A New Type of Antipsychotic

In a previous post, the six major groups of antipsychotics were identified. Only a few months ago, in December of 2012, researchers in China identified and synthesized yet another antipsychotic derivative. This chemical group called Tetrahydroprotoberberine (THPB) derivatives have long been known to antagonize dopamine receptors. Now, they can be called a type of antipsychotic and be synthesized at a larger scale.

The researchers working at the at the Shanghai Institute of Materia Medica have found an efficient method that can be used to create an integral intermediate that is involved in the complete synthesis of THPBs.  They eventually produced 31 specific THPB compounds, each containing different substituents on their carbon rings. All 31 were tested, resulting in the identification of compounds 18k and 18m as partial agonists of dopamine receptor D1, antagonists of D2, and agonists of serotonin receptor 5-HT(1A). These results suggest that the substances could reduce psychotic symptoms. When tested in animals, it was discovered that these two compounds do indeed work as antipsychotics.  The researchers were able to conclude that if the two substances are targeted to different neurotransmitter receptors in the brains of people suffering from psychotic disorders, the symptoms of psychosis can be treated. Clearly, this research may lead to the development of drugs that can fight conditions of the brain in novel ways.

By Mariel Hohmann

The Effect Antipsychotics Have on the Brain

When multiple genes and environmental factors are combined, one can be begin to suffer from psychosis. The current theory is that psychotic disorders are triggered by an abnormal increase in dopaminergic activity in the brain. Dopamine likely works on neural circuits that are involved in filtering the information that may be processed in the prefrontal cortex. If too much dopamine is active in the brain, this process may be affected. Changes in dopaminergic activity can negatively affect cognitive domains that concern the prefrontal cortex, like working memory, cognitive flexibility, attention, and interference control. Problems with each of these domains are present in people suffering from schizofrenia and other psychotic disorders.

Luckily, antipsychotics are capable of binding to many types of dopamine receptors (D1, D2, D3, and D4). Antipsychotic molecular structures allow these drugs to bind to the receptors more strongly than dopamine does.  However, they cannot activate the protein that causes a postsynaptic response, which is what is trying to be avoided. With the antipsychotic in the way, dopamine can no longer bind to the receptor and, therefore, cannot open the sodium ion channel. In this way, antipsychotics reduce dopaminergic activity, and therefore reduce the symptoms of psychosis.

Typical antipsychotics are mainly attracted to D2 receptors. By binding to D2, they help the patient with their psychosis, but also cause problems. This is because D2 receptors have been found on more than just the post-synaptic membrane. As a result, antipsychotics also reduce dopaminergic activity in other pathways that are not related to psychotic symptoms. Typical antipsychotics cause side effects for this reason. Atypical antipsychotics, on the other hand, do not bind as well with D2, but instead, are highly attracted to D3 and D4. These two types of dopamine receptors are only expressed on neurons of the limbic system and cerebral cortex. This means that atypical drugs almost exclusively affect the pathology of psychosis and, therefore, cause fewer side effects.

Most of the six chemical groups (discussed in this blog post) are known to bind to specific dopamine receptors. For example, the typical  phenothiazines and thioxanthenes are known to bind to D1 and D2 receptors. Diphenylbutylpiperidines, on the other hand, have a mysterious mechanism. Still, these derivatives definitely slow dopaminergic activity. Clozapine (a type of dibenzodiazepine) reduces dopaminergic activity without blockage, but antagonizes serotonin receptors 5-HT2A and 5-HT2C.

In order to reduce the symptoms of psychosis, dopaminergic activity in the brain must first be reduced. Because of their special structures, antipsychotics are capable of doing this.

By Mariel Hohmann

Concerta

CONCERTA® (methylphenidate HCl) Structural Formula Illustration

methyl α-phenyl-2-piperidineacetate hydrochloride

Concerta is a stimulant designed to treat people affected by ADHD but it can also be used for narcolepsy and clinical depression as an alternative to antidepressants. Specifically, it is a methylphenidate. It is a central nervous system (CNS) stimulant, so it works directly on the brain by reducing the reuptake of both dopamine and norepinephrine. It blocks the norepinephrine transporter (NET) and dopamine transporter (DAT) increasing the extracellular concentration of both neurotransmitters thus increasing focus.  Like most other ADHD drugs, it comes in the form of a sustained release pill. This type of methylphenidate would normally be white odorless, crystalline powder.

As mentioned before, Concerta is a extended release pill meant to be taken once a day. So how does it work? Unlike most pills of its kind that contain fillers to increase the break down time, it uses a three stage system. 22% of the drug is found in the outer coating of the pill and is, therefore, immediately released into the recipient’s system. Once the outer layer is gone, a tiny drill hole is uncovered at one end of the pill that the methylphenidate can be released through over time. Within the pill, there are three compartments. Two of these contain methylphenidate while the third contains a material that swells like a sponge as it becomes wet. The material slowly swells pushing the methylphenidate through the tiny drill hole.

It is important to keep in mind the side effects of Concerta before deciding whether or not it is the ADHD medication for you. These include:

  • Decreased appetite
  • Cry mouth
  • Trouble sleeping
  • Dizziness
  • Stomach ache
  • Increased sweating
  • Headache
  • Nausea
  • Anxiety
  • Weight loss
  • Irritability

As a methylphenidate, Concerta also increases attention and focus and therefore, it can be abused by students wishing to obtain higher grades. Taking this drug may lead to tolerance and dependence especially when taken unregulated/unsuscribed. Following a familiar pattern, using this drug unprescribed in order to improve studying abilities is not a good idea. However, for those who have ADHD, it is another option to consider especially with its unique sustained release feature.

Author: Maggie Martinez

Blog Feedback

We received some great feedback from some of the people involved in research we based a previous post on.
 “I like your concise and easy to read summary. I think my main comment is that our emphasis is slightly different. Overall, our systematic review was not specifically on the effect of atypical antipsychotics for the treatment of ADHD. It was focused primarily on the effect of atypical antipsychotics in the group of disorders called disruptive behaviour disorders which include conduct disorder, oppositional defiant disorder and disruptive behaviour not otherwise specified. However ADHD coexist in  5 out of the 8 studies we reviewed.  This idea was explored specifically in one of the article (Armenteros 2007) that looked at augmentation of treatment of ADHD with risperidone specifically on treatment of aggression in ADHD kids. I think that in the future, there may be potentially more studies looking at the use of atypical antipsychotics for ADHD as it is a novel area of research. I also read with interest an article from the Vancouver Star from Jan 2013 on your blog and that it was related to an article in the Journal of Canadian Psychiatry and it also seemed related to our systematic review. I will check it out further.” Jik Loy on behalf of Sally Merry, Karolina Stasiak and Sarah Elisabeth Hetrick
On another note, new post on Concerta coming soon!
Author:Maggie Martinez

Drug Shelf Life

Have you ever needed a medicine but only had expired pills? In this situation, some will throw out the old pills while others will take the medicine regardless. So the questions arise: How accurate is the expiration of drug? Is it unsafe to take a medication that is expired?

Expiration dates tell us until when a company can guarantee the effectiveness of drugs. Expiration dates have huge variations with some as short as 18 months. Some require refrigeration and some require specialized containers with desiccants, or a substance that has an affinity for water, to keep the product try and enhance stability. Expiration dates are important for the safety of the drug users, so it is, therefore, part of regulation. It is important to keep in mind that expiration dates are based on testing in previously unopened bottles under normal conditions. If a drug is moved to another container or is placed under extreme conditions, its stability is compromised and the expiration date is no longer reliable.

The U.S. Food and Drug Administration has established a number of required quality tests that any drug needs to pass. Drug expiration is dependent on stability tests. Once it is a known that a drug works effectively and consistently, it needs to be established how long this will continue. How long will it take for a drug to deteriorate? The first thing you need to know is how expiration dates are calculated. It is impractical to wait a few years to see the effect time has on a medication, so an alternative method is utilized. This alternative method is known as a stress test, or a degradation test. The specifics of a stress test varies for each individual case, but in general, stress tests includes checking the effect of temperature, oxidation, photolysis, and sometimes humidity. It also includes testing the susceptibility of a drug to hydrolysis across a wide range of pH’s. Stress testing is useful as it can not only determine an approximate time for a drug to degrade, but it also can help establish the degradation pathway. Therefore, it is known what exactly is happening to the drug over time under certain conditions. For liquid and injectable drugs, additional testing is required to determine bacterial purity and chemical stability.

So now we come to the question of the safety of expired drugs. Fortunately, there is currently no data that shows  harmful effects of expired drugs besides a discontinued drug (tetracyline) from the 1920’s. There are case occurrences, but these are quite rare. Also, stability testing requires that drugs should identify if the expired product will pose any safety risks. The effectiveness just decreases with time. However, the effectiveness is still quite high for a while after expiration typically.  The Shelf Life Extension Program (SLEP) has studied 122 different drugs and 88% were still effective at least 1 year after expiration. The average was a 66 month expiration extension. Therefore, if properly stored, it is safe to use drugs past expiration and the drug might still be very effective. So the next time you only have expired medication left, you know the information you need to make a decision to take it or not.

Author:Maggie Martinez

Strattera

Atomoxetine Synthesis

(-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride (AKA atomoxetine AKA Strattera) can be synthesized via the reactions shown above. The first step, a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine is not shown.

Strattera, otherwise known as atomoxetine, is a non-stimulant drug that can be used to treat ADHDSpecifically, it is a selective norepinephrine (noradrenaline) reuptake inhibitor. This type of drug is also used as an antidepressant in other forms. This means the drug works by affecting the nerve cells in the brain and inhibiting the reuse of specific neurotransmitters. Strattera focuses on the level of norepinephrine in the brain while its stimulant counterparts focus on the levels of that and dopamine. Its exact mechanism is currently unclear. It is the only non-stimulant ADHD drug sold in the U.S. and is approved for adults as well as children over 6 and teenagers. Like many ADHD drugs, it is in the form of a capsule to be taken with water. You can opt to take one pill or two evenly divided pills in a day.

As with all drugs, Strattera has a list of side effects:

  • Upset stomach
  • Decreased appetite
  • Nausea or vomiting
  • Dizziness
  • Tiredness
  • Mood swings
  • Chest pain
  • Shortness of breath
  • Constipation
  • Dry Mouth
  • Trouble sleeping
  • Menstrual cramps
  • Trouble passing urine
  • Sexual side effects

Now, with those side effects in mind, let’s discuss the overall pros and cons of Strattera. A big pro  is that research has found it to be safe and effective for long term use besides growth possibly being slightly stunted for children. As you may recall, in our previous posts, we have noted significant problems over the long term including addiction. Strattera is not a U.S. controlled drug because of this. If you are at risk for abuse, this might be a good option to consider. The lack of focus on dopamine is what allows this drug to be nonaddictive. Dopamine is involved in happiness or pleasure, so messing with dopamine levels may lead the body to crave a certain drug to be happy. This is why taking Ritalin or Adderall to concentrate is a BAD IDEA unless of course, you would like to be hooked and deal with the side effects for the remainder of your possibly shortened life. The downside of Strattera, on the other hand, as it works similarly to antidepressants, it can also cause an increase risk of suicide in the young.  It is also not quite as quick acting as a stimulant drug would be. It is significantly less efficient than some stimulant medications available such as methylphenidate (Ritalin). To give you an idea of its effecitveness, in a 2008 study published in the Journal of Attention Disorders, for almost 400 adults who took Strattera for four years, the general trend was over a 30% reduction of ADHD symptoms with no unexpected side effects. Although these statistics are not quite as impressive as those of some other alternative drugs would be, this is still pretty significant and the benefits may outweigh the costs depending on the situation. Once again, with the facts presented, I leave it up to you to form your own personal opinion on the drug.

Author: Maggie Martinez

Antidepressants and Depression

Depression can be caused by events in one’s life, but also due to genetics and the functions of the person’s brain and body.  For example, the hippocampus, which is a small part of the brain that is vital for the storage of memories, appears to be smaller in people with a history of depression than in those who have never been depressed.  The smaller hippocampus allows for fewer serotonin receptors, which contain the chemical that allows communication between the brain and body.  Scientists have also discovered that the stress hormone cortisol is produced at a higher rate in those who are depressed.

Researchers first have to understand depression before creating the antidepressants used today.  Antidepressants became quite common after they were first approved by the Food and Drug Administration.  In 1988, a year after the FDA approved Prozac, 2,469,000 prescriptions for it were dispensed in America.  Fourteen years later, that number had risen to 33,320,000.  Then, in 2008, antidepressants were the third-most-common prescription drug taken in America.  Prozac was such an effective drug because its goal was to increase serotonin levels in the brain, which depressed people would have less of.

ImageProzac is listed 3rd, in a rating of the top 10 antidepressants used today.

Image

Now are antidepressants and Prozac truly helpful, or are they just “placebos with side effects”?  In all tests performed, the antidepressants had better outcomes than that of the placebo drugs, but at what cost?  The difference was minute for certain tests including patients with a less specific disorder.

After many complications with antidepressants having the opposite effect of what they should, doctors came to a new realization: depression was nothing more than a chemical imbalance.  No smaller parts of the brain or anything of that matter.  This chemical imbalance led to a “flaw in love” as Andrew Solomon, a writer in this field, likes to call it.  The flaw in love leads to flaws in self-love, such as guilt, shame, or suicidal thoughts, or flaws in love for others, or even the desire for love.  This relates to blame, aggression, withdrawal, and dullness, which can all be seen in a depressed person in different moderation.

Scientists today are still trying to find the best drug to aid people with depression and get rid of those suicidal thoughts, aggression, or withdrawal.

Author: Julia Monaco

More ADHD drugs

Quillivant XR

Quillivant XR, also known as methylphenidate hydrochloride, is a liquid form of ADHD medication recently developed by a private company known as NextWave Pharmaceuticals. It is the first of its kind in the world of ADHD drugs and hits the stores this January 2013. So what’s the difference with this new medication? What should you consider about it? Quillivant, like many ADHD medications,  is a stimulant containing methylphenidate. If you can recall, this is also what the drug Ritalin consists of. Methylphenidate can also refer to drugs like Concerta and  Methylin.

Stick structure of Methylphenidate

 

Like all drugs, Quillvant XR has its fair shareof side effects. These include:

  • Decreased appetite
  • Weight loss
  • Nausea
  • Stomach pain
  • Dry mouth
  • Vomiting
  • Trouble sleeping
  • Anxiety
  • Nervousness
  • Restlessness
  • Mood swings
  • Agitation
  • Irritability
  • Dizziness
  • Shaking (tremor)
  • Blurred vision
  • Increased blood pressure
  • Fast heart beat
  • Increased sweating
  • Fever

Also, like Ritalin, Quillvant XR is likely to be addictive and likely to be abused. This is a bad combination, so make sure to only use the drug if you need it. Talk to your doctor before taking the medication as always.

Typically liquid medications have a faster rate of absorption than pill medication. The issue that has been faced in the past with creating a liquid medication for something like ADHD is making it an extended release medication, so the drug works throughout the entire day for the user. Extended release liquid medication can be obtained by coating very fine drug particles that are typically of the micrometer size. LiquiXR is one drug known to use this method.

In testing, Quillivant XR was shown to have the proven efficacy, or ability to produce a desired result, of methylphenidate for 12 hours after dosing.  This was determined in a “randomized, double-blind, placebo-controlled, crossover, multicenter, laboratory classroom study of 45 children with ADHD. There was an open-label dose optimization period (four to six weeks) with an initial 20mg dose of Quillivant XR once daily in the morning. The dose was titrated weekly in 10 or 20mg increments until an optimal dose or maximum dose of 60mg per day was reached. Patients then entered a two-week double-blind, crossover treatment of the individually optimized dose of Quillivant XR or placebo.”  Quillivant XR was shown to significantly improve ADHD symptoms compared to the placebo used according to the SKAMP (Swanson, Kotkin, Agler, M-Flynn and Pelham) rating scale. In a secondary analysis, significant improvement was seen at every point measured from 45 minutes to 12 hours proving its ability as an extended release medication.

So how does a liquid version of Quillivant differ from its pill counterparts? The liquid medication fixes a problem that has long existed in the ADHD medication industry. There are many of us who have some difficulties swallowing pills, so this new Quillivant XR allows for an easy way to take ADHD medication. Aside from just preference among users, generally liquid medications have been seen to have a shorter shelf life. This is not yet certain of Quillivant XR as its shelf life is not yet available, but it is likely to follow the trend.

With all this in mind, there is no clear winner in the choice of pill vs. liquid. It is simply a matter of preference it seems. So the choice is up to you: pill or liquid?

 

Author: Maggie Martinez

 

Narcotics as Antidepressants?

Ketamine, also known as “Special K,” is a powerful dissociative hallucinogen which causes a user to feel completely detached from the world, their perceptions of sight and sound completely distorted by the drug.  It has been reported by drug users that it provides an almost instantaneous relief from depression, and these reports have been followed up by scientists doing real research.  This research has shown that the claims of ketamine’s almost miraculous antidepressant properties are indeed true, and that this “club drug” may be the solution to depression.

For the past 40 years, since the discovery of Prozac, the treatment of depression has not changed, and for many people the traditional drugs do not work.  Most traditional antidepressants work by decreasing the reabsorption of seratonin and allowing normal cellular communication to happen.  This can take weeks for the process to start in a way that is observable, and it doesn’t always work.  Ketamine allows the brain to quickly regrow neural connections, but it unfortunately also causes hallucinations so it should not be used as a common drug.

The structure of a drug is a hugely important part of how the drug affects the brain, so by observing the structure of ketamine scientists can develop other drugs that treat depression in the same way that ketamine does but without the side effect of hallucinations.

ketamine 1               atorvastatin

                   Ketamine                                                                                  Lipitor

Ketamine is absorbed extremely quickly into tissues such as brain tissue when put in the body parenterally (through a means that is not the mouth), which is what causes the very fast relief from depression.  The fact that ketamine is a relatively small molecule compared with many drugs such as Lipitor, Prograf, and amoxicillin would account for the quick absorption.  A drug that works in a way similar to ketamine would have to be of a similar size, and with a similar structure to allow it to work with the same chemicals in the brain that ketamine does.

http://www.ncbi.nlm.nih.gov/pubmed/20724638

http://www.foxnews.com/health/2012/01/31/ketamine-miracle-antidepressant/

http://www.policymic.com/articles/15943/special-k-drug-psychedelic-is-powerful-anti-depressant-says-new-study

http://www.sciencemag.org/content/338/6103/68

http://mtnviewfarm.net/drugs-poisons-0913.html 

http://www.theatlantic.com/health/archive/2012/10/the-biggest-breakthrough-in-depression-research-in-50-years-is-ketamine/263400/

http://psycnet.apa.org/psycinfo/2000-07308-010

http://www.mayoclinic.com/health/antidepressants/MM00660

http://oceanexplorer.noaa.gov/explorations/12fire/background/pharmacology/pharmacology.html