Your psychiatrist tends to listen to drug reps. You need to listen to the facts.

by John McManamy


THIS ARTICLE, together with the companion article on mood stabilizers, is meant to be read with the other articles in this series. Reading about various meds in isolation - with no regard to treatment strategies and recovery goals - is like trying to appreciate a book by only looking at the letters. You've been warned ...

Antipsychotics - The Wonder Years

Antipsychotics are best known for treating schizophrenia, which is how the FDA indicates their treatment. In reality, the meds treat psychosis in schizophrenia, often at the expense of worsening the cognitive and flat affect symptoms that also define this illness. The meds were later approved to treat mania in bipolar, and are also an obvious choice to treat psychosis in bipolar. In recent years, three of these meds have been approved in different capacities to treat bipolar depression.

Antipsychotics were discovered by accident in the 1940s. The introduction of Thorazine as a "neuroleptic" or major tranquilizer in the early 1950s promised to do to psychiatry what antibiotics and other "wonder drugs" did to internal medicine. Indeed, deliverance from psychosis could be regarded as a medical miracle, and over the next ten years 50 million patients were administered the drug. Haldol, which came a bit later, is the best-known old-generation antipsychotic still in service.

The drugs bind to the neuron's dopamine D2 receptors, blocking dopamine transmission in the brain's mesolimbic pathway, thus serving as a damper against the type of overstimulation that results in psychosis. Unfortunately, antipsychotics also act on other dopamine pathways, resulting in a very high cost of doing business.

The introduction of Risperdal and Zyprexa in the early and mid 1990s raised false hopes of a "new and improved" class of antipsychotic for treating schizophrenia. These new generation antipsychotics (referred to as atypical antipsychotics) bind more loosely to the dopamine D2 receptors, which reduces the risk of side effects such as EPS and tardive dyskinesia. In addition, there is a downstream serotonin affect. But their actions on other brain (and physical) systems creates a whole panoply of additional, and equally troubling, side effects.

Similarly, the introduction of Abilify in the next decade generated a buzz over a new breed of "Goldilocks" atypical antipsychotic that was purported to be "just right." But by then the reality was setting in that the new antipsychotics were simply newer versions of the old antipsychotics, albeit with better side effect profiles in certain respects, worse in others. Nevertheless, the proliferation in brands of the new antipsychotics is justified in giving patients a choice, but the principal choice appears to be in terms of side effects rather than efficacy. Annual world sales of antipsychotics total about $20 billion.

Antipsychotics - Cynicism Sets In

The 2005 publication of Phase 1 of the NIMH-underwritten schizophrenia trials (CATIE) served notice that the new generation meds were no more effective than the older ones. Moreover, only 26 percent of the patients completed the 18-month trial, a figure that corresponds with other clinical trial drop-out rates. The later publication of successive phases of CATIE revealed an extremely depressing picture of medicated patients struggling with both their illness and side effects, with low quality of life, and in terrible physical shape.



All of this information had long been available to the psychiatric profession - in studies published previously, on product labeling, and in daily litanies of complaints from patients - but only in light of CATIE are doctors actually beginning to pay attention.

Basically, the pharmaceutical industry oversold psychiatry on the new generation meds. Psychiatrists, in turn, paid more attention to smooth-talking drug reps than to their own patients. We know these meds work well in certain specific contexts (such as quickly knocking out mania and psychosis and in some cases to prevent future episodes), but we need to accept their limitations and exercise sound judgment in using them.

Clinical treatment guidelines recommend their use during the crisis phase of the mania, psychosis, and (for Seroquel in particular) depression. Owing to their burdensome side effects, these same guidelines only recommend these meds for the maintenance phase of treatment as a last resort.

Antipsychotics Combination Therapy

No clinical benefit has been established for combining two antipsychotic medications. The dangers of combining two meds, each with high side effect profiles, on the other hand, are self-evident. The exception may be very low-dose Seroquel as a sleep med when added to a different full-dose antipsychotic.

In the acute phase of mania or depression, an antipsychotic may be combined with a mood stabilizer, but the general rule is to drop the antipsychotic during the maintenance phase (with the idea of possibly redeploying the med in the event of a breakthrough episode).




Antipsychotics Side Effects

If you are in a psychiatric emergency, the least of your worries is long-term weight gain or over-sedation or loss of sexual function or other effects. In general, the real problems occur should you continue on an antipsychotic after your crisis has resolved. There may be valid reasons for remaining on an antipsychotic (such as to control persistent psychosis), but long-term use poses major challenges in side effects management.

The following is not meant to be read as a complete run-down. Moreover, you may experience no side effects at all, or just minor ones. Here are the more common major ones:

Antipsychotics in general: Sedation, cognitive difficulty, loss of pleasure, apathy, loss of motivation, blunted awareness, EPS (extrapyramidal symptoms that include transient involuntary muscular contractions such as facial twitches in the early going), tardive dyskinesia (permanent involuntary muscular contractions after prolonged exposure to the med), weight gain, metabolic syndrome, diabetes, sexual dysfunction.

In 2003, a joint panel of the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity issued a consensus statement advising that patients taking atypical antipsychotics may be at increased risk for obesity, diabetes, high cholesterol, and heart disease. The panel recommended that doctors screen and monitor their patients on atypical antipsychotics for: 1) personal and family history of obesity diabetes, high cholesterol, hypertension, or cardiovascular disease; 2) weight and height; 3) waist circumference; 4) blood pressure; 5) fasting blood glucose; 6) fasting blood cholesterol.

Haldol: EPS, tardive diskinesia, sedation, hyperprolactinemia (breast milk production and related symptoms).

Clozaril: Sedation, severe weight gain, risk of agranulocytosis (failure of bone marrow to make enough white blood cells, weekly blood monitoring required), risk of seizures, risk of myocarditis.

Zyprexa: Sedation, severe weight gain.

Seroquel: Sedation, severe drowsiness, weight gain.

Haldol, Risperdal, Invega (Son of Risperdal): Hyperprolactinemia.

Geodon: QT syndrome (heart irregularity), though to date no deaths have been reported.



Antipsychotics and Pregnancy

No decision is risk-free. Please consult with both your psychiatrist and personal physician. The following is a general guideline, drawn from a number of expert sources, and should not be construed as medical advice:

As a general rule, a drug-free first trimester is recommended.

In 2011, the FDA updated labeling in atypical and old generation antipsychotics to warn of risk of EPS in newborns for moms treated with these meds in the third trimester.

A 2015 Canadian study published in the British Medical Journal found that "antipsychotic drug use in pregnancy had minimal evident impact on important maternal medical and short term perinatal outcomes. However, the rate of adverse outcomes is high enough to warrant careful assessment of maternal and fetal wellbeing among women prescribed an antipsychotic drug in pregnancy."

The study outcomes painted a better pciture than earlier studies. The sttudy authors suggest that other factors - such a being on antipsychotics prior to pregnancy - may cloud the picture.

In women with bipolar disorder, the risk of postpartum psychosis runs about 25 to 30 percent, much higher than in the general population. In psychosis, a new mom is in no position to bond with her child, much less care for it. In rare cases, the new mom may harm both herself and her child. Thus, any concern about the safety of antipsychotics during pregnancy needs to be weighed against the considerable risk of postpartum psychosis.

My good friend and video partner, Maggie Reese, is about to publish a book on her horrific experience with postpartum psychosis. In a video we shot together, she strongly urges that mothers-to-be have contingency plans ready and support systems in place well ahead of time.

Shrinking Brain Volume

A 2011 study led by preeminent schizophrenia researcher Nancy Andreasen of the University of Iowa found subtle though measurable reductions in both gray matter and white matter volumes for those who had been adminstered first and second-generation antipsychotics over the long-term. The study recruited 211 newly diagnosed schizophrenia patients and tracked them over seven years (in some cases up to 14 years), scanning their brains on average three times over that period. Dr Andreasen ruled out shrinkage based on the effects of the illness and drug abuse.

Her study concluded:

Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.

Supersensitivity Psychosis?

Robert Whitaker's 2010 Anatomy of an Epidemic raised the talking point that antipsychotics may create the ironic effect of worsening the course of psychosis, perhaps to the point of no-return. Whitaker presents his argument as unassailable fact, but the evidence is far more tenuous.

Whitaker bases his case on the investigations of Guy Chouinard and Barry Jones of McGill University back in the late 1970s.

Supersensitivity psychosis is analogous to rebound symptoms that occur in other illnesses when a medication is abruptly withdrawn or too rapidly lowered.

In this case, we are talking about the brain, over the course of long-term antipsychotic administration, habituating to the med. In response to dopamine blockade from an antipsychotic, post-synaptic neurons compensate by increasing their receptor binding sites, setting up - the hypothesis goes - the ironic side effect of psychosis.

Chouinard and Jones clearly regard the effect as temporary, which may be countered by meds adjustments, which you won't find mentioned in Whitaker's book. Whitaker does bolster his case with a 15-year longitudinal study by Harrow and Jobe that found that patients with schizophrenia who weaned off their antipsychotics fared significantly better over the long term than those who stayed on their meds. What Whitaker failed to mention was the patients who went off their meds had been identified at the beginning of the study as "good prognosis" patients.

Lest we dismiss Whitaker as a propaganist, indirect support came in the form of a 2013 blog by Thomas Insel, then head of the NIMH. Citing the Harrow and Jobe study, plus another more recent corraborating finding, Dr Insel observed: "For some people, remaining on medication long-term might impede a full return to wellness. For others, discontinuing medication can be disastrous."

Keep in mind, these discussions tend to take place in the context of schizophrenia, but are fully relevant to those who experience psychosis in bipolar, or who have been disagnosed with schizoaffective disorder.

Nevertheless, Whitaker Is a Wimp

It turns out that the harshest critics of antipsychotics are those engaging in cutting edge schizophrenia research. John Krystal of Yale, for instance, told a packed room at the 2007 American Psychiatric Association that antipsychotics "aren't that great," especially when dopamine hyperactivity "can't account for the sustaining features of schizophrenia." Dr Krystal is researching a new class of meds targeting the GABA-glutamate pathways.

Ironically, should a completely new class of drugs find their way to market (which has not happened since the 1960s), the strongest critics of antipsychotics will turn out to be the very drug companies that marketed their antipsychotics as the best thing since sliced bread. Then we will be exposed to drug industry marketing along the lines of how their newest best thing since sliced bread leaves their old best thing since sliced bread for dead.

Alas, both the hype and the criticism obscure one important fact - that for a good many people antipsychotics have been a godsend, or, at the very least, have offered an invaluable leg-up to individuals in distress. The wisest choice you make may be to remain on an antipsychotic med over the long term. It may also be the worst.

A Cautionary Tale

A 2013 blog by author Pete Earley featured a harrowing acount by the mother of an adult with schizophrenia. For years, her boy had been lost to the streets. Finally, someone who ran a homeless shelter managed to gain the son's trust, and he went on medication. When he stopped taking his meds, his schisophrenia would come roaring back. Eventually, he saw the merit in staying on his meds and was able to move back in with his family.

Then he heard Robert Whittaker give a talk. According to the mom:

From the moment Mr. Whitaker’s speech was over, my son became fixated on the idea medication was harmful. That night, he met with other consumers who had been at that speech. One of them had stopped taking medications a long time ago and she talked about how she felt better and how Whitaker was right. Medications had hurt her internal organs and caused her to gain weight. I don’t doubt that is true.

I tried to talk my son out of it, but when we got home he announced he didn’t need his medicine anymore. He had been on them long enough. I begged him to wait and talk to his psychiatrist but he refused. Medications are placebos. That’s what he got from what Mr. Whitaker said.

Then ...

Today when we came down to check on him — his room is in our walk out basement — he was gone. He left us a long handwritten note filled with nonsense about how a voice was telling him we were devils, our house was haunted by evil spirits and we were trying to poison him. He said God was commanding him to not live with us anymore.

We have spent all day looking for him. The police have been no help because our son is an adult and has not violated any laws.

I don’t know if either my husband or me can go through this again.

See also: Lithium and Mood Stabilizers * The Problem with Bipolar Meds * Treating Mania * Treating Hypomania * Treating Bipolar Depression

For a more global look at managing bipolar, check out the other articles under Treatment (including supplements and talking therapy), as well as the articles in the Recovery section.

Revised July 4, 2016


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