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Clozapine and Tyrosine: Combining Medications with supplements to treat ADHD

Posted Jan 22 2009 6:54pm

It is not uncommon to see non-stimulant medications or medications which typically serve other purposes to be used off-label for ADHD. One such drug of potential use for this disorder may be clozapine. While typically used as an antipsychotic medication, often for treatment of schizophrenia and related disorders, clozapine may be a useful alternative to stimulants for treating ADHD (especially for cases in which the ADHD is accompanied by schizophrenia-like symptoms. We will explore this at a later time). What is even more interesting is that when coupled to a specific natural supplement, the amino acid tyrosine, clozapine can gain new powers that increase its ADHD treatment potential.

One caveat here about clozapine: The medication clozapine has some drawbacks to it, including several potential hazardous side effects. Among these are increased seizure risks, and agranulocytosis (an immune disorder as a result of a reduced white blood cell count). As a result, frequent blood tests are often administered (often weekly, at least initially), for this type of medication.

Based on a study done by George Jaskiw and Colleagues and published in the journal of Neuroscience Letters in 2004, we see that the clozapine-tyrosine combo is one of intrigue and of possible use for treating ADHD. Keep in mind, that the study was done on rats, not humans. However, there is usually a good carryover and relevance of these studies, aside from dosing difference adjustments between the two species. I will summarize some of the key findings below:

  • While clozapine treatment results in dopamine release in the prefrontal cortex region of the brain, combining it with tyrosine leads to an even greater release of free dopamine in the middle part of this key brain region (individuals with ADHD typically have low levels of the free compound dopamine in this region of the brain, and many stimulant medications are thought to act by, in part, correcting some of this imbalance). Thus this treatment combination can act as a non-stimulant pair that can produce stimulant-like effects.

  • Boosting these dopamine levels appears to be limited to specific brain regions. This is also important, because in treating disorders such as ADHD, we often want to target specific spots in the brain as opposed to blasting the whole system with higher levels of a specific neuro-chemical. The tyrosine-clozapine treatment combination did not boost levels of the signaling agent dopamine in another region of the brain (also connected to ADHD) called the striatum. (The role of the striatum will be addressed a bit further down this post).

  • Dopamine can be manufactured from the amino acid Tyrosine, which is available via supplementation. However, this typically requires the action of an enzyme tyrosine hydroxylase to occur. Mutations to or deficiencies of this enzyme can seriously inhibit this key conversion and are thought to be tied to ADHD.

  • When combined with clozapine, tyrosine has been shown to boost dopamine levels in that ADHD-critical region of the brain, the Medial Prefrontal Cortex (MPFC). However, tyrosine by itself has trouble boosting dopamine in this key region. Hence pure supplementation with tyrosine appears to fall short, but when the MPFC region of the brain is “primed” with medication by pre-treating with clozapine (about 30 minutes prior to tyrosine treatment), then the desired dopamine boost in this brain region can occur.

  • Food apparently plays a role in the process, albeit a limited one. Lower levels of tyrosine were needed to achieve the desired dopamine-boosting effect when delivered on an empty stomach. One of the reasons mentioned in the article is the fact that the amino acid tyrosine “competes” with other similar amino acid nutrients to get into the brain (amino acids are simply the small units that are connected together to make proteins, acting as “building blocks”. There are 20 “main” ones that make up most proteins in nature, tyrosine being one of them). The presence of other food introduces more of these potential “competitor” amino acids for tyrosine to come into play, thereby competing with tyrosine for access and entry into the brain. This can inhibit the tyrosine to dopamine conversion and ultimately reduce dopamine levels in key brain regions.

  • In addition to this, evidence suggests that tyrosine supplementation follows an upside-down “U” curve. In other words, saturating with higher amounts of tyrosine beyond a certain dose may result in a decreased effect of the desired dopamine release used to treat ADHD symptoms. This is important to note, because, often if a medication or supplemental treatment is administered and is found to be ineffective, the natural inclination is to up the dosage and try again. Here we see that more is not always better, and that sometimes a reduced dosage leads to a more desired effect. As a result, I think we will begin to see a trend toward lower doses of tyrosine supplementation, especially as we begin to perfect the region-specific targeting for increasing or reducing certain “brain chemicals” such as dopamine.

  • It appears that in addition to clozapine, tyrosine can boost the effectiveness of other medications that could potentially be used to treat ADHD. Haloperidol, another anti-psychotic medication also used to treat schizophrenia, can also be combined with tyrosine to boost dopamine levels. However, unlike the clozapine-tyrosine combination, which limited the dopamine boost to the frontal region of the brain, the haloperidol-tyrosine combo appears to act as a dopamine booster to the striatum (located more in the midbrain, see the second point in this post regarding the striatum region). In other words, tyrosine can essentially act as an amplifier to different psychiatric medications that target completely different regions of the brain.

  • My last points here are not from the article, but needs to be mentioned, as it is relevant to the treatment of ADD and ADHD. We must remember that ADHD is not a one-size-fits-all type of disorder, it needs to be seen more as a spectrum, with a wide variety of symptoms and biological and chemical features. One of the main brain regions associated with ADHD is the prefrontal cortex, which is located in the front of the brain behind the forehead. This area typically has low levels of activity in most cases of ADHD, with regards to blood supply, glucose and the neurotransmitter dopamine. This ties in to some of the common symptoms seen in ADHD, namely the lack of impulse control and poor concentration. The clozapine-tyrosine combination appears to boost the dopamine levels of this part of the brain, thereby alleviating some of the negative ADHD symptoms.

  • Meanwhile, a second region of the brain, more towards the center is also connected to ADHD. This region, the striatum, is often connected to coordination and fine-motor skills. Low dopamine levels in this region can often impair fine-motor activities, in areas such as handwriting. Not surprisingly, a number of ADHD individuals have below average levels of dopamine in this region too, and many have poor handwriting as well.

  • This just goes to show that tyrosine supplementation may be beneficial as it can boost the desired effects of some non-traditional drugs to treat ADHD. As a result, I believe that we will begin to see more and more clinicians beginning to prescribe medication / supplement combinations instead of med/med or lone supplement treatments for ADHD.
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