe environment during treatment induction.

Table 2

Manic and Hypomanic Episodes: DSM-5 Criteria^a

Milder episodes of mania, such as hypomania, which is characteristic of bipolar II disorder, are more easily missed. For many patients, a hypomanic episode represents a period of “wellness” after an episode of depression, and they may not report hypomanic symptoms unless specifically questioned. These patients may even challenge their bipolar diagnosis. The provision of information in the form of written materials, recommended Web sites, and support group details can help these patients to accept their diagnosis.

Suspicion of a depressive episode.

Depressive symptoms are experienced most frequently and for the longest duration in bipolar disorder, and are the most common reason for patients to seek care (Figure 1).¹⁰^–¹²

The symptoms of depression in bipolar disorder closely resemble those in MDD,⁵^,¹³ and, so, it is recommended that every patient presenting with depression should be evaluated for bipolar disorder (Table 3). Patient characteristics that can help to differentiate bipolar depression and MDD are included below and in Figure 2.¹⁴^–¹⁶

(1) A history of mania or hypomania. This is the major differentiator of bipolar disorder from MDD (mania in bipolar I and hypomania in bipolar II disorder). All patients with depression should be questioned about current or prior manic or hypomanic symptoms (see Table 2). As discussed later, use of a bipolar screening tool in all patients diagnosed with a major depressive episode may represent a time-efficient practice routine as a first step, followed by a confirmatory clinical interview guided by the responses.
(2) Age at onset. The age at onset for bipolar depression is typically earlier than for MDD, with first symptoms often manifesting between the ages of 13 and 18 years.¹⁷ By contrast, the symptoms of MDD first manifest, on average, in the mid- to late 20s.¹⁸
(3) Atypical features. Patients with bipolar disorder more often experience “atypical” features of depression, such as hypersomnia, hyperphagia, and rejection sensitivity, when compared with MDD. Mood lability, psychotic symptoms, psychomotor retardation, and pathological guilt are also more predictive of bipolar disorder.
(4) Course of illness. Bipolar disorder is characterized by more frequent and more rapid onset of recurrences than MDD. A history of frequently recurring depression, especially with melancholic or psychotic features, may be an indicator of bipolar disorder.
(5) Treatment history. A history of lack of response to antidepressants may point to a bipolar diagnosis. Antidepressant monotherapy may also increase the risk of rapidly “switching” a bipolar patient from a depressive to a manic episode.¹⁹
(6) Family history. A history of mood disorders in the family is a strong predictor for bipolar disorder.

Table 3

Major Depressive Episode: DSM-5 Criteria^a

Figure 2

Key Differentiating Features of Depressive Symptoms in Bipolar Disorder Versus Major Depressive Disorder (MDD)^a

Suspicion of mixed features.

“Mixed features” is a new specifier in the DSM-5, which is added in place of “mixed episodes” in the DSM-IV-TR. Patients with concurrent manic and depressive symptoms may experience significant energy, impulsivity, and irritability in combination with depression and hopelessness.⁵^,²⁰ The presence of mixed states is a particular danger to patients, because the combination of dysphoria, high energy, and decreased sleep places them at high risk for suicide.²¹

The DSM-5 includes minimum duration criteria for bipolar I (7 days) and bipolar II (4 days) manic or hypomanic episodes, respectively.⁵ These criteria are useful in a research context to identify patients with a high likelihood of these conditions. However, in clinical practice, patients frequently have episodes that do not meet these minimum duration criteria. The DSM classification of bipolar disorder not otherwise specified (NOS) may be used in such cases.⁵ These criteria are retained in the recently published DSM-5, although NOS is changed to “not elsewhere defined.” A new bipolar classification proposed by the DSM-5 is “other specified bipolar and related disorders,” which includes individuals with a past history of MDD who meet the criteria for hypomania except for the duration (hypomania requires at least 4 consecutive days of symptoms) or individuals with insufficient hypomanic symptoms to establish a bipolar II diagnosis (although the duration is at least 4 days). The division of bipolar disorder into subtypes is discussed in further detail elsewhere in this article.

The Role of Case-Finding Tools

Once a suspicion of bipolar disorder is raised, case-finding tools can offer a rapid assessment that helps to differentiate mood disorders (Figure 1). Case-finding tools cannot by themselves establish a bipolar diagnosis but are helpful in combination with the clinical interview (discussed below). A conflicting outcome from a case-finding tool and the interview may justify specialist consultation or referral.

Widely used instruments are the Mood Disorder Questionnaire (MDQ) and the Composite International Diagnostic Interview, version 3.0 (CIDI). The MDQ is a tool, completed by the patient, that includes 13 items to establish the presence of mood disorders and 2 questions to determine the level of functional impairment (Table 4).²² If the patient endorses 7 or more of the 13 items, confirms that 2 or more symptoms occurred at the same time, and rates the functional impairment as moderate to severe, then the MDQ is considered positive. Many patients with bipolar disorder lack insight into their symptoms, so it can be informative to ask a family member or friend to complete the MDQ on the patient’s behalf as well.

Table 4

The Mood Disorder Questionnaire^a

The CIDI is a structured interview performed by the physician.²³ A positive answer to 1 of 2 “stem questions” leads to 12 questions that are designed to identify manic symptoms (Table 5).¹⁴^,²³ The more questions that are answered in the affirmative, the greater the likelihood of a positive diagnosis. As with the MDQ, the CIDI can be performed in a few minutes. Information and training are available on how to apply tools such as the MDQ and CIDI.²⁴^,²⁵ Both tools have been found useful in primary care practice.¹⁴

Table 5

The Composite International Diagnostic Interview (CIDI)^a

Recently introduced, Web-based case-finding tools include the My Mood Monitor (M3), which consists of 27 questions to screen for bipolar disorder, MDD, anxiety, posttraumatic stress disorder (PTSD), and substance abuse.²⁶ Questions in the M3 are designed to assess both symptoms and functioning.²⁷

Electronic health record–based case findings represent another emerging technique.²⁸ A screening tool for bipolar disorder that is incorporated into the electronic health record is activated automatically when a patient presents with depressive symptoms. Typically, the patient’s responses are recorded by a health care assistant for later assessment by the physician.²⁸

While case-finding tools are valuable supportive measures, it is important to stress that none are infallible. These tools can help the clinician to recognize patients who are likely to have the diagnosis and can improve the efficiency of the clinical interview by identifying symptoms that the clinician should pursue during the interview. However, they are not diagnostic instruments and cannot be used in place of the patient interview.¹⁴

The Patient Interview

The detailed clinical interview formally establishes a diagnosis of bipolar disorder, based on a comprehensive history of past and current symptoms, augmented by medical records and family interviews (Figure 1). The clinical interview also can begin the process of educating the patient about the diagnosis and its impact.

In particular, the patient interview should establish²^,¹⁴:

(1) The presence of past or current episodes of manic or depressive symptoms, as described for example in the DSM-IV, recently updated to DSM-5 (Tables 2 and and33);
(2) The duration and severity of the episodes including the presence of suicidal or homicidal ideation;
(3) The impact of the episodes on functioning in work, social, and family roles;
(4) The presence of comorbidities (such as substance abuse, personality disorder, and anxiety disorder including PTSD);
(5) The history of treatments administered and the response to treatments;
(6) The family history.

Besides establishing the diagnosis, these characteristics are an important element of treatment planning, helping to select the optimal medication(s) and the site of treatment—whether in the primary care setting or involving specialist psychiatric support.

In cases of continued diagnostic uncertainty, the formal diagnosis of bipolar disorder may require a follow-up patient interview by an experienced primary care physician or psychiatrist to confirm the presence of DSM-5criteria, as well as to categorize the specific subtype of bipolar disorder that is present.⁵

Bipolar disorder is commonly divided into subtypes with distinct features, including I and II (Table 6). A classification of bipolar I disorder requires the presence of mania, while bipolar II disorder is distinguished by hypomania in combination with at least 1 major depressive episode.⁵ Bipolar II disorder is more common than bipolar I, and the subtlety of the symptoms of hypomania may mean that bipolar II disorder is mistaken for MDD.²⁹ Clinical trials have historically focused more on the treatment of bipolar I than bipolar II disorder.

Table 6

DSM-5 Bipolar Disorder Subtypes^a

Confirmation of manic symptoms.

The DSM-5 criteria for mania or hypomania should be applied to all patients in whom a diagnosis of bipolar disorder is suspected or who provided a positive case-finding test (Table 2). DSM-5 criteria (compared with DSM-IV-TR) emphasize the importance of increased activity and energy in addition to mood in confirming the presence of manic or hypomanic symptoms. Physicians should also ensure that the manic symptoms identified are not better accounted for by other causes, such as substance abuse, concurrent medications, or other medical etiologies.

A review of the lifetime occurrence of manic episodes may reveal an exacerbation of symptoms over time, from initially mild episodes of hypomania, to mania accompanied by delusions, to delirious mania characterized by marked intensification of symptoms and a loss of self-control. In other patients, the intensity of symptoms never passes beyond hypomania.

Confirmation of depressive symptoms.

Depression is the presenting symptom of bipolar disorder in most patients.¹⁰ DSM-5 criteria specify that depressed mood and/or a loss of interest or pleasure must be present for at least 2 weeks, in combination with the symptoms itemized in Table 3.⁵ Physicians should ensure that the depressive symptoms identified are not better explained by other causes, including medical conditions, alcohol or drug abuse, or bereavement.⁵ Of particular importance for patients who are experiencing depressive symptoms is to assess for risk of suicide and self-harm. The DSM-5 provides guidance on the prominence to be given to suicide prevention in treatment planning for an individual with bipolar disorder.

The DSM-5-based criteria for diagnosing a bipolar depressive episode are identical to those for MDD,⁵ and additional clinical features including past and concurrent symptoms are required for differential diagnosis (Figure 2). The depressive symptoms of bipolar disorder can also be attributed mistakenly to a number of other disorders, notably PTSD, anxiety disorders, schizoaffective disorder and schizophrenia, and personality disorders (Table 7).¹⁴^–¹⁶^,³⁰^–³⁴

Table 7

Differential Diagnoses for Bipolar Disorder

Confirmation of mixed features.

The presence of depressive features during a manic episode or manic features during a depressive episode confirms the presence of mixed features.⁵ Insomnia, agitation, appetite changes, psychotic features, and suicidal ideation are common presenting symptoms.⁵ It is important to eliminate other potential causes of a mixed state, among which are antidepressant medications, electroconvulsive or light therapy, and medical treatments (eg, corticosteroids).

Patients who experience mixed episodes or features may, over time, progress to depressive-only episodes or, less frequently, to manic-only episodes.⁵

Functioning.

Certain behaviors that are commonly associated with bipolar disorder can help to establish the diagnosis.³⁵ These behaviors may include instabilities related to the patient’s family (eg, estrangement from the family of origin, divorce, frequent remarriage) or employment (frequent job changes, difficulties at work, unemployment), financial difficulties (bankruptcy, “boom and bust” cycles), or a history of impulsive or reckless behavior (sexually transmitted infections, unwanted pregnancies, substance abuse, accidents).

Understanding the severity and the type of functioning disorder can help to differentiate mania from hypomania. Disinhibition, poor judgment, risk-taking, and aggressive behaviors are all associated with a more severe, manic episode.⁵^,³⁵

Comorbidities.

Patients with bipolar disorder are predisposed to other psychiatric disorders at elevated rates. Anxiety disorders (such as PTSD), personality disorder, ADHD, and alcohol or drug dependence are particularly common comorbidities.³⁶^,³⁷ The DSM-5 acknowledges the clinical evidence that anxiety is an important modifier of bipolar prognosis by incorporating the disease specifier “anxious distress” in the diagnosis of bipolar disorder (Table 6).

Certain chronic physical conditions are also commonly found in the bipolar population, such as cardiovascular and metabolic disorders. Obesity, for example, affects about one-half of patients with bipolar disorder.³⁸ These conditions may in part reflect the lifestyle and behaviors associated with bipolar disorder, and they can significantly shorten life expectancy.³⁹^,⁴⁰

Family History

Family history can be highly informative for diagnosing bipolar disorder. Between 80% and 90% of bipolar patients describe family members with a history of mood disorders including bipolar disorder and MDD.⁴¹The children of bipolar patients are also at elevated risk (most studies suggest a 5%–15% risk⁴²^,⁴³) of developing bipolar disorder,⁴⁴ indicating a strong genetic element in the predisposition to the condition. Of note, the “absent” parent or other relative—for instance, one who might have abandoned the family, been incarcerated, or was deceased when the current patient was a child—may, on further inquiry, be likely to have had a bipolar condition.

Other Elements of the Patient Interview

Physical examination.

Physical examination cannot confirm a diagnosis of bipolar disorder, but it can, in combination with the medical history, help exclude the diagnosis by identifying illnesses that mimic bipolar symptoms.²^,³³ For example, a physical examination may identify hypothyroidism or hyperthyroidism, which are associated respectively with depressive and manic symptoms.

Laboratory tests and imaging.

No laboratory test is required to establish the diagnosis of bipolar disorder. However, in conjunction with the physical examination, laboratory tests can help to exclude alternative etiologies for mood symptoms.² Laboratory tests may include a urine toxicology screen (in cases in which substance misuse is suspected but denied) and a complete blood count (to exclude infection or anemia as potential causes of depression). Fasting glucose and lipid assessments are important for establishing the presence of diabetes or hyperlipidemia and for determining baseline values before initiation of treatment. MRI or other neuroimaging techniques are rarely indicated, but in selected cases can be valuable to exclude an organic etiology for mood symptoms, such as a brain tumor or multiple sclerosis in cases of recent-onset mania.⁴⁵

Treatment response.

A history of a lack of response to antidepressant monotherapies may suggest that a patient has bipolar disorder rather than MDD. Any patient who has experienced no symptom benefit from multiple trials of antidepressants should be reassessed for bipolar disorder. Conversely, patients who demonstrate a significant treatment response to antidepressant monotherapy or in whom the response is very rapid should be screened for possible precipitation of a manic/hypomanic episode.⁴⁶^,⁴⁷

Differential diagnosis.

A number of common psychiatric disorders may mimic the symptoms of bipolar disorder and should be considered in the differential diagnosis.³¹ These disorders are summarized in Table 7.

The Family/Partner Interview

A history of the patient’s symptoms obtained from a relative or close friend (with the patient’s consent) can be highly informative, given that bipolar patients frequently lack insight into their own behavior and the effects of their behavior on others.⁴⁸ In other cases, the family will not be aware of the bipolar patient’s condition.

Once a bipolar diagnosis is established, the primary care physician can offer considerable practical support to both the patient and family, helping them to cope with daily life activities and to prepare for stressful life transitions such as moving away to college, entering the job market, marrying, and starting a family.

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MANAGING THE BIPOLAR PATIENT IN PRIMARY CARE

Decision steps in bipolar management are summarized in Table 8.

Table 8

Clinical Decision Steps in Bipolar Management

Establishing a Care Pathway

Patients in danger of self-harm or of causing harm to others require immediate specialist psychiatric intervention, which may entail escorted transport from the primary care setting. The preparation of a management plan that specifies the current medications and other information relevant to the emergency services will assist the transition from primary to specialist care.

For other patients, primary care physicians should decide on the level of intervention that they wish to offer: whether providing acute and longer-term treatment themselves or involving specialist psychiatric intervention (through referral or as collaborative care) (Figure 1). The ability of a primary care physician to offer successful care to a bipolar patient depends on factors such as the severity of the condition, its complexity (including the presence of comorbidities), the wishes of the patient, the experience of the physician, and the organization of the practice team. It is the rare primary care physician who has the expertise, time, and resources available to manage bipolar I patients, particularly during their manic phases.

Organization of a practice team entails effective staff training and coordination, provision of patient-monitoring systems, and establishment of links to referral and support services.⁴⁹^,⁵⁰ A patient-centered, collaborative team approach that includes health care professionals with complementary skills offers the greatest likelihood of success.⁴⁹^–⁵² This team typically includes nursing staff, community support workers, and specialist psychiatrics and psychologists, with the primary care physician taking a coordinating role at the center.¹^,⁵² The primary care physician and psychiatrist should communicate frequently regarding any change in patient symptoms or functioning and should have an explicit understanding between them and with the patient regarding the management of medications. Because of the potential for drug-drug interactions with medications used for common comorbid medical conditions, both the psychiatrist and primary care physician should keep the other informed of any medication adjustments at the times they are being made.

Treatment Principles: Pharmacologic and Nonpharmacologic Treatments

For most patients, the foundation of acute and maintenance treatment is pharmacologic therapy.⁵³^,⁵⁴

Acute pharmacologic treatment has the objective to reduce symptoms promptly with acceptable safety and tolerability. The treatment that is selected is based on the characteristics of the mood episode (ie, its polarity and symptom severity) and on the patient’s general health status, including the presence of concurrent medical conditions such as diabetes or obesity, which can be exacerbated by certain therapies. A lack of response or an adverse effect to a medication may prompt a change in dose or a switch to another medication class. For many patients, particularly those with severe manic episodes or mixed states, combination therapy may be required—either using 2 or more medications concurrently or by the introduction of psychosocial approaches.⁵⁵^–⁵⁷

Approximately 1 in 5 bipolar patients will eventually require 4 or more concomitant pharmacologic medications to control their symptoms.⁵⁸ High rates of comedication use are particularly common in patients with a high burden of depressive symptoms and at elevated risk for suicidality.⁵⁸ While combination therapy may provide greater symptom control, it is also associated with an increased burden of adverse effects, cost, and potential for drug-drug interactions.⁵⁹

Acute Treatments

Manic symptoms.

Established medications for the treatment of manic symptoms include lithium, divalproex, carbamazepine, and the atypical antipsychotics asenapine, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone (Table 9).⁵¹^,⁶⁰^,⁶¹

Table 9

US Food and Drug Administration–Approved Oral Medications in the Treatment of Adults With Bipolar Disorder^a

Lithium is a conventional mood stabilizer with a slower onset of action than the antipsychotics. The need to dose titrate lithium to reduce its toxicity also delays the time to achieve a response.⁶² Lithium is associated with a moderate improvement in symptoms in 40%–80% of patients after 2 to 3 weeks of treatment for acute mania.⁶³ Lithium is one of the few medications that has been demonstrated to reduce the occurrence of suicide.⁶⁴ Divalproex and carbamazepine are at least as effective in reducing symptoms as lithium, with a faster onset of action.⁶³ More than one-half of patients treated with divalproex or carbamazepine experience significant improvement in their manic symptoms.⁶³

Atypical antipsychotics have gained widespread acceptance as a first-line treatment in mania,⁵⁵ offering the advantage over typical antipsychotics of a reduced propensity to extrapyramidal adverse effects.⁶⁵ Each of the atypical antipsychotics has broadly similar efficacy in the treatment of acute mania, with response rates ranging from 49%–73% across different studies.⁶³ Trial evidence does point, however, to characteristic differences in the safety profile of these agents (discussed below).

Combination therapy for patients whose manic symptoms fail to respond to monotherapy frequently consists of a mood stabilizer (eg, lithium, divalproex, or carbamazepine) with an atypical antipsychotic.⁴⁵^,⁶⁶

Depressive symptoms.

When compared with mania, there are few medications with proven efficacy in the treatment of acute bipolar depression, particularly bipolar II depression. Quetiapine monotherapy, olanzapine in combination with fluoxetine, and (most recently) lurasidone monotherapy or in combination with lithium or valproate are the sole US Food and Drug Administration (FDA)–approved medications for bipolar I depression, while only quetiapine is approved for bipolar II depression.⁵⁵ Lamotrigine showed a small but significant improvement in depressive symptoms compared with placebo in a pooled analysis of 5 acute randomized controlled trials,⁶⁷ but 4 of these 5 studies were underpowered and failed to show a superiority of lamotrigine over placebo.⁶⁸ The role of lamotrigine in the maintenance treatment and prevention of depressive episodes is more convincing, with 2 favorable, randomized, placebo-controlled trials that have led to FDA approval of lamotrigine for this indication.⁶⁹^,⁷⁰

Quetiapine is the only medication that is FDA approved as monotherapy for the treatment of both manic and depressive episodes of bipolar disorder.⁷¹ The extended-release (XR) formulation of quetiapine is approved for once-daily dosing for both manic and depressed episodes, while the immediate-release (IR) formulation of quetiapine is dosed twice daily for bipolar mania and once daily for bipolar depression.⁷²^,⁷³ A medication with broad-spectrum mood-stabilizing potential may offer opportunities for simplified therapy in specific patients.⁷⁴ It may also be noted that the XR formulation of quetiapine, aripiprazole, and lurasidone are the only atypical antipsychotics approved as adjunctive therapy in MDD.⁷³^,⁷⁵ Compared with the IR formulation, quetiapine XR offers the benefit of once-daily dosing in all approved indications, which is achieved through its distinct pharmacokinetic profile, characterized by a lower peak concentration and more stable plasma concentrations over time.⁷⁶ Quetiapine XR also has a distinct tolerability profile relative to the IR formulation, including a reduction in sedation intensity during initial dose escalation.⁷⁶^–⁷⁸

Mixed features/mixed episodes.

Divalproex and the atypical antipsychotics (aripiprazole, olanzapine, quetiapine XR, risperidone, ziprasidone, and asenapine) are recommended as first-line treatments for mixed states.⁷⁹ By contrast, lithium does not appear to confer significant benefit in mixed states.² Combination therapies, typically including an atypical antipsychotic and a mood stabilizer, are likely to be required for many patients experiencing mixed states.⁷⁹

Maintenance Treatments

Maintenance treatment can reduce, although not entirely eliminate, the recurrence of mood episodes. In part, this limitation reflects the limited efficacy of medications, but, in part, it is also explained by poor adherence, which is encouraged by a suboptimal symptom response or the development of treatment-related adverse effects.⁸⁰^,⁸¹

In many patients, the medications that were effective for the acute phase are the first choice in maintenance treatment.⁵⁵ Lithium at optimal doses reduces the rate of recurrence by 50% in clinical trials.⁶³ The long-term benefits of lithium are hindered by poor adherence due to the narrow therapeutic window and significant adverse effects.⁸² Lithium is generally associated with greater efficacy in the prevention of manic rather than depressive episode recurrences,⁴⁵^,⁶³ which is consistent with its predominantly antimanic effects in acute treatment. Divalproex has an efficacy equivalent to lithium for the prevention of recurrence,⁸³ while carbamazepine may be found to be more effective than lithium in patients with atypical features, such as mixed states and delusion.⁶³

Among the atypical antipsychotics, olanzapine, risperidone (long-acting injection), and aripiprazole are approved as monotherapies for maintenance treatment, while quetiapine and ziprasidone are approved in combination with lithium or divalproex for prevention of recurrence.⁶⁰^,⁷¹^,⁸⁴^,⁸⁵ Combining a mood stabilizer and an antipsychotic agent generally provides superior relapse prevention compared to single agents alone.⁸⁶^,⁸⁷

Adverse Effects of Pharmacologic Treatments

All primary care physicians, whether or not they participate in the management of bipolar symptoms, should be aware of the safety profiles of the medications used in bipolar disorder (Table 10).⁵⁵^,⁵⁶

Table 10

Characteristic Adverse Effects of Pharmacologic Treatments for Bipolar Disorder^a

The potential of lithium to cause progressive renal insufficiency and fatalities through overdose should be considered when making long-term therapy choices,⁸⁸ as should the deleterious effects of lithium, divalproex, and carbamazepine during pregnancy.⁵⁵^,⁸⁸ A main concern with lamotrigine is the serious, although rare, side effect of Stevens-Johnson–like rash.⁵⁵

The adverse effects of atypical antipsychotics differ between the individual agents.⁵⁵^,⁸⁹^–⁹² Olanzapine is associated with a higher risk of weight gain, diabetes mellitus, and dyslipidemia than other antipsychotics.⁸⁹^–⁹¹ Risperidone induces marked hyperprolactinemia, whereas other atypical antipsychotics have minimal or even favorable effects on prolactin.⁹³ Ziprasidone is reported to have a lower risk for weight gain, and quetiapine has a decreased risk for extrapyramidal symptoms relative to risperidone.⁹⁴

Children and adolescents with bipolar disorder may be particularly vulnerable to the weight gain associated with olanzapine, as well as the extrapyramidal symptoms and metabolic changes reported with other atypical antipsychotics.⁹⁵

Monitoring

Long-term monitoring for medication adverse effects is essential to ensure continued safety (Table 11).²^,⁵⁵^,⁶²As mentioned previously, the propensity to weight gain and dyslipidemia is particularly high for olanzapine, although other atypical antipsychotics carry some level of risk.⁹⁰^,⁹⁵ The presence of cardiometabolic factors may signal the impending development of metabolic syndrome (which also includes hyperglycemia and hypertension), a condition that is a precursor to diabetes and cardiovascular disease. Prevention of these metabolic disorders and related premature death warrants dedicated routine monitoring for weight gain, blood pressure, and increases in triglyceride and glucose levels.²^,⁹⁶

Table 11

Recommended Monitoring for Pharmacologic Treatments^a

Physicians must also monitor patients closely for emergence of mania or psychosis, changes in functioning and disability, and subjective reports of depressive symptoms and quality of life.⁹⁷ A rapid reinitiation or modification to therapy may be required if prodromal symptoms (eg, sleep disruption, increased irritability, resumption of substance use) or full-blown episodes emerge (ie, it is important to “treat the disease, don’t blame the patient”). Given the high frequency of coexisting medical conditions in bipolar disorder, routine monitoring should include an evaluation for medical morbidities.²^,⁵⁵^,⁵⁹

Patient and family education has been shown to enhance the success of goal-setting, decision-making, and collaboration with the health care team, thereby increasing the likelihood of an improved long-term outcome.⁵² In particular, educating patients on how to monitor their symptoms for signs of impending relapse can assist physicians in monitoring and management (Table 12).⁵⁰^,⁹⁸ Patient-directed educational resources are widely available to support health care professionals in this regard.⁹⁹^,¹⁰⁰

Table 12

Early Signs of Relapse (in order of decreasing frequency)^a

Adherence

The primary care physician has a fundamental role in encouraging adherence. Nonadherence to medication is an acknowledged barrier to effective treatment over the long term.¹⁰¹ Discussion of the treatment options available and their possible adverse effects (and how to manage them) can enhance treatment adherence. Patients may give many reasons for nonadherence to medication, but a common underlying reason is a lack of insight into the impact of symptom recurrence.¹⁰¹^,¹⁰² Encouraging patient education and forging a therapeutic alliance between physician and patient helps to maintain adherence to therapy.¹⁰³^,¹⁰⁴

Psychosocial Treatments

While outside the remit of this review, psychosocial treatments—psychoeducation, cognitive-behavioral therapy, family-focused therapy, and interpersonal and social rhythm therapy—have an established role in management, with efficacy in regularizing daily activities, reducing substance misuse, identifying early warning signs of relapse, and enhancing medication adherence.¹⁰⁵

General Medical Care

Patients with bipolar disorder have an increased incidence of certain medical comorbidities and are at elevated risk of early death, particularly cardiovascular-related death.⁴⁰ Medications used in the treatment of bipolar disorder can cause weight gain, lipid abnormalities, and other long-term effects, which may exacerbate the propensity to medical complications.¹⁰⁶

Bipolar patients are also at elevated risk of not following routine preventive health care measures. For this reason, preventive care tactics tailored to the individual patient, such as hepatitis immunization or long-term birth control methods, are the most appropriate. Because sleep changes may trigger (as well as be an indicator of) a change in mood states, interventions to improve sleep can be helpful in this population.

For women who are pregnant, it is essential that treatment is maintained to stabilize their mood. The choice of the treatment administered requires careful consideration, given the potential teratogenicity of medications including lithium, divalproex, and carbamazepine.⁵⁵

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CONCLUSION

Primary care physicians are the initial as well as the continued point of contact for many patients with bipolar disorder, with responsibility for accurate diagnosis and appropriate ongoing care. Diagnostic accuracy can be improved by attentiveness to the key symptoms and signs of bipolar disorder. Pharmacologic and psychosocial treatments can provide effective management for manic and depressive symptoms and maintain remission over the long term in many patients.

As with any chronic illness, the objective of working with bipolar patients to improve their adaptive and problem-solving skills and their self-management and self-monitoring skills should be a priority. Ensuring that both patient and family are familiar with local and national support networks will also be helpful.

Whether they manage bipolar patients directly or refer them to specialist psychiatric care, primary care physicians are vital to the long-term management of these patients, both through re-engaging them with therapy for future mood episodes and in ensuring that they obtain quality preventive and chronic disease care.

Drug names: aripiprazole (Abilify), asenapine (Saphris), carbamazepine (Carbatrol, Equetro, and others), divalproex (Depakote and others), fluoxetine (Prozac and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon).

Potential conflicts of interest: Dr Culpepper has served as a consultant for Forest, H. Lundbeck A/S, Merck, Sunovion, and Takeda and has made presentations regarding a federally funded study of methods to reduce hospital readmissions (with no mention of pharmaceutical agents) supported through Merck^’s speaker^’s bureau.

Funding/support: Writing of the manuscript was funded by AstraZeneca.

Acknowledgment: The author thanks Bill Wolvey, BSc, of PAREXEL for medical writing support, which was funded by AstraZeneca.

Disclaimer: Dr Culpepper, the journal’s editor in chief, was not involved in the editorial review or decision to publish this article.

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Stress management: How to strengthen your social support network

Posted on August 20, 2016 by JmaC

Stress is a normal and unavoidable part of life — but too much stress can affect your emotional and physical wellbeing. According to APA’s 2015 Stress in America survey¹, average stress levels today are slightly higher than they were in 2014. On a scale of 1 to 10 where 10 is “a great deal of stress” and one is “little or no stress,” American adults rated their stress level at a 5.1 today, up from 4.9 in 2014. But worrisomely, a significantly greater percentage of adults reported experiencing a stress level of 8 or higher on the 10-point scale. Twenty-four percent of American adults reported this extreme level of stress in 2015, up from 18 percent the previous year.

Emotional support is an important protective factor for dealing with life’s difficulties. The 2015 survey found the average stress level for those with emotional support was 5.0 out of 10, compared to 6.3 for those without such support.

Loneliness has been associated with a wide variety of health problems including high blood pressure, diminished immunity, cardiovascular disease and cognitive decline.² In fact, low levels of social support have even been linked to increased risk of death from cardiovascular disease, infectious diseases and cancer.³

The good news is that there are ways to seek out such support, and to nurture your supportive relationships.

The benefits of social support

As important as social support is, many Americans don’t feel they have access to this valuable resource. When asked if there is someone they can ask for emotional support, such as talking over problems or helping make difficult decisions, 70 percent said yes. However, more than half (55 percent) also said they could have used at least a little more emotional support.

In fact, experts say, almost all of us benefit from social and emotional support. And though it may seem counterintuitive, having strong social support can actually make you more able to cope with problems on your own, by improving your self-esteem and sense of autonomy.

You don’t need a huge network of friends and family to benefit from social support, however. Some people find camaraderie among just a handful of people, be they co-workers, neighbors or friends from their church or religious institution, for instance.

Yet social skills don’t always come naturally. Some people have trouble making social connections. Many others lose established connections due to life changes such as retirement, relocation or the death of a loved one. In any case, it’s possible to forge new connections to reap the benefits of a healthy support network.

Grow your support network

Cast a wide net. When it comes to your social supports, one size doesn’t fit all. You may not have someone you can confide in about everything — and that’s okay. Maybe you have a colleague you can talk to about problems at work, and a neighbor who lends an ear when you have difficulties with your kids. Look to different relationships for different kinds of support. But remember to look to people you can trust and count on, to avoid disappointing, negative interactions that can make you feel worse.

Be proactive. Often people expect others to reach out to them, and then feel rejected when people don’t go out of their way to do so. To get the most out of your social relationships, you have to make an effort. Make time for friends and family. Reach out to lend a hand or just say hello. If you’re there for others, they’ll be more likely to be there for you. And in fact, when it comes to longevity, research suggests that providing social support to friends and family may be even more important than receiving it.⁴

Take advantage of technology. It’s nice to sit down with a friend face-to-face, but it isn’t always possible. Luckily, technology makes it easier than ever before to stay connected with loved ones far away. Write an email, send a text message or make a date for a video chat. Don’t rely too heavily on digital connections, however. Some research suggests that face-to-face interactions are most beneficial.

Follow your interests. Do you like to hike, sing, make jewelry, play tennis, get involved in local politics? You’re more likely to connect with people who like the things you like. Join a club, sign up for a class or take on a volunteer position that will allow you to meet others who share your interests. Don’t be discouraged if you don’t make friends overnight. Try to enjoy the experience as you get to know others over time.

Seek out peer support. If you’re dealing with a specific stressful situation — such as caring for a family member or dealing with a chronic illness — you may not find the support you need from your current network. Consider joining a support group to meet others who are dealing with similar challenges.

Improve your social skills. If you feel awkward in social situations and just don’t know what to say, try asking simple questions about the other person to get the ball rolling. If you’re shy, it can be less intimidating to get to know others over shared activities — such as a bike ride or a knitting class — rather than just hanging out and talking. If you feel particularly anxious in social situations, consider talking to a therapist with experience in social anxiety and social-skills training.

Ask for help. If you lack a strong support network and aren’t sure where to start, there are resources you can turn to. Places of worship, senior and community centers, local libraries, refugee and immigrant groups, neighborhood health clinics and local branches of national organizations such as Catholic Charities or the YMCA/YWCA may be able to help you identify services, support groups and other programs in your community.

Seek professional help

If you’re feeling stressed and don’t have anyone to rely on, psychologists can help. As experts in human behavior, psychologists can help you develop strategies to manage stress and improve your social skills. Use the APA’s Psychologist Locator Service to find a psychologist in your area. You can also visit www.mentalhealth.gov, a website of the U.S. Department of Health & Human Services that offers resources in English and Spanish.

Thanks to psychologists Mary Alvord, PhD, Bert Uchino, PhD, and Vaile Wright, PhD, who assisted with this article.

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