“Coming of Age on Zoloft” by Katherine Sharpe is one such memoir.

Prozac, the first and probably the most prominent of the Selective Serotonin Reuptake Inhibitors (SSRIs) was approved as treatment for depression in 1987.

By the 90s, it was so widely used that it had become embedded in American popular culture. The memoirs of Lauren Slater, “Prozac Diary,” Elizabeth Wurtzel, “Prozac Nation,” and the touting of its effectiveness by psychiatrist Peter Kramer, “Listening to Prozac,” were important factors in this embedding.

In the same spirit, Sharpe describes the experience of a new second generation of SSRI users in her “Coming of Age on Zoloft.” She tells the story of those who were put on the medication in their teens. In Sharpe’s words, “This is a book about what it’s like to grow up on antidepressants.”

The writing alternates skillfully between the memoir of Sharpe’s own coming of age, interviews with forty fellow depression sufferers ranging from late teens to early middle age, and chapters about the history and social meaning of this phenomena that are truly scholarly. This last should not deter readers, because the writing is very clear.

The author states that her hope is that the book will be useful to antidepressant users and their families as well as contributing to the ongoing debate about Zoloft and the “medicalization” of society to the extent that ordinary feelings of sadness and anxiety are treated as symptoms.

Memoirs of mental illness and recovery have proliferated in recent years and Sharpe is following people like Slater, Kay Jamison, Elyn Saks, Martha Manning, and Annie Rodgers among others. Sharpe’s memoir does not approach these others for emotional impact. However, it’s a convincing and worthwhile account.

The memoir portion is well supported by the interviews which address many of the questions that Sharpe dealt with: Who am I really on medication? Is having to take medication a weakness? Will taking medication over time harm me physically? Do I have a real mental illness? How do I quit the meds? My only criticism is that some of the interviews were repetitive s the redundancy of some of the interviews.

The portions of the book where Sharpe’s offers the big perspective are very strong. Having covered some of the same material that she did, I can say that she captured almost all of the main points of the SSRI revolution. She does an especially good job on the rickety theoretical foundation that underlies the antidepressants. She points out how backwards the theory is in that “the cure” was found first and then the condition of depression was fleshed out. In her words, “Antidepressants were invented by accident — twice — and scientists drew conclusions about the nature of the illness by investigating the action of the drugs.”

She’s also scathing about the theory that depression results from a chemical imbalance, i.e. an insufficiency of serotonin. “The phrase ‘chemical imbalance’ gestures at the truth, while deftly concealing all that we don’t know as well as the quotient of subjective reasoning that plays a part in any discussion of mental disorder.” She deals with the question of whether medication is more effective than psychotherapy through her own experience and research findings.

There are a number of issues covered in this book, including questions that people on antidepressants ask themselves.  Sharpe expresses the universal question, Who am I?, from her own drug-shadowed perspective. “When I first began to use Zoloft my inability to pick apart my ‘real’ thoughts and emotions from those imparted by the drugs made me feel bereft.”

She touches broader issues,  such as the “medicalization” of negative feelings and the incestuous relationship between big Pharma and psychiatry. Sharpe discusses the economics of contemporary psychiatric practice, where she points that a psychiatrist out can bill four patients an hour for med checks rather than seeing one patient for an hour of psychotherapy. She also mentions that the antidepressants  have made psychiatry less of the ugly stepchild of medicine.

This is a very solid book  that is thoughtful, well written, and wide ranging. I would have liked to see more discussion about if the drugs really work? However, I realize that she couldn’t explore every issue in detail.

I’m a retired clinical psychologist who uses antidepressants and confess my own fear that what I’m using not only may not work, but may cause long-term damage. I’m thinking of quitting, but fear a relapse of my depression if I stop. I recommend this book for anyone contemplating starting antidepressants, current users, affected families, and especially psychiatric residents.

Coming of Age on Zoloft: How Antidepressants Cheered Us Up, Let Us Down, and Changed Who We Are
Katherine Sharpe
Harper Perennial, June 5, 2012
Paperback, 336 pages
$10.94

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.

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.

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.

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.

Effexor’s chemical structure is unlike any other antidepressant. It works to restore the balance of brain chemicals called neurotransmitters — specifically serotonin and norepinephrine. Effexor is in a class of medicines called serotonin and norepinephrine reuptake inhibitors (SNRIs). Effexor is prescribed to treat depression. Effexor XR is prescribed to treat depression, Generalized anxiety disorder (GAD), and Social anxiety disorder (SAD).

• Manufacturer: Wyeth-Ayerst Laboratories
• FDA Approved for: Depression, General Anxiety Disorder
• Off-Label Uses: Bipolar disorder, Fibromyalgia, Arthritis, Chronic Fatigue, Multiple Sclerosis, Lupus, Headaches, Irritable Bowel Syndrome (IBS), ADD/ADHD, Eating Disorders
• Dosing Range: Effexor initially 75 mg. in two or three divided doses. Usual maximum dose is 225 mg one time a day. Effexor XR initially 37.5 mg or 75 mg once daily. Usual maximum dose is 225 mg daily.
• Effexor Patient Information Sheet (PDF)

FDA ALERT [07/2006] – Potentially Life- Threatening Serotonin Syndrome When Used With Triptan Medicines

A life-threatening condition called serotonin syndrome can happen when medicines called selective serotonin reuptake inhibitors (SSRIs), such as Effexor, and medicines used to treat migraine headaches known as 5-hydroxytryptamine receptor agonists (triptans), are used together.  Signs and symptoms of serotonin syndrome include the following:

• restlessness
• hallucinations
• loss of coordination
• fast heart beat
• increased body temperature
• fast changes in blood pressure
• overactive reflexes
• diarrhea
• coma
• nausea
• vomiting

Serotonin syndrome may be more likely to occur when starting or increasing the dose of an SSRI or a triptan.  This information comes from reports sent to FDA and knowledge of how these medicines work.  If you take migraine headache medicines, ask your healthcare professional if your medicine is a triptan.

Before you take Effexor and a triptan together, talk to your healthcare professional.  If you must take these medicines together, be aware of the possibility of serotonin syndrome, and get medical care right away if you think serotonin syndrome is happening to you.

Who Should Not Take Effexor?

Never take Effexor if you are taking another drug used to treat depression, called a Monoamine Oxidase Inhibitor (MAOI), or if you have stopped taking an MAOI in the last 14 days. Taking Effexor close in time to an MAOI can result in serious, sometimes fatal, reactions, including:

• High body temperature
• Coma
• Seizures (convulsions)

MAOI drugs include Nardil (phenelzine sulfate), Parnate (tranylcypromine sulfate), Marplan (isocarboxazid), and other brands.

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.