Thursday, January 28, 2010

Does Schizophrenia Need to Be Treated?

The short answer is "Yes."

However, the dogma about the illness is one of chronicity, that is, schizophrenia is an illness of unremitting symptoms even with the best of treatments.

Is this depiction accurate?

Not entirely, according to Harrow et. al, who set out to answer this question (and many more) in the Schizophrenia Bulletin article "Do Patients with Schizophrenia Ever Show Periods of Recovery? A 15-year Multifollow-Up Study."

The authors wanted to answer 4 questions:
1. Do some or even a large percentage of patients with schizophrenia show periods of recovery? If so, what percentage?
2. Do patients with schizophreniform disorders show more favorable courses and outcomes than patients with schizophrenia? (Yes)
3. Is schizophrenia associated with slower recovery than other psychotic disorders? (Yes)
4. Is psychosis in nonschizophrenia patients a risk factor for subsequent poor outcome? (Maybe)
Since the focus of this post is on the answer to that first question, I've provided the answers to the other questions for brevity (the article is available for free).

Methodology and Study Outcomes:
The study consisted of 274 DSM-III diagnosed patients (64 of whom had schizophrenia) who were studied at 5 different intervals over 15 years. The total diagnostic breakdown and numbers of patients within each diagnosis assessed during each follow-up period are listed below:

Patients were assessed at 2 years, 4.5 years, 7.5 years, 10 years, and 15 years post-initial hospitalization. 

Other schizophrenia patient demographics are listed below:
Recovery was defined rather strictly:
1. the absence of major symptoms throughout the follow-up year (i.e., absence of psychotic activity and absence of negative symptoms).
2. adequate psychosocial functioning, including instrumental (or paid) work half-time or more during the follow-up year.
3. the absence of a very poor social activity level.
4. no psychiatric rehospitalizations during the follow-up year.
The data provided include, "(a) percentage of patients with schizophrenia in recovery at any follow-up year and (b) the cumulative percentage of schizophrenia patients who, over 15 years, ever show the potential for an interval or period of recovery." In other words,the number of patients with schizophrenia who had at least one interval of recovery during the 15 year period.

Here are the percentages of patients that were in recovery during each follow-up interval for each diagnostic group:
On average, during any given follow-up period, approximately 19-22% of schizophrenia patients (out of 64 total) were in remission. All patients groups had their lowest period of recovery during the first two years after hospitalization. The schizophrenia group had the lowest frequency of patient recovery during all follow-up periods.

Here are the cumulative percentages of the patients that had at least one interval of recovery during the entire study period:
As time progressed, the number of patients who experienced at least 1 interval of recovery in each diagnostic group increased. Again, the schizophrenia group had the lowest cumulative number of patients who achieve recovery; 3 out of every 5 schizophrenia patients did not achieve remission.

Here is where it gets interesting:
The majority of the schizophrenia patients, who had at least one interval of recovery, were not being treated with any medications. In the authors' words, "very poor outcome patients with schizophrenia are more likely to be on antipsychotic medications."

One can generate many different hypotheses based on this result. For example, you could argue that psychotropic medications in general, and antipsychotic medications specifically, are dangerous drugs that cause more harm than good.

That's just how two individuals chose to spin this result:
Indeed, these findings indicate that not receiving treatment works better than pharmaceutical intervention. Similarly, University of Illinois researchers recently found that only 5 percent of medicated schizophrenia patients recover, but 40 percent of non-medicated patients recover (Harrow, Grossman, Jobe, and Herbener 2005; also see Harrow and Jobe 2007). In other words, schizophrenia patients are eight times more likely to recover if they are not on medications!(1)
Quick! Somebody notify the APA! We need to start revising all those treatment algorithms, STAT!.

Unfortunately, the authors of that piece, which appeared in the September/October 2008 edition of Skeptical Inquirer, are full of shit (excuse my French, but to call them liars would be considered libel).

Harrow and Thomas, with the same patient cohort, did another study: Factors Involved in Outcome and Recovery in Schizophrenia Patients Not on Antipsychotic Medications - A 15-Year Multifollow-Up Study.

One goal of this study was to examine the "clues on whether the better functioning of the subgroup of unmedicated patients with schizophrenia versus those on antipsychotics at the 15-year follow-up was a function of their current medication status" or "other long-term characteristics marked them off as different types of patients."

They answered this question by comparing the two groups on various premorbid and prognostic factors that were assessed near the beginning of the study.

 In the figure above, we see that unmedicated patients scored better on indices of "favorable prognosis." In the figure below, we also see that unmedicated patients had better scores on "premorbid achievement" measures as well. Keep in mind that these two factors (i.e., favorable prognosis and premorbid achievement) were assessed near the beginning of the study, and not afterward. This means that being on antipsychotics was not a major factor in patient outcomes, suggesting that the better overall recovery of the unmedicated patients was mainly due to long-term patient characteristics.
In the discussion section, the authors summarize their main findings:
"Looking at from a different viewpoint, the data suggests that schizophrenia patients with good prognostic features, with better premorbid developmental achievements and with more favorable personality characteristics are the subgroup more likely to stay off antipsychotics for a prolonged period."
What was identified is a small subset of patients who are able to experience episodes of recovery in the absence of antipsychotics. According to the authors, those patients "who go off antipsychotics are a different type of patient."

There are many things to keep in mind regarding these two research papers. First, the sample is rather small (64 cases of schizophrenia). Of those diagnosed, the majority never did achieved remission. At the end of the study, only 12/64 (19%) patients had been in remission the previous study year. Of those who did achieve remission, many eventually relapsed. And, overall, the schizophrenia patients had significantly poorer outcomes when compared to all other clinical groups...Oh screw it, who wants pie?

Harrow M, Grossman LS, Jobe TH, & Herbener ES (2005). Do patients with schizophrenia ever show periods of recovery? A 15-year multi-follow-up study. Schizophrenia bulletin, 31 (3), 723-34 PMID: 16020553

Harrow M, & Jobe TH (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. The Journal of nervous and mental disease, 195 (5), 406-14 PMID: 17502806

Wednesday, January 27, 2010

Now That's Change I Can Believe In!

In this week's issue of the Medical Letter (1), a brief review regarding medical marijuana is included, which concluded that,
"Medical marijuana may be effective for treatment of nausea, anorexia, pain and some other conditions, but published data supporting its efficacy for treating patients with intractable cancer pain are limited, dosage is not well standardized, and cannabis is often poorly tolerated, especially by older patients. " (Jan 25 issues, 2010)
This conclusion was based on a review of the three forms in which marijuana is usually consumed: botanical, oral synthetic, and oromucosal. As it relates to the botanical form (most popular among the 18-34 demographic), the Medical Letter stated that for nausea, pain, anorexia, asthma, glaucoma and spasticity,
"It appears to be modestly effective, depending on the dose, for some of these disorders, but well-controlled studies large enough to be convincing are lacking, and non-standardization of dosage makes the available data difficult to interpret." (my emphasis)
Let's forget about the controversy surrounding marijuana as a medicinal agent or as an illicit schedule I controlled substance (i.e., high abuse potential; no legitimate medical use). Just focus on the reason why, this drug, which is legal for medicinal use in 14 states, lacks "well-controlled studies large enough to be convincing" as a medicinal agent: the federal government has a monopoly on the supply of marijuana for large scale, FDA approved study:
"DEA's final ruling rejecting the application of UMass Amherst Professor Lyle Craker for a license to cultivate research marijuana for use by scientists in FDA-approved research. The ruling, which contradicts the recommendation of DEA Administrative Law Judge Mary Ellen Bittner, maintains the unique government monopoly over the supply of marijuana available for FDA-approved research." (2)
Here's the back story: Professor Craker and the Multidisciplinary Association for Psychedelic Studies (MAPS) applied for that license 7 years ago. A DEA administrative judge, Ms. Ellen, recommended the license because "competition with NIDA would be in the public interest." Still the DEA rejected the application.

Marijuana must be a very, very dangerous drug because every other Schedule I drug (e.g., cocaine) can be produced by government-licensed independent laboratories.

The only organization that conducts research on marijuana in large scale studies is the National Institute on Drug Abuse (NIDA). (3) As the name of the organization betrays, their interest lie in showing how bad marijuana can be. Since the Institute on Drug Abuse is a federal organization, the research produced there is used to produce legislation. (4) This lack of competition is what prevents real discoveries and innovations, which can be a benefit to the public, from being made.

The individual responsible for making this final DEA ruling is Michele Leonhart, whom Obama just nominated as the new head of the DEA. (5) I vaguely remember Obama promising some sort of Change as it relates to marijuana policy (i.e., no more raids). (6) However, raids on marijuana clinics still continued. In response to this apparent hypocrisy, Mr. Obama's White House said that,
"It expects those kinds of raids to end once Mr. Obama nominates someone to take charge of DEA, which is still run by Bush administration holdovers."
Mr. Leonhart is one of those Bush holdovers. Now that's Change!

Medical Letter, Inc. (2010). Medical Marijuana The Medical Letter, 52 (1330)

Friday, January 22, 2010

Schizophrenia Treatment: The Future

A reader request:
"I know you wrote that you're frustrated with reading clinical drug research but I was wondering if you could dedicate a post to explaining the barrier of entry for new antipsychotics that are *different* from the "new" antipsychotics. Also, I do not understand why you've stated the old antipsychotics are better (for whatever reasons) than the new antipsychotics. My husband has been on Risperdal for years and it works. I'm vigilant about exercise and diet so as to try to curb the potential diabetes side-effect. The fear on both our parts of psychotic episodes and the potential destruction that one could cause, is far outweighed by the benefits of risperidone. That is our choice, but I'm hopeful breakthroughs will occur in drug research that improve beyond the current "new" drugs that are simply more of the same.
I love your blog and plan to visit frequently."
I cannot say that there is just one "barrier of entry" for new drugs to treat psychosis. Many new chemicals go through a very lengthy developmental process that takes years of preparation before testing human subjects is possible. Only a minority of drugs make it that far, and an even smaller percentage actually make it to market. As I do not work in this particular field, I cannot comment beyond this.

Both the first and second generation antipsychotics are thought to treat psychosis through blockade of D2 dopamine receptors. This is know as the dopamine hypothesis of schizophrenia.

The third wave of antipsychotics that are currently under development are driven by the glutamate hypothesis of schizophrenia. In order to explain how these newer agents might work, I first need to give an overview of the glutamate system.

Organization of the Glutamatergic System: (Very BORING, but necessary to understand how these compounds work)

Glutamate is the primary excitatory neurotransmitter of the nervous system. It is composed of both metabotropic and  ionotropic receptors, the latter of which produce fast postsynaptic reactions. Because glutamate neurons are present throughout the brain (as opposed to specific, concentrated nuclei such as the median raphe and substantia nigra), its role in specific behaviors and other brain functions is difficult to determine. For sure, however, its major functions discovered so far include synaptic plasticity, and learning/new memory (especially long-term potentiation).

Glutamate Synthesis, Release, and Inactivation:
Glutamate can be synthesized by many different chemical processes. It is primarily made by the breakdown of glucose. The primary precursor to glutamate is known as glutamine (which is located in glial cells as well as glutamate neurons), which is converted into glutamate via an enzyme called glutaminase (located in glutamate neurons). The process works like this: after a neuron releases glutamate, in will be transported back either into the nerve terminal or into glial cells (astrocytes in this case) and is then converted into glutamine by the enzyme glutamine synthetase. Glutamaine can be later released again by astrocytes and taken up by neurons that converted it back into glutamate by the enzyme glutaminase.

Ionotropic Glutamate Receptors:

There are three subtypes of glutamate ionotropic receptors. The three receptors are AMPA, Kainate, and NMDA (see the image above). Most fast excitatory responses to glutamate are mediated by activation of the AMPA receptor (even though the NMDA receptors gets all the press these days).

For both the AMPA and kainate receptors, the effect of depolarization is mainly caused by the influx of sodium (Na+) ions into the cell. NMDA activation is very different. These receptors allow sodium AND calcium (Ca++) into the cell. Calcium is responsible for activation of various second messenger systems.

Similar to the nicotinic receptor described in this post, recall that the complete receptor contains five separate subunits that come together to form the receptor channel. The other feature that distinguishes the NMDA receptor from the AMPA and kainate receptors is that it requires TWO different neurotransmitters to cause depolarization. Glutamate is the first neurotransmitter required. The other neurotransmitter is the amino acid glycine (see below).

If glycine is not binding to its specific site along with glutamate, the receptor channel remains closed. Another amino acid, d-serine, can also bind to this site in place of glycine. Glycine and d-serine are considered co-agonists. There are two additional binding sites on the NMDA receptor that affects its function. One site is within the cell that binds to magnesium (Mg++) ions. The magnesium ions block the flow of sodium and calcium until it is released from the receptor. Here is where it gets complicated: the presence of both glutamate and glycine at their respective sites is not enough to release the magnesium ion from within the cell. The cell must be depolarized first by either the AMPA or kainate receptors, in addition to glutamate and glycine latching onto their NMDA receptors, which then frees the magnesium ion from within the cell allowing sodium and calcium to flow inside, thereby activating a second messenger system (phew!).

You'll also notice from the above image that there is a site for the illicit drug phencyclidine (PCP) and also ketamine (AKA special K). Both PCP and ketamine, when binding to their receptor site, act as an antagonist. As it turns out, the behavioral effects of both of these drugs produce a syndrome very similar to schizophrenia, which is why the NMDA receptor is a new target for treatment in schizophrenia.

Metabotropic Glutamate Receptors:
In all, there are eight metabotropic glutamate receptors. They have the designations of mGluR1-mGluR8 (metabotropic Glutamate Receptor #). Similar to other metabotropic receptors, some are excitatory while others are inhibitory. Some are also located on neuronal terminals, where they act as presynaptic autoreceptors that inhibit glutamate release.

Third Generation Antipsychotics:
Most of what you are about to read is from Essential Pharmacology by Stephen Stahl (1). There will not be the usual links to research studies for two reasons: I am too lazy to look them up, and Stephen Stahl doesn't cite shit (thus, making his opinions suspect).

Glutamate Antagonist and Agonist
Currently, there is a split in the field as to whether glutamate agonists or antagonists will be effective treatments. Some feel that excessive glutamate activity, which leads to excitotoxicity, occurs at the beginning of schizophrenia, thus making an antagonist a reasonable choice for treatment (by preventing cell death). However, if you recall from the above section, certain drugs that are glutamate antagonists (e.g., PCP) lead to a syndrome very similar to schizophrenia. Finding a drug that is "just right" will be difficult (memantine is a current candidate). Also proposed are drugs that stimulate the glutamate autoreceptors (see section below), which have the benefit of not causing psychosis. Lamotrigine has been proposed as a possible treatment option.

Others theorize that the glutamate system is hypofunctional and needs a little boost (the theory being that if glutamate blockade leads to psychotic symptoms, then reactivation will treat the illness). One class of drugs being researched to achieve this goal is glycine agonists. If you recall, glycine is a co-agonist that is integral for the depolarization of the NMDA cell. The amino acids which bind to this receptor site (i.e., glycine, d-serine, & d-cycloserine) all "have been tested in schizophrenia, with evidence that they can reduce negative and/or cognitive symptoms" (pg. 441).

GlyT1 inhibitors
This is a class of drugs that inhibit the reuptake of glycine into glial cells. The theory is that glycine levels in the brain are lower than normal. In this sense, they would work like SSRI antidepressants and increase the amount of glycine available. According to Stahl, "several GlyT1 inhibitors are now in testing" and have been "shown to improve negative, cognitive, and depressive symptoms, including symptoms such as alogia and blunted affect" (pg. 442). Possible agents include: sarcosine, SSR 504734, SSR 241586, JNJ17305600, and Org25935.

mGluR2/3 presynaptic agonist

These are the autoreceptors that I mentioned earlier. Current compounds include LY404039, LY35470, LY379268, and MSG0028. LY404039 has been tested through its prodrug version (allows for better absorption) LY2140023, which is eventually converted into LY404039. It has demonstrated "significant improvement of positive and negative symptoms of schizophrenia compared to placebo" possibly making it the "first example of an antipsychotic agent that does not directly block dopamine 2 receptors." These results should be viewed with caution (2). The Last Psychiatrist reviewed this study briefly:

"One side effect the authors did not discuss is the 4% rate of increased CPK.  CPK increases from antipsychotics indicate that excess muscle rigidity is causing muscle breakdown; muscle proteins then clog up your kidneys, leading to death, a disorder called, neuroleptic malignant syndrome (NMS).  In this study, placebo and Zyprexa did not cause increased CPK."

Recall that AMPA (or kainate) activation is required for the NMDA receptor to depolarize. This class of compound focuses on increasing activity at the AMPA receptor. One drug that has been tested, CX 516, produced results that have been characterized as "disappointing." Still, other similar compounds are being developed: CX 546, CX619/Org 24448, Org 25573, Org 24292, Org 25501, and LY 293558.

Other Compounds
Many other compounds are also being tested, which have nothing to do with glutamate. These include: 5HT2A antagonist/agonist, 5HT1A/2C/6/7 agonist/antagonists, D3 antagonists, D1 agonists, nicotinic agonists, muscarinic agonists, cannabinoid antagonits, and many, mamy more.

Glutamate is currently the neurotransmitter du jour. Any novel antipsychotic that hits the market will likely manipulate this particular system. If you trust Stahl (which I don't) there is a lot of promise here. My opinion is that everything is still in the gestational phase, and a major break through could happen or it could not. Moreover, I believe that it is unlikely that any one drug alone will treat all the symptom domains of schizophrenia. More likely, a polypharmacoligic approach will be needed. However, side-effects are always additive, so finding the right combination of drugs will be difficult. But hopefully, with the advent of new classes of drugs, that combination will be more effective than currently available treatments.

P.S. I do not specifically recall stating that first generation antipsychotics are "better" than second generation antipsychotics. Both appear to be equal in efficacy. Where they differ is side-effect profile (e.g., tardive dyskinesia versus metabolic syndrome).

Friday, January 8, 2010

Great Acts of Stupidity or How Science Shouldn't Work

Has anyone read the book Freakonomics? I have. And by "have," I mean that I read the first page of the table of contents (1). What I learned from that brief, yet informative passage is that "conventional wisdom is so often wrong."

Here's an example. "Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder" (2).

For reasons of brevity, articles are worded so that certain assumptions are implied (implicit), while the main aim of the article can be stated explicitly.

What is the implicit assumption in this introduction?

It's this: Valproate (Depakote) and lithium are reasonably effective maintenance therapies. How do we know this? Because both drugs are recommended as monotherapy for the prevention of relapse in bipolar disorder.

Here is where it gets interesting (or pathetically sad). Lithium has over four decades of research supporting its efficacy. If we define a mood stabilizer as a drug that treats acute mania, acute depression, and prevents relapse into either mood episode, then lithium is the only drug on the market that meets those criteria (3). Valproate, on the other hand, has evidence to support its efficacy as an anti-manic agent. It meets only 1 out 3 criteria for a mood stabilizer.

"Then why is it recommended as a maintenance treatment?" Because of this study (4), which found that "divalproex...did not differ significantly from the placebo group in time to any mood episode."

If you are exceedingly sharp, you'll notice that it's a negative study. Yet valproate has managed to become a recommended monotherapy. To read more about this, check out this post (5).

This article, released online ahead of print, is known as the BALANCE study. (BALANCE is a backronym that stands for Bipolar Affective disorder Lithium/ANticonvulsant Evaluation). Here is the saddest fact of this study: Most of the mental effort that when into it was for creating the backronym. It goes down hill after that.

Here are the results: "For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy."

It other words, lithium monotherapy or lithium with valproate adjunctive therapy is more effective at preventing relapse than valproate alone. The difference between lithium and the combination treatment was not statistically significant.

Here is where it gets really sad (6): "Welcome back lithium. After losing its luster because of concerns over potentially serious adverse effects, this drug is drawing increasing respect...This study, along with other recent research, goes a long way toward putting lithium back on top as the preferred treatment for bipolar disorder, said lead study author John R. Geddes, MD...We’ve got more evidence purporting the lithium efficacy, safety, and its antisuicidal effects than we’ve ever had before," Dr. Geddes told Medscape Psychiatry. "So don’t throw lithium away; it’s a highly effective treatment, and if people can tolerate it, then it’s worth trying."

"don't throw lithium away!?" Exactly, what study suggested that? Some of you might be thinking that atypicals have replaced lithium since they too are effective as anti-manic and maintenance treatments, but lithium's efficacy was compared to valproate, not an atypical.

In other words, lithium was more effective than a drug that is no more effective than placebo. Why is this a major finding? Why was this study done?

"Although the study could not confirm a benefit of the valproate-lithium combination therapy over lithium alone, its findings should challenge current clinical guidelines that recommend valproate monotherapy as a first-line option for long-term treatment of bipolar disorder."

There is one study, ONE! on maintenance treatment. It's NEGATIVE! That alone should have prevented valproate from becoming a first-line option.

Here is a special kind of stupid: "In an accompanying editorial (7), Rasmus W. Licht, MD, Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark, praised the BALANCE study, describing it as 'outstanding work' and 'an impressive example of international collaboration.'

He said that even without a placebo group*, the study 'confirms the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.'

On the basis of the study’s results, 'the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment."

Make sure you read the above carefully. I highlighted the parts that celebrate acts of stupidity. This "outstanding work" took an "international collaboration" to "confirm the long-term efficacy of lithium," which "rightly challenge" clinical guidelines.

Lithium has been the most empirically supported bipolar drug to date. It's the only drug that meets all three defining criteria for a mood stabilizer. Valproate has proven efficacy as an anti-manic only. This study, along with the accompanying editorial, and subsequent press releases should not exist. This is just plain fucking stupid!

A few years ago, articles, based on data that has been around for 20 years, stated that that antidepressants were not as effective as initially stated.

Last year, research showed that vaccines didn't cause autism (even though no research showed that they did).

Now, research is showing us that lithium is effective (never disputed) when compared to a drug that was never shown to be effective.

This is science, telling us what we should already know!

* Just as a side note. The press releases for this study (8) are pushing the combination treatment as the preferred method of treatment. Here is my problem with that: I don't interpret these results as supporting polypharmacy as superior. Although there was a trend for the combination treatment over lithium alone, the difference was not statistically significant. Second, since valproate never had proven efficacy, I view it as an "active placebo," which could also explain the the better performance of the combination treatment. Sadly, the damage is done.

The BALANCE investigators and collaborators (2009). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial The Lancent : doi:10.1016/S0140-6736(09)61828-6

Tuesday, January 5, 2010