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."

AMPA-kines
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.

Conclusion:
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).