Given my relationship with a woman experiencing the disorder, Jane Thompsonʼs Reboot: A Novel of Bipolar Disorder resonated quite strongly with me. Thompsonʼs book offers a fictional but true-to-life account, with her writing clearly based on her own struggle with the illness.

What struck me most is how Thompson reveals, in detail, the importance of what took me years to learn: that, due to the very nature of bipolar disorder, the person who is bipolar does not recognize this and may often forget or highly distort what happens in their manic state. In their euphoria they may imagine and remember, quite incorrectly, that everything was oh-so-wonderful, which is often quite far from the case. Particularly for an adult with bipolar disorder, recognizing the illness is a key step in the possibility of regaining stability and mental health. Without this recognition, an adult with bipolar disorder may quit taking medication, not prepare for the next manic episode, or put themselves and others at risk.

In the beginning, we find this lack of recognition in Marie, the protagonist suffering from the disorder and whose story parallels the authorʼs (and my girlfriendʼs). Marie misses appointments, remembers meetings cancelled when in fact, they had not been, and loses friends who seem standoffish to her. Before her treatment, she only dimly understands why her actions are irrational, rude, or possibly hypersexual. 

What makes Thompsonʼs book so fascinating and hopeful is the contrast between Mariaʼs lack of understanding before she realizes that she is bipolar and her later recognition of what was more likely going on when she finds a medication that works for her.

“Reboot” details another important facet of bipolar disorder. While it is defined as a psychiatric mood disorder with disruptive mood swings, characterized by one or more episodes of abnormally high energy levels, accompanied by racing thoughts and euphoria, with or without depressive episodes, no one truly knows what causes it and what can stop it. Treatment and medication are thus experimental. In the book, Marie takes several different medications with no apparent effect. After reporting this to her physicians, she is told that the medications will eventually work, or that she doesnʼt realize that they are indeed working.

Thompsonʼs novel also correctly illustrates the dangerous side-effects of these medications. Marie is advised to take Haloperidol, which could lead to tardive dyskinesia, i.e., involuntary repetitive body movements, and is told incorrectly that she is not old enough to develop the symptoms. My own reading of the dangers of such medications had me worry when my girlfriend Elle, at about the same age, temporarily developed a habitual puckering and pursing of her lips after taking the many medications, including Haloperidol, that she was prescribed. For both Marie, in the novel, and Elle, in my own life, therapy is trial and error. One hopes to find a treatment or medication that works.

Without giving away the bookʼs lovely ending: Marie finally finds a drug that works for her. As her moods stabilize, so does her life. She gets a significant raise at her job of several years, makes friends, and begins to enjoy going out. She starts to feel appreciated for who she is, and is happy.

I wiped tears from my eyes and broke out laughing several times as I read “Reboot.” For those of us who are close to someone suffering from bipolar disorder, this book means a lot.

Reboot: A Novel of Bipolar Disorder
CreateSpace Independent Publishing Platform, June, 2012
Paperback, 264 pages
$15 

Oxford Handbooks offer up-to-date, critical reviews of original research by leading figures in the discipline. Despite the comprehensive and highly academic nature of “The Oxford Handbook of Traumatic Stress Disorders,” it is well organized to make it easy to locate key findings, summaries and abstracts. An extensive index and references are included, and it is all searchable online.

The tome aimed at professionals dealing with the diagnosis and treatment of traumatic stress disorders provides an extremely thorough and detailed look at all aspects and issues surrounding the disorders.

In “Defining Traumatic Events: Research Findings and Controversies,” the editors examine the history of the controversy over “Criterion A,” the trigger for post-traumatic stress disorder. It has significant clinical and legal implications.

Criterion A defines those stresses that may be considered a potentially traumatic event:

• The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others.
• The person’s response involved intense fear, helplessness, or horror.

A major aspect of the controversy is over whether the definition is too broad or too narrow. Too broad of a definition would dilute it and could lead clinicians to misidentify normal reaction to stressful events. Too narrow a definition leaves out those deserving eligible care. Revisions to criterion A are proposed the upcoming edition of the primary “Manual of Mental Disorders.”

Currently, a diagnosis of acute stress disorder requires criterion A, plus clinically significant functional impairment as well as at least three of five dissociative symptoms.

In a later chapter, proposed changes to the acute stress disorder diagnosis and future directions for research into early predictors of post-traumatic stress disorder are discussed.

Chapter 4, “Classification of Posttraumatic Stress Disorder,” reviews the current criteria of PTSD. It examines the symptoms and their overlap with symptoms for other disorders.

The authors observe, “Although many traumas do involve the acute experience of intense fear, helplessness, or horror, events evoking primary emotions of anger or shame can also generate PTSD.”

Later the handbook addresses modifications to the definition of PTSD and proposed changes for the DSM-5 manual. Authors of this chapter note, “The precise factor structure of PTSD has been addressed by many research teams over the past 15 years. The structure of the construct as described in the DSM-IV is that PTSD consists of three symptom clusters: Re-experiencing, Avoidance/ numbing, and Hyper-arousal. Utilizing confirmatory factor analysis strategies, studies tested whether the three symptom clusters of DSM-IV provide the best model for the latent structure of PTSD. In short, the overwhelming majority of studies support a four-factor model.” and, “Among these four-factor models, re-experiencing, avoidance, and hyper-arousal have emerged as distinct clusters in all of these studies.” Rationale for the addition of new symptoms is examined and future research is suggested.

Chapter 7, which is called “Epidemiology of Posttraumatic Stress Disorder in Adults,” summarizes information on the prevalence of PTSD in U.S. veterans of the Vietnam War as well as the soldiers returning home more recently from deployment in Iraq and Afghanistan. It gives an overview of PTSD research, risk factors, and the risk for other post trauma disorders. Some of the concluding results are:

• There is a direct relationship between the intensity of conflict and risk of PTSD.
• At least 80 percent of residents in the United States qualify for the diagnosis of PTSD.
• Only a small proportion of those exposed to traumatic events actually develop PTSD.
• Exposure to a violent assault is more likely to result in PTSD than other types of traumatic events.
• Women are at higher risk for PTSD than men.

The chapter reaches the conclusion, “The most important impact of the extensive epidemiological literature of PTSD has been a sharp shift away from the original model in DSM-III that PTSD was a normal response to an abnormal stressor. The idea that traumatic events would cause PTSD in most victims, regardless of preexisting vulnerabilities, has been refuted. PTSD is seen as a pathological response by a minority of persons.”

Another section examines populations of people with psychiatric, behavioral, cognitive, or physical disabilities who have a higher than normal likelihood to be exposed to psychological trauma.  “Individuals with severe psychiatric disorders, substance abuse disorders, developmental disabilities, and persons who are incarcerated are more likely to experience trauma throughout their lives, especially interpersonal victimization, and are more likely to develop posttraumatic stress disorder (PTSD),”according to the book.

“Contributions from Theory,” the fourth section of the extensive handbook, looks at the current research in genetics and genomics of PTSD, related biological issues, learning models and family models of PTSD.

The next section of the book covers assessment. The most widely used assessment tools for PTSD are described, including structured interviews, self-reports, and psychophysiological methods. Key PTSD issues are discussed, including identifying an index traumatic event, the linking of symptoms, detecting malingering and reporting false or exaggerated symptoms. Psychophysiological measurements vary, but often include recordings of heart rate, skin conductance, musculature contraction/relaxation and electrocortical measures such as EEG. While psychophysiological procedures provide more evidence for PTSD, these tests have limitations. Roughly 40 percent of people with PTSD show little or no physiologic reactivity. The authors conclude that an approach using one or more of each type of measurement is the best way to go.

Overall, The Oxford Handbook of Traumatic Stress Disorders is an invaluable, comprehensive guide for clinical psychologists, psychiatrists and social workers who care for those with traumatic stress disorders.

J. Gayle Beck and Denise M. Sloan have prepared an extremely detailed gem that I highly recommend for graduate students, scholars and practitioners in psychology and related fields.

The Oxford Handbook of Traumatic Stress Disorders
Edited by J. Gayle Beck, Denise M. Sloan
Oxford University Press, Inc., February, 2012
Hardcover, 576 pages
$150

Challenge: Uncontrollability

“Bipolar disorder can feel uncontrollable,” according to Sheri L. Johnson, Ph.D., professor of psychology at the University of California-Berkeley and director of the Cal Mania (CALM) Program. Symptoms, such as mood changes, can seem to appear suddenly and without provocation. And they can diminish daily functioning and ruin relationships, said Sheri Van Dijk, MSW, a psychotherapist and author of The DBT Skills Workbook for Bipolar Disorder.

Strategies: While bipolar disorder can seem unpredictable, there are often patterns and triggers you can watch out for. And even if you can’t prevent symptoms, you can minimize and manage them.

One way to monitor changes is to keep a mood chart, Van Dijk said. Depending on which chart you use, you can record everything from your mood to the number of hours you slept, your anxiety level, medication compliance and menstrual cycle, she said. (This is a good chart, she said.) For instance, you can anticipate a potential depressive episode if you see that your mood has been progressively sinking in the last few days, Van Dijk said.

Practicing healthy habits is an effective way to lessen the hold emotions have on you. Make it a priority to get enough sleep, going to bed at the same time and waking up at the same time, Van Dijk said. Create a calm bedtime routine, avoid substances such as alcohol – which disrupts sleep – and don’t exercise in the evenings, said Johnson, also co-author of Bipolar Disorder: A Guide for the Newly Diagnosed.

Sleep deprivation can trigger mania, and “it makes you more susceptible to being controlled by your emotions, such as irritability,” Van Dijk said. On the other hand, sleeping too much can cause lethargy and also reduce your ability to manage emotions, she said.

Exercise helps to reduce depressive symptoms. Eliminating caffeine can reduce irritability and anxiety and improve sleep, Van Dijk said. She suggested cutting out caffeine for two weeks and paying attention to any changes. Some people also find that certain foods exacerbate their mood swings. You can check by cutting out specific foods from your diet, and watching the results, she said.

You also can use a variety of strategies to stave off the negative consequences from your symptoms. For instance, if impulsive spending is a problem, gain control by having a low limit on your credit cards, Johnson said. When you’re experiencing early signs of mania, have someone else hold onto your checks and cards, Johnson said. If you do overspend, return your purchases, she said. You can even ask a friend to go with you, she added.

Challenge: Medication

“There is no ‘one size fits all’ medication that helps everyone with bipolar disorder,” Johnson said. Lithium is typically the first line of treatment. But for some people the side effects are especially troublesome, she said. Finding the right medication (or combination of medications) can seem like a daunting process.

Strategies: Learn as much as you can about mood-stabilizing medications, Johnson said, including their potential side effects. “Find a doctor who will work with you to make adjustments based on your experiences with the different medications,” she said. Expect that it might take several tries to figure out the best medications for you.

Many of the side effects dissipate after the first two weeks, Johnson said. Changing the dose schedule helps to minimize side effects. For instance, if you feel groggy, your doctor might suggest taking your medication in the evening, she said.

Support groups are another valuable tool, Johnson said. (She suggested looking at the Depression and Bipolar Support Alliance website for a group.) For instance, individuals in these groups are usually familiar with compassionate doctors in the area, she said.

Challenge: Relationships

Bipolar disorder is hard on relationships. The very symptoms – swinging moods, risky behaviors – often leave loved ones feeling confused, exhausted and like they’re walking on eggshells, Van Dijk said.

She also sees loved ones have difficulty distinguishing between the illness and the person. They might invalidate the person’s feelings and either blame everything on the illness or believe the person is making conscious choices when it is the illness.

Strategies: Bipolar disorder is difficult to understand, Van Dijk said. “Different affective episodes, [such as] depression versus hypomania, result in different symptoms, and one episode of depression or hypomania can be different from the next within the same person,” she said.

So it’s incredibly important for loved ones to get educated about the illness and how it functions. Individual therapy, family therapy and support groups can help. Refer loved ones to self-help resources and biographies or memoirs of people with bipolar disorder, Johnson said.

Getting a handle on your emotions also improves relationships, she said. Working on assertiveness is key, too, she said. Individuals with bipolar disorder tend to have a tough time being assertive. Therapy is a good place to learn assertiveness skills. But if you’d like to practice on your own, Van Dijk suggested using “I statements”: “ I feel _____ when you ______.” She gave the following example: “I feel scared and hurt when you threaten to leave me.”

Challenge: Anxiety

According to Johnson, about two-thirds of people with bipolar disorder also have a diagnosable anxiety disorder.

Strategies: Johnson stressed the importance of using relaxation techniques and not using avoidance behaviors. As Van Dijk explained, “the more you avoid things because of your anxiety, the more your anxiety will actually increase, because you never allow your brain to learn that there’s nothing to be anxious about.”

Psychotherapy is tremendously helpful for managing bipolar disorder and the above challenges. If you’ve been prescribed medication, never stop taking it abruptly – this boosts the risk for relapse – and communicate regularly with your doctor.

These are the top 25 psychiatric medications by number of U.S. prescriptions dispensed in 2011, according to IMS Health. I’ve also provided their 2009 and 2005 ranking (you can view the 2009 list here).

To put the percent changes below into perspective, the U.S. total population rose approximately 1.6 percent from 2009 to 2011. That suggests that anything above 1.6 percent change was driven by other factors — more people seeking treatment, more pharmaceutical advertising and marketing, or some other factor.

The biggest movers and shakers on the list were Celexa — moving up 15 spots to grab the second most-prescribed psychiatric drug in 2011 — and Wellbutrin XL, moving from 22 to 13.

Drugs used to treat attention deficit hyperactivity disorder (ADHD) — generic amphetamine salts and methylphenidate — enjoyed big gains as well.

Notes:

If no percentage change is listed, we did not track it in 2005.

NA – Rank not available for this year.

* – This is not a psychiatric medication, but is often prescribed for a mental health issue.

How This Data is Derived

Information in the National Prescription Audit (NPA) is derived from IMS Health’s Xponent service, one of the most complete, national-level prescription databases in the U.S. Xponent captures roughly 70% Market Share of all prescriptions in the U.S. IMS then uses a patented projection methodology from a stratified and geographically balanced sample to represent 100% Market Share coverage of U.S. prescription activity at retail, mail service, long-term care, and managed care outlets.

Suzy Johnston began to experience symptoms of depression in her mid-teens after a life-changing physical illness left her bedridden for months. As a very active teenager, being confined for so long caused her an understandable amount of grief. By the time she went to college she was becoming more nervous and withdrawn. Convinced it was only the stress of college life taking its toll, she dropped out of school for a year to take it easy. The rest helped but it didn’t last long. Soon she was back at school but taking medication, which she avoided talking about with both friends and family. It wasn’t until she had logged several stays at a new, smoothly run local psychiatric hospital that Suzy came to terms with the fact that the illness would be with her for the rest of her life. She switched gears to focus on structuring her life around the illness and living despite her difficulties rather than within them.

In The Naked Bird Watcher and The Snow Globe Journals Suzy Johnston spends a lot of time describing how she lives her life to keep herself relaxed and happy:

My routine isn’t very exciting and maybe that’s why I like it. I take pleasure in the small things … I enjoy my life and most of all I enjoy being well so it makes sense that I adopt a lifestyle that places few stressful demands on me.

She plays guitar in a local band, participates in sports when she can, and talks to her cat. She often laughs at herself thinking that people see her as a “crazy cat lady” but if it makes her feel better, who cares? She promotes proactive prevention and insists that her entire circle of support knows not only her illness but also its warning signs, questions to ask to evaluate her mood, her medications, contact information for her doctors, and what to do if she is becoming more symptomatic. Prevention and self-awareness can mean the difference between hitting bottom and being pulled back up.

The Snow Globe Journals is a very personal book full of Suzy’s thoughts and reflections on being ill and going through the long process of recovery written in a flowing prose that can range from ranting to song. It gives readers a more intimate view of her experiences with touchy subjects including medication, self injury, psychosis, and suicidal thoughts. But it also has lighthearted moments and celebrates recovery, music, and her relationship with with a wonderful man who also happens to be bipolar.

Suzy’s mother, Jean Johnston, wrote To Walk on Eggshells, a short and concise book for caregivers and family members. Her book describes what it’s like to stand beside someone with a mental illness and be the emotional rock by telling her side of the same story Suzy tells in The Naked Bird Watcher. In addition to relating how she responded to her own ordeal, Jean offers tips and encouragement in times of stress and confusion with a practical “labor of love” outlook:

I have had people say that they could not have coped if one of their children had an episode of mental illness. Really? I dispute that for I think that most people would at least try. For those who say they couldn’t I hope they will give the subject some thought and try joining the real world.

Not only do all three books relate personal stories of illness and recovery, they also paint a very positive picture of the mental health system including doctors, nurses, and inpatient facilities. Showing the positive side of treatment was very important for both Suzy and Jean because they both believe strongly in the importance of seeking medical professionals and trusting them when you need to. They, along with Suzy’s younger brother, work to spread knowledge and acceptance of bipolar disorder, depression, and mental illness in general to help erase stigma and encourage people to talk to someone and get help instead of being ashamed and frightened of peoples’ opinions.

I found Suzy and Jean Johnston’s collection of books to be both engaging and helpful. Suzy has a gift for writing as if she were telling you her story over tea. All three books are casually presented in such a way that anyone could pick them up and almost immediately understand all sorts of vague mental health issues as simply as a game of Go Fish. The only thing that detracts from the books’ readability is the occasional formatting error or typo — no doubt a result of being published by the Johnstons’ own small publishing house.

To Walk on Eggshells is possibly one of the best books for parents who, having recently discovered their child is mentally ill, are looking for something that they can read now. Jean packed a lifetime of encouragement into fewer than 100 pages, making it as nonthreatening as it is helpful. But when it comes to nonthreatening books The Snow Globe Journals takes the top spot. It is easy to read and something you can go back to each time you need some reassurance.

What the Johnstons’ book trilogy leaves out is almost as important as what it contains. It is not a technical manual or a case study. You will not learn the mechanics of bipolar disorder or the names of medications; although you may learn some triggers of depression and expected side effects of medication. They are entirely practical books geared toward the patient and his or her family, making them perfect for being passed around rather than stuck on a shelf.

The Naked Bird Watcher (paperback, 248 pages, 2004, $18) and The Snow Globe Journals (paperback, 92 pages, 2009, $14) by Suzy Johnston; To Walk on Eggshells (paperback, 84 pages, 2005, $18) by Jean Johnston

For decades, the dominant hypothesis of depression has been that low levels of monoamines in the brain cause this debilitating disorder.

In the ‘80s, the selective serotonin reuptake inhibitor (SSRI) fluoxetine (brand name: Prozac) heralded a new era of safer drugs which also target the monoamine system. Since then, various SSRIs and serotonin-norepinephrine reuptake inhibitors (or SNRIs) have been developed as new antidepressants. While these drugs aren’t more effective than older antidepressants, they are less toxic.

But SSRIs and SNRIs don’t work for everyone, so MAOIs and TCAs still are prescribed.

Two out of three patients with depression do not fully recover on an antidepressant medication according to findings from STAR*D, the largest clinical trial study of treatments for major depressive disorder, funded by the National Institute of Mental Health. (One-third of patients do have a remission of their depression symptoms.)

These results “are important because previously it was unclear just how effective (or ineffective) antidepressant medications are in patients seeking treatment in real-world settings,” said James Murrough, M.D., board-certified psychiatrist and a research fellow at the Mount Sinai School of Medicine Mood and Anxiety Disorders Program.

As Murrough explained, depression treatment can be thought of in thirds: “for one third of patients, symptoms remit; another third don’t have as good of an outcome, experiencing residual symptoms and waxing and waning course or chronic course and are at risk for relapse whether they’re on or off medication; and then a third don’t get much benefit at all.”

He added that around “10 to 20 percent have persistent clinically significant symptoms that aren’t decreased by current treatment — these are the patients that we are the most worried about.”

So there’s a real need to find treatments that work for these patients. Since the 1950s and 1980s breakthroughs, researchers haven’t discovered drugs that target chemical systems in the brain other than the monoamine system.

“We haven’t been able to find any new systems, because we don’t understand the underlying biology of depression,” Murrough said.

But researchers are studying other mechanisms of depression and various drugs have recently been approved to treat depression. Below, you’ll learn about these drugs along with several chemical systems research is exploring.

Recently Approved Drugs for Depression

Recently approved drugs for depression are generally “me-too” drugs. A “me-too drug is a drug whose mechanism of action (what it does at the molecular level in the brain) is not meaningfully different than its predecessor,” Dr. Murrough said.

Prime examples of me-too drugs are desvenlafaxine (Pristiq), an SNRI, and escitalopram (Lexapro), an SSRI, he said. Pristiq is simply Effexor’s main metabolite. Lexapro is essentially a close relative derivative of citalopram (Celexa). Interestingly, sales still skyrocketed when Lexapro came out.

As Murrough said, there is value in some me-too drugs. Generally, all drugs within the classes SSRIs and SNRIs are me-too drugs. But the side effect profiles for each drug have slight differences, which can help patients.

For instance, Prozac tends to be more activating, so a doctor may prescribe it for patients with low energy, Murrough said. In contrast, paroxetine (Paxil) makes people more tired, so it’s prescribed to patients who have trouble sleeping, he said.

The drug Oleptro was approved this year for depression. It doesn’t target new mechanisms, and it isn’t even a me-too drug, Murrough said. It’s a reformulation of trazodone, an atypical antidepressant that’s been used as a sleeping aid by psychiatrists and other doctors. Because it’s so sedating, its earlier form would just put patients to sleep. “It is unclear if the new formulation will offer any benefit for patients over the original,” Murrough said.

These recently approved medicines “characterize the state of drugs in psychiatry,” Murrough said, and speak to “what’s wrong with antidepressant drug development today.” Novel treatments just aren’t on the market.

Augmentation of Depression Drugs

Recently, the biggest development in depression treatment has been the use of augmenting agents, said David Marks, M.D., assistant professor at the Department of Psychiatry & Behavioral Sciences at the Duke University Medical Center.

Specifically, some research has found that adding atypical antipsychotic drugs, like aripiprazole (Abilify) and quetiapine (Seroquel), to an antidepressant can boost its effectiveness.

Atypical antipsychotics are used to treat schizophrenia and bipolar disorder. “Abilify has three strong studies that show how well it works in patients that have partially responded to antidepressants,” Marks said. According to Murrough, augmentation has become a common strategy in depression treatment.

The Glutamate System and Depression

Researchers have looked at the role of the glutamate system in depression. Glutamate is abundant in the brain and is one of the most common neurotransmitters. It’s involved in memory, learning and cognition.

Some research has implicated the dysfunction of the glutamate system in medical conditions, such as Huntington’s chorea and epilepsy, and psychological disorders, such as schizophrenia and anxiety disorders.

Recent research suggests that drugs targeting a specific type of glutamate receptor in the brain — called the NMDA receptor — may have antidepressant effects.

Studies have explored ketamine, an NMDA antagonist, in treating treatment-resistant depression and acute suicidal ideation. Ketamine has a long history in analgesia and anesthesiology.

Currently, when a person is at imminent risk for attempting suicide or has attempted suicide, they’re admitted to a psychiatric hospital and closely monitored. But, as Murrough explained, medically, there’s nothing doctors can do to help with suicidal ideation or intense depressed mood. Antidepressants typically four to six weeks to work.

Ketamine appears to have fast antidepressant effects — within hours or a day. Thus, it may help protect patients from suicidal thinking or acute dysphoria when they’re in the hospital. Unfortunately, its effects only last seven to 10 days.

This research is “highly experimental, and probably less than 100 patients in the country have participated in controlled depression studies of ketamine,” Murrough said. The patients in these studies typically have treatment-resistant depression: They haven’t responded to several antidepressants and have moderate to severe symptoms of depression.

They’re admitted to the hospital and receive ketamine intravenously from an anesthesiologist, while their vital signs are closely monitored.

Ketamine is a drug of abuse, known by such street names as “Special K.” It induces trance-like or hallucination states. It also produces mild to moderate cognitive side effects, like other anesthetics. People report feeling “out of it,” intoxicated and disconnected in general.

These side effects actually “introduce a potential bias to the study design” because participants know they’re getting the treatment (when saline is given in the placebo condition), Murrough said.

To eliminate this bias, Murrough and his team are conducting the first-ever study to compare ketamine to a different anesthetic — the benzodiazepine midazolam (Versed) — which has similar transient effects as ketamine, he said. The study is currently recruiting participants.

Murrough cautioned that ketamine isn’t meant to be a treatment administrated at your doctor’s office. In a recent article in the journal Nature Medicine, he said ketamine treatment may be “akin to electroconvulsive shock treatment.”

Studying ketamine may reveal mechanisms underlying depression and help to find drugs that can be prescribed as antidepressants to a wider patient population.

Pharmaceutical companies have started exploring other NMDA receptor antagonists for treatment-resistant depression. For instance, in July 2010, the pharmaceutical company Evotec Neurosciences began testing a compound in a Phase II study, which evaluates the safety and efficacy of a drug.

The reality is that it is possible to safely discontinue any medication, including psychiatric ones.

Stop your medication for the right reasons.

“Timing is everything,” according to Dr. Michael D. Banov, medical director of Northwest Behavioral Medicine and Research Center in Atlanta, and author of the book Taking Antidepressants: Your Comprehensive Guide to Starting, Staying On, and Safely Quitting. Just because someone wants to stop taking their medicine doesn’t mean they’re actually ready, he said.

There are many reasons individuals decide to stop taking medicine. For instance, they might feel better and think they don’t need treatment anymore. Their family might be pressuring them to stop, they read something about a drug that scares them, or they’re afraid that the drug will affect their personality, Banov said. Sometimes people want to stop after making major changes in their lives, such as getting a divorce, moving or changing jobs. But, according to Dr. Banov, this is actually “the worst time” to stop.

Also, some mental health conditions require taking medicine indefinitely. Ultimately, how long a person takes a psychotropic drug depends on his or her individual illness, its responses to treatment and their personal situation, according to Dr. Ross J. Baldessarini, professor of psychiatry and neuroscience at Harvard Medical School and director of the psychopharmacology program at the McLean Division of Massachusetts General Hospital. For instance, some individuals struggling with depression may take an antidepressant for nine months to a year and get better; others may need two to five years; and still others, may be “so genetically loaded for depression, that they may need to stay on them indefinitely,” Dr. Banov said.

Don’t stop your medication abruptly.

“Stopping abruptly is especially dangerous,” Baldessarini said.

Depending on the medicine, stopping abruptly or “cold turkey” can cause a variety of distressing reactions, ranging from mild to moderate early discontinuation symptoms with antidepressants, rapid return of the illness being treated, or even potentially life-threatening seizures with a high dose of benzodiazepines.

Consult your doctor before stopping any medicine, and never attempt to do it on your own.

Consider if you’ve received a thorough assessment.

A comprehensive assessment is required prior to stopping medicine. Among other indicators, your doctor needs to consider “your current clinical condition and life circumstances, your past clinical history, reasons to consider stopping versus continuing treatment, side effects and the presence of stressors and supports, as well as the dose and the length of time you’ve been taking a medicine,” Baldessarini said. You and your doctor should talk about these indicators along with how he or she plans to discontinue the drug.

There are no firm, established rules for discontinuing psychiatric medicines. However, there is one major rule of thumb: Reduce the dosage gradually whenever possible. “We still do not know for sure how long is long enough to reduce doses safely,” Baldessarini said. Still, the “slower the dose-reduction, the greater the chances of preventing return of symptoms of the illness for which treatment was started. Very slow discontinuation is especially important when a person has been taking high doses of a medicine over a long time,” he said.

Discontinuing multiple drugs is like peeling an onion, Baldessarini said. He usually leaves the most essential medicine for last. He then reduces doses of one or more optional or supplemental drugs slowly and gradually. Stopping all medicines at once is not safe.

Dealing with small final doses is tricky when dropping from a low dose to nothing. Sometimes doctors decrease the dose to one pill a day or one every two days or split the pill in half, he said. Pill-splitting can be very helpful. You can find pill splitters at your pharmacy.

Don’t expect stopping medication to be a quick process.

Gradually and safely discontinuing a drug doesn’t happen in a few days. Some drugs, including antidepressants, don’t show benefits for several weeks when they’re started; it seems best to avoid discontinuing faster than over several weeks, Banov said.

If you’ve been taking a medicine for years, Banov recommended reducing the dose, stepwise, over at least six weeks. While this may be a conservative practice, he said that “sometimes, you might not detect a change for a few weeks, but later, problems may arise.” Discontinuation symptoms usually occur within days of stopping a medicine, but relapse of the illness being treated can be delayed for weeks after initially feeling well.

In bipolar disorder, Baldessarini and his research team found years ago that the rate of discontinuing ongoing treatment determines the risk and timing of relapse, he said. Initially, their research found that risk for relapse after discontinuing lithium was reduced by one half or more when slow dose-reduction over several weeks was compared to abrupt discontinuation (Baldessarini et al., 2006). Gradual discontinuation of antipsychotic drugs also resulted in lower risk of relapse in schizophrenia (Viguera et al., 1997). In a recent study, he and his colleagues found that stopping an antidepressant abruptly or only over several days resulted in a much greater risk for depression or panic than gradual discontinuation over two weeks or more (Baldessarini et al., 2010).

If you’re switching from one medicine to another, you can be more aggressive than when discontinuing altogether, Banov said. Usually you switch drugs because of ineffectiveness or side effects, and commonly a new drug is introduced as the previous one is gradually removed. This way, there’s little concern about either withdrawal symptoms or relapse, assuming that both drugs have similar effects or belong to the same class, he said. If you’re switching classes, it’s usual to “cross-taper” the medicines: You take both drugs for a while, and then, the doctor reduces the dose of one and ups the dose of the other.

Your doctor may prescribe another medication.

If you’re taking a relatively short-acting antidepressant, such as paroxetine (Paxil) or venlafaxine (Effexor), and you experience bothersome symptoms, “your doctor may prescribe a long-acting antidepressant such as Prozac for a time, and then gradually discontinue the long-acting drug to limit risk of discomfort of withdrawing,” Baldessarini said. “The principal byproduct of the metabolism of fluoxetine has an extraordinarily long half-life or duration of action,” he said, and can take weeks to leave your system.

This method is not well established for discontinuing other classes of psychotropic drugs, including antipsychotics and mood stabilizers, so the best option usually is to “discontinue such drugs gradually, with close clinical monitoring by your doctor,” Dr. Baldessarini said.

Dr. Jacqueline Frayne from the King Edward Memorial Hospital for Women in Perth, Western Australia, says, “Although pregnancy and childbirth can be a time of great joy, for some women and their families it may also be a time of turmoil.” She explains that the rate of serious mental illness, such as schizophrenia, is fairly low but up to one in five women will experience “clinically diagnosable depression or anxiety” during pregnancy and the postpartum period.

Taking medication for these conditions can be a cause of anxiety for both the patient and her physician. The pros and cons of medication to mother and baby need to be considered, alongside many other factors that impact on maternal and fetal wellbeing.

Dr. Frayne recommends that “specialist opinion is sought early and a multidisciplinary approach with access to specialist care offered if possible. Continuity of care, especially in the context of a trusting therapeutic relationship, is optimal,” she adds.

She says the treatment plan during pregnancy should be based on the woman’s current mental state and medication, as well as her history of past mental illness and previous treatment, and family history of mental illness during pregnancy. Her support network, pregnancy-related fears, drug and alcohol use should also be considered.

A recent study found that “medications with potential for fetal harm” were being taken by 16 percent of women treated for depression. There is a lack of pregnancy safety data for many medications. However, stopping treatment suddenly is not recommended as this can cause side effects and possible relapse.

For example, in the case of bipolar disorder, relapse is often due to the discontinuation of preventive drugs. Although mild manic episodes can often be managed without drugs, severe manic episodes need to be treated because the possible consequences of injury, stress, malnutrition, profound sleep deprivation and suicide could pose more risk to the fetus than the side effects of the drug.

Lithium should be avoided in the first trimester of pregnancy, whenever possible, as it has been linked to a small but significantly increased risk of birth defects, particularly of the heart. The normal maintenance dose should be re-established as soon as possible following delivery, or if lithium is the only medication that controls symptoms, it can be re-introduced in the second trimester.

Other bipolar medications such as carbamazepine (Tegretol) and sodium valproate (Depakote) also carry some risks of fetal malformation, but physicians may still consider using these medications on the minimum effective dose, alongside regular monitoring.

For generalized anxiety disorder and panic disorder, low-risk medications are available. As an alternative to drugs, patients should be offered cognitive behavioral therapy or psychotherapy, as should those with obsessive-compulsive disorder or post-traumatic stress disorder.

The selective serotonin reuptake inhibitor (SSRI) antidepressant paroxetine (sold as Seroxat, Paxil) is not considered safe during pregnancy. The prescribing information says, “Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations.

“If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant.”

Antidepressant medications cross the placental barrier and may reach the fetus, but research has shown that most other SSRIs are safe during pregnancy. Birth defects or other problems are possible, but they are very rare.

Tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (SNRIs) have not been found to have any serious effects on the fetus, and have been safely used thoughout pregnancy for many years. On the other hand, monoamine oxidase inhibitors (MAOIs) have been associated with increased risk of malformations and may interect with drugs used in labour (e.g., meperidine).

Nevertheless, there have been reports of neonatal withdrawal symptoms after the use of SSRIs, SNRIs, and tricyclics during late pregnancy. These include agitation, irritability, a low Apgar score (physical health at birth) and seizures.

Benzodiazepines should not be used during pregnancy, particularly in the first trimester, as they may cause birth defects or other infant problems. The U.S. Food and Drug Administration has categorized benzodiazepines into either category D or X meaning potential for harm in the unborn has been demonstrated.

If used in pregnancy, benzodiazepines with a better and longer safety record, such as diazepam (Valium) or chlordiazepoxide (Librium), are recommended over potentially more harmful benzodiazepines, such as alprazolam (Xanax) or triazolam (Halcion).

Pregnancy outcomes for antipsychotic medications vary widely depending on the type of drug. Exposure to low-strength antipsychotics during the first trimester is associated with a small additional risk of congenital anomalies overall. Haloperidol (Haldol) has been found not to cause birth defects.

The National Institute of Mental Health states, “Decisions on medication should be based on each woman’s needs and circumstances. Medications should be selected based on available scientific research, and they should be taken at the lowest possible dose. Pregnant women should be watched closely throughout their pregnancy and after delivery.”

Women taking these medications and who intend to breastfeed should discuss the potential risks and benefits with their physicians.

References

Frayne, J. et al. Motherhood and mental illness: Part 1 – toward a general understanding. Australian Family Physician, Vol. 38, August 2009, pp. 594-600.

Cleary, B. J. et al. Medication use in early pregnancy-prevalence and determinants of use in a prospective cohort of women. Pharmacoepidemiology and Drug Safety, Vol. 19, April 2010, pp. 408-17.

Medication, Pregnancy and Breastfeeding

Antenatal Mental Health Problems

Rubinchik, S. M., Kablinger, A. S. and Gardner, J. S. Medications for Panic Disorder and Generalized Anxiety Disorder During Pregnancy. Primary Care Companion to the Journal of Clinical Psychiatry, Vol. 7, 2005, pp. 100-105.

Mental Health Medications

Howard, L., Webb, R. and Abel, K. Safety of antipsychotic drugs for pregnant and breastfeeding women with non-affective psychosis. The British Medical Journal, Vol. 329, October 23, 2004, pp. 933-34.

From her work in primary care settings, Risa Weisberg, Ph.D, assistant professor (research) and co-director of the Brown University Program for Anxiety Research at Alpert Medical School, has seen “firsthand how a great many patients accept a prescription from their provider without asking many questions about it, or often, without even knowing for what symptoms/disorder it is being prescribed.”

Such a scenario can stall or sabotage your treatment. Confused, you’re likely left with tons of questions, unaware of what you’re taking and how it’s supposed to help. You may be feeling helpless — a spectator in your own recovery — and hopeless, if the medication doesn’t seem to work or has bad side effects. Your doctor likely is clueless about your real concerns, not having all the information to guide his or her decision-making process.

But you don’t have to feel like a powerless bystander, on the outskirts of your own treatment. In order to become a sharp self-advocate, you just need some information. Here’s some hints for for taking medication safely and effectively. At the end, you’ll also find a basic glossary of common medication-related terms.

1. Haven’t picked a physician yet? Do your homework and conduct an interview. Before you decide on a doctor, whether it’s a primary care physician or a psychiatrist, ask some questions about qualifications and see if he or she is a good fit for you. Questions to get you started: Where did you go to school and do your training? Do you specialize in a specific mental illness? Do you have hospital privileges? Here’s a list of excellent questions to ask a psychiatrist during and after your first appointment. They focus on bipolar disorder, but you can easily adapt them to any disorder.

2. Ask the doctor about your diagnosis. You have the right to know precisely what you’re diagnosed with and how the doctor came to that conclusion. Making a diagnosis doesn’t happen in a 5-minute interview. You want to make sure that the doctor conducted a thorough evaluation. Did the doctor get your medical and mental health history? Did you complete a standardized test? Did the doctor ask about your symptoms and recent experiences?

3. Seek out psychotherapy. Medication isn’t your only option. Depending on the disorder, you may only need psychotherapy or you may take medication and see a therapist. Psychotherapy provides lasting benefits, whereas a medication’s effects stop as soon as you stop taking it. Cognitive-behavioral therapy effectively treats depression, anxiety disorders and bipolar disorder. To find a therapist, you can ask your doctor for a recommendation, browse the Web or check with universities and medical schools. Be sure the therapist specializes in your mental illness. For advice on finding a good therapist, check out this eBook.

Some Web sources for finding a therapist:

• Psych Central’s therapist finder
• The Association for Behavioral and Cognitive Therapy for CBT-trained therapists
• Children and Adults with Attention Deficit/Hyperactivity Disorder
• Anxiety Disorders Association of America
• National Eating Disorder Association

4. Before taking the medication, ask specifics. Peter Roy-Byrne, M.D., professor and chief of psychiatry at the University of Washington at Harborview Medical Center, and Michael R. Liebowitz, M.D., professor of clinical psychiatry at Columbia University and managing director of The Medical Research Network, suggest asking:

• How will I know if this medication is working?
• What are the side effects, and what do I do if I experience them?
• When will the medication start to work?
• How long will I have to take it?
• If I take it for X amount of time, what’s the likelihood of reducing symptoms?
• What are the dose requirements?
• Will you be monitoring me throughout the course of this medication?
• When will you talk to me next?

The Agency for Healthcare Research and Quality has a basic handout with more questions. Here’s a thorough list if your child is taking medication, which you can easily revise for your situation.

5. Unsure about medication? Explore why. Are you on the fence because of potential side effects, the stigma of having a disorder or taking medication, a bad past experience, fears of addiction or uncertainty about the validity of your diagnosis? Talk to the doctor about your concerns before making the decision to take or refuse the medication.

Approximately 2.6 percent of American adults have bipolar disorder (formerly called manic depression and manic depressive disorder), according to the National Institute of Mental Health. These mood swings include “highs” (mania), when individuals feel either on top of the world or on edge, and “lows” (depression), when they feel sad and hopeless. Suicide attempts are common in bipolar disorder, especially during depressive episodes.

Bipolar disorder can be effectively treated with medication and psychotherapy. With proper treatment, individuals with bipolar can lead fulfilling, productive lives. This is why it’s so important to recognize the symptoms and see a mental health professional for an evaluation.

What Causes Bipolar Disorder?

There is no single cause for bipolar disorder. Indeed, like all psychological disorders, bipolar disorder is a complex condition with multiple contributing factors, including:

• Genetic: Bipolar disorder tends to run in families, so researchers believe there is a genetic predisposition for the disorder. Scientists also are exploring the presence of abnormalities on specific genes.
• Biological: Researchers believe that some neurotransmitters, including serotonin and dopamine, don’t function properly in individuals with bipolar disorder.
• Environmental: Outside factors, such as stress or a major life event, may trigger a genetic predisposition or potential biological reaction. For instance, if bipolar disorder was entirely genetic, both identical twins would have the disorder. But research reveals that one twin can have bipolar, while the other does not, implicating the environment as a potential contributing cause.

What Are the Different Types of Bipolar Disorder?

• Bipolar I is considered the classic type of bipolar disorder. Individuals experience both manic and depressive episodes of varying lengths.
• Bipolar II involves less severe manic episodes than bipolar I; however, their depressive episodes are the same.
• Cyclothymia is a chronic but milder form of bipolar disorder, characterized by episodes of hypomania and depression that last for at least two years.
• Mixed episodes are ones in which mania and depression occur simultaneously. Individuals might feel hopeless and depressed yet energetic and motivated to engage in risky behaviors.
• Rapid-cycling bipolar individuals experience four or more episodes of mania, depression or both within one year.

What Are the Risk Factors for Bipolar Disorder?

Risk factors include having:

• Cyclothymia (see definition above). About half of individuals with cyclothymia will experience a manic episode.
• Any other psychological disorder
• A family history of bipolar or other psychological disorders
• Alcohol and substance abuse
• Medication interactions. For instance, antidepressants may trigger mania.
• Major life changes
• Severe stress

Symptoms of Bipolar Disorder

There are four possible bipolar states:

1. Mania
2. Hypomania
3. Depression
4. A mixture of mania and depression (called a “mixed episode”).

Mood states are highly variable. Some people can experience mood changes in one week, while others can spend months or even years in one episode.

What Does Mania Look Like?

• Feelings of euphoria and elation or irritability and anger
• Impulsive, high-risk behavior, including grand shopping sprees, drug and alcohol abuse and sexual promiscuity
• Aggressive behavior
• Increased energy and rapid speech
• Fleeting, often grandiose ideas
• Decreased sleep (typically the individual doesn’t feel tired after as few as three hours of sleep)
• Decreased appetite
• Difficulty concentrating; disorganized thoughts
• Inflated self-esteem
• Delusions and hallucinations (in severe cases)

What Does Hypomania Look Like?

Hypomania is less severe than a full-blown manic episode. Hypomanic individuals can seem pleasant, friendly, energetic and productive. Though it doesn’t sound problematic, increasing hypomania can lead to risky behaviors and full mania.

What Does Depression Look Like?

• Feelings of hopelessness and sadness
• Inability to sleep or sleeping too much
• Loss of interest in formerly enjoyable activities; loss of energy (sometimes to the point of inability to get out of bed)
• Changes in appetite and weight
• Feelings of worthlessness and inappropriate guilt
• Inability to concentrate or make a decision
• Thoughts of death and suicide

What Does a Mixed Episode Look Like?

Mixed episodes involve simultaneous symptoms of mania and depression, including irritability, depressed mood, extreme energy, thoughts of suicide and changes in sleep and appetite.

A Note about Suicide

Because of the high suicide risk in those with bipolar disorder, it’s important to note the warning signs. In addition to those mentioned in the depression symptoms above, others include:

• Withdrawing from loved ones and isolating oneself
• Talking or writing about death or suicide
• Putting personal affairs in order
• Previous attempts

For more information about suicide, check out Frequently Asked Questions about Suicide.

How Is Bipolar Disorder Diagnosed?

There are no medical tests to diagnose bipolar disorder. However, a psychologist, psychiatrist or other trained mental health professional can diagnose the disorder by conducting a face-to-face clinical interview. Your clinical interview will include detailed questions about your and your family’s medical and mental health history and your symptoms.

What Treatments Exist for Bipolar Disorder?

Bipolar disorder can be effectively managed with a combination of medication and psychotherapy to help in reducing both the number of episodes and their intensity. Treatment also can help prevent future episodes if the individual is willing to work on personal issues and develop healthy habits.

What Kinds of Medication Are Used for Bipolar Disorder?

• Mood stabilizers. These medications are prescribed to help stabilize manic symptoms, prevent future episodes and reduce suicide risk. The most well-known of these is lithium, which is effective in 60 to 80 percent of manic and hypomanic episodes. Anticonvulsant (or anti-seizure) medications also have mood stabilizing effects. These include valproate (Depakote), carbamazepine (Tegretol), lamotrigine (Lamictal), gabapentin (Neurotin) and topiramate (Topamax).

  Every medication has its own set of potentially serious side effects. For instance, Lamictal can cause Stevens-Johnson syndrome, a potentially fatal skin disease, though this is rare and is entirely avoidable by careful, slow dose titration.

• Atypical antipsychotics. The newest medications, atypical antipsychotics were originally developed to treat psychosis (a symptom of schizophrenia). Like the mood stabilizers above, atypical antipsychotics help to control mood swings. These seven medications are commonly prescribed for bipolar: aripiprazole (Abilify), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), clozapine (Clozaril) and olanzapine/fluoxetine (Symbyax).

  Contrary to popular belief, these medications aren’t without significant side effects, including rapid weight gain, high cholesterol and risk for diabetes, which occurs most commonly with olanzapine and clozapine. In some cases, atypical antipsychotics have been associated with a life-threatening condition known as diabetic ketoacidosis (DKA).

  In June 2004, the U.S. Food and Drug Administration (FDA) requested that all companies who manufacture atypical antipsychotics include a warning about the elevated risk for hyperglycemia and diabetes (see here ).

  In addition, several organizations, including the American Diabetes Association and American Psychiatric Association, have published recommendations for doctors on how to treat patients taking these medications. For more information, read the press release at the American Diabetes Association website.

• Calcium-channel blockers. Used to treat angina and high blood pressure, these medications — including verapamil (Calan, Isoptin, Verelan) and nimodipine (Nimotop) — also have mood stabilizing effects. They have fewer side effects than other bipolar drugs but aren’t as effective.
• Combination therapy. When one medication isn’t working, a doctor might prescribe two mood stabilizers or a mood stabilizer along with an adjunctive medication to treat symptoms such as anxiety, hyperactivity, insomnia and psychosis. For example, Xanax (alprazolam), a fast-acting benzodiazepine, typically is taken for two weeks before mood-stabilizing medication starts to work. Antidepressants might be prescribed for patients who are in a depressive phase, but research suggests they aren’t effective, can trigger mania and exacerbate episodes long term.

Psychotherapy

Psychotherapy is a crucial component of long-term bipolar disorder management. Even when your mood swings are under control, it’s still important to stay in treatment.

Several different psychotherapeutic methods have proved to be effective in treating bipolar disorder.

• Cognitive behavioral therapy (CBT) helps individuals develop strategies to cope with their symptoms, change negative thinking and behavior, monitor their moods and predict their mood to try to prevent a relapse.
• Interpersonal and social rhythm therapy is a combination of interpersonal therapy and CBT. This newer treatment focuses on circadian rhythms to help clients establish and maintain routines and build healthier relationships.
• Psychoeducation teaches individuals about their disorder and treatment and gives them the tools to manage it and anticipate mood swings. Psychoeducation also is valuable for family members.

How Else Can I Manage Bipolar Disorder?

• Take your medication.
• See a therapist regularly.
• Learn more about bipolar disorder and its treatment
• Participate in online communities or in-person support groups
• Adopt healthy habits, including exercising, practicing stress management techniques, eating healthy, avoiding alcohol and drugs, getting seven to eight hours of sleep and avoiding any potential triggers.

What Do I Do Next?

By starting to learn about bipolar disorder, you’ve already taken a significant first step. If you’d like to learn more, check out our detailed guide here.

If you think you or a loved one has bipolar disorder, it’s important to be evaluated by a trained mental health professional. To find a therapist in your area, use a search engine such as this one, or check with your primary care physician or community mental health clinic for referrals.

Further Reading

The Numbers Count: Mental Disorders in America

National Institutes on Mental Health

University of Maryland Medical Center

National Alliance on Mental Health (NAMI)

Depression and Bipolar Support Alliance (DBSA)

This is referred to as “discontinuation syndrome.” Some studies have shown that up to 80% of people discontinuing certain antidepressant medications, for instance, experience symptoms of discontinuation syndrome.

What is Discontinuation Syndrome?

Discontinuation syndrome is characterized by one or more of the following symptoms (Haddad, 2001):

• Dizziness, vertigo or ataxia (problems with muscle coordination)
• Paresthesia (tingling or pricking of your skin), numbness, electric-shock-like sensations
• Lethargy, headache, tremor, sweating or anorexia
• Insomnia, nightmares or excessive dreaming
• Nausea, vomiting or diarrhea
• Irritability, anxiety, agitation or low mood

How Do I Prevent Discontinuation Syndrome?

Discontinuation syndrome is relatively easy to minimize or prevent altogether in most people. The key to discontinuing many psychiatric medications is to do so under a doctor’s supervision in a slow and gradual process over weeks’ time. This process is called titration — gradually adjusting the dose of the medication until the desired effect is achieved, in this case, stopping it. Gradually tapering the dose of the medication over a few weeks (and sometimes, months) usually minimizes the appearance of any discontinuation syndrome symptoms.

Most people who experience this syndrome do so because they either abruptly stop taking their medication, or try to remove themselves off of it much too quickly, and in many cases, not under the guidance of their prescribing physician. One should never stop taking any medication prescribed by a doctor until one has talked to their doctor about stopping.

Sometimes people feel embarrassed or uncomfortable talking to their physician about stopping a medication because they feel like they are a failure in doing so. Doctors, however, have patients who need to stop taking their medications for a wide variety of reasons every day, and usually have no trouble helping a person discontinue the medication gradually. Perhaps the medication isn’t working for you, perhaps its causing uncomfortable side effects, perhaps you just want to try something else. Share the reason with your doctor, and work with him or her to minimize the possibility of discontinuation syndrome.

Reference: Robinson, D.S. (2006). Antidepressant Discontinuation Syndrome. Primary Psychiatry, 13(10):23-24.

Drugs for Depression

Although the Phase III pipeline of drugs for the treatment of depression is deep, including several compounds with new mechanisms of actions, none is expected to be approved in 2009. Pristiq (desvenlafaxine, the major metabolite of venlafaxine), Wyeth’s follow- up to Effexor (venlafaxine), was approved for depression in adults by the FDA in March and could gain ground in the clinic next year.

AstraZeneca submitted an sNDA in May for Seroquel XR for the treatment of generalized anxiety disorder, which was the first submission of an atypical antipsychotic medication for this indication. In February, the company submitted an sNDA for Seroquel XR for the treatment of depression.

In September, LaboPharm submitted an NDA for DDS-04A for the treatment of depression. This compound is the well-known antidepressant trazodone a 5-HT2 receptor antagonist, formulated for once-daily administration. The NDA was based on data from five pharmacokinetic studies and a North American study that included more than 400 patients.

New drugs on the horizon for late 2009/2010 U.S. approval include Valdoxan (agomelatine), which is in development by Novartis and Servier, and Saredutant (SR 48968), a Sanofi-Aventis compound. Valdoxan, which has a novel mechanism of action—melatonin (MT1 and MT2) receptor agonist and 5-HT2C receptor antagonist—and an attractive side-effects profile (i.e., no sexual dysfunction or weight gain), is anticipated.

Novartis is currently conducting four large-scale Phase III trials in the United States, all of which are scheduled to complete in 2009. A U.S. NDA might be submitted in 2009. Saredutant, a neurokinin-2 (NK2) receptor blocker, is well tolerated but has produced mixed results in long-term Phase III trials. Sanofi-Aventis will decide on regulatory submissions based on the results of two ongoing trials assessing saredutant in combination with escitalopram and paroxetine, which are scheduled for completion in the first half of 2009.

Drugs for Bipolar Disorder

Longer-acting injectable and oral formulations of approved atypical antipsychotic medications are the focus of late-stage drug development for bipolar disorder.

Janssen is currently marketing Risperdal Consta, a long-acting, injectable formulation of risperidone for the treatment of schizophrenia. The drug was developed by combining risperidone with the Alkermes’ Medisorb delivery system to maintain a therapeutic drug concentration when administered once every two weeks.

In 2008, Janssen submitted two supplemental New Drug Applications (sNDA) for bipolar indications. An sNDA submitted in April seeks approval for adjunctive maintenance treatment to delay the occurrence of mood episodes in patients with frequently relapsing bipolar disorder. A July sNDA submission looks to indicate Risperdal Consta as monotherapy for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in adults.

Another long-acting atypical antipsychotic, AstraZeneca’s Seroquel XR (quetiapine extended-release tablets), was approved in October 2008 for acute treatment of depressive episodes associated with bipolar disorder and manic and mixed episodes associated with bipolar I disorder, as well as maintenance treatment of bipolar I disorder as adjunctive therapy to lithium or divalproex.

Drugs for Schizophrenia

Late-stage drug development for schizophrenia includes a new injectable formulation of an approved atypical antipsychotic and two new drug candidates with atypical antipsychotic mechanisms of action.

Janssen developed an injectable formulation of its antipsychotic, Invega (paliperidone extended-release) by combining it with Elan’s NanoCrystal technology to enable administration by intramuscular injection on a once-monthly schedule. In October 2007, the company submitted an NDA for the treatment of schizophrenia and prevention of symptom recurrence. In August 2008, the FDA requested additional data before approving the NDA, but did not require any additional studies. Janssen is currently evaluating the FDA response and will work with the agency to resolve outstanding questions. Potential advantages of Invega over Risperdal Consta include reduced dosing frequency (once monthly vs. once every two weeks) and no need for refrigeration.

In September, Lundbeck’s NDA submission seeking approval for Serdolect (sertindole) for the treatment of schizophrenia was accepted for review by the FDA. Serdolect is a new-generation atypical antipsychotic. It exhibits a higher level of limbic-selective increased dopaminergic activity than other atypical agents, which may contribute to an attractive extrapyramidal side-effect profile. Serdolect has been launched in Europe, South and Central America, Asia and the Middle East and has been administered to more than 70,000 patients.

Schering-Plough’s NDA submission for its new 5-HT2A- and D2 receptor antagonist Saphris (asenapine) was accepted by the FDA in November 2007 and is undergoing a standard review. Saphris is a fast-dissolving, sublingual tablet acquired by Schering-Plough when it combined with Organon BioSciences earlier in November 2007. The NDA seeks approval for schizophrenia and acute or mixed episodes associated with bipolar I disorder. In November 2008, top-line Phase III clinical trial results demonstrated the efficacy of Saphris in long-term schizophrenia relapse prevention. Approval and launch in 2009 are possible.

Drugs for Attention Deficit Disorder (ADHD)

A new drug with a nonstimulant mechanism of action may be approved in 2009 for the treatment of attention-deficit/hyperactivity disorder (ADHD). Intuniv (guanfacine extended-release tablets) is a selective alpha2A-agonist in development by Shire for the once-daily treatment of ADHD. The company submitted an NDA for monotherapy for the treatment of ADHD symptoms throughout the day in children aged 6 to 17 years and received an approvable letter from the FDA in June 2007. The FDA requested additional information, and the company has been conducting additional clinical work related to the drug’s label.

Immediate-release guanfacine, a medication used to treat high blood pressure, also is used off-label in ADHD.

Anticipated advantages of Intuniv over guanfacine include FDA approval specifically for ADHD and maintenance of blood concentration in the therapeutic range, which is problematic with immediate-release formulations. Another potential advantage: Intuniv is not a controlled substance, and is not associated with any known mechanisms for potential abuse or dependence.

An estimated 30% of children with ADHD cannot tolerate stimulant drugs or do not benefit from currently available ADHD medications. Intuniv also might have applications in combination with stimulant drugs to reduce aggression and insomnia associated with stimulants and adult patients. Shire hopes to gain FDA approval and launch Intuniv in the second half of 2009.