Depression affects over 120 million people worldwide, carrying a heavy burden of disability, mortality, and cost.
While medications like SSRIs have provided relief for many, most patients fail to achieve full remission.
After 30 years with few advances in pharmaceutical options, it may be time to rethink our approach to treating depression.
Exciting new research suggests that directly boosting serotonin synthesis in the brain by targeting the enzyme tryptophan hydroxylase-2 (TPH2) could lead to more effective antidepressants with fewer side effects.
Key Facts:
- Depression is a serious global health concern affecting over 120 million people worldwide. It carries high costs in terms of disability, mortality, and healthcare spending.
- Current antidepressants like SSRIs increase serotonin indirectly by blocking reuptake, but 60-70% of patients fail to achieve remission with initial treatment.
- No major advances in pharmaceutical management of depression have occurred in the past 30 years.
- TPH2 is an enzyme expressed exclusively in the brain that catalyzes the rate-limiting step in serotonin synthesis.
- Several mutations in TPH2 have been linked to depression susceptibility, highlighting its central role.
- Directly activating TPH2 could boost serotonin levels in the brain specifically, leading to more targeted antidepressants.
Source: J Psychopharmacol.
The Heavy Burden of Depression
Depression is a common and serious medical illness with wide-ranging symptoms including persistent sadness, lack of energy, feelings of guilt, and poor concentration.
Over 121 million people worldwide suffer from depression, including around 16 million American adults each year.
In addition to the emotional suffering and disability caused by depression, it also increases risk of mortality from suicide as well as medical conditions like heart disease and diabetes.
When depression accompanies other chronic illnesses, it tends to worsen their progression and outcome.
All in all, the economic burden of depression is staggering, estimated around $80-100 billion per year in the U.S. alone from medical costs, lost productivity, premature mortality, and other factors.
With depression being so widespread and impactful, safe and effective treatments are desperately needed.
While medications and psychotherapy help many patients, there is still substantial room for improvement.
The Serotonin Hypothesis: A Flawed Foundation?
The prevailing hypothesis guiding antidepressant development over the past 50 years has been the “serotonin hypothesis”.
This theory proposes that depression results primarily from low levels of the neurotransmitter serotonin in the brain.
Serotonin regulates mood, emotion, appetite, sleep, cognition, and more.
Back in the 1970s, scientists found that depressed patients tended to have lower serotonin metabolite levels, leading to the theory that boosting serotonin could improve symptoms.
Current antidepressants like SSRIs are based on this hypothesis.
They work by blocking reuptake of serotonin that has been released, leaving more available in the synaptic cleft between neurons.
However, the serotonin theory is likely an oversimplification, since depression involves many neurotransmitters and brain circuits.
While SSRIs can be effective, they have significant limitations:
- They take weeks to months to take full effect
- Initial treatment only helps 60-70% of patients reach remission
- Side effects like nausea, fatigue, sexual dysfunction, and weight gain often lead to non-compliance
- Few options exist when SSRI treatment fails initially
After 30 years with no major advances in pharmaceutical options, it is becoming clear that new approaches to treating depression are desperately needed.
One promising strategy is to focus further upstream – directly boosting serotonin synthesis itself.
TPH2: A Key Enzyme for Brain Serotonin Production
Serotonin synthesis starts with the amino acid tryptophan, obtained through the diet.
An enzyme called tryptophan hydroxylase (TPH) catalyzes the first and rate-limiting step of adding a hydroxyl group, producing 5-hydroxytryptophan.
For many years it was thought there was just one TPH enzyme responsible for all serotonin production in the body and brain.
But around 2003, researchers discovered a second TPH gene (TPH2) that encodes a new isoform of the enzyme.
It turns out this TPH2 enzyme is expressed exclusively in the brain, concentrated in regions like the raphe nuclei that have lots of serotonergic neurons.
In contrast, the originally known TPH1 is abundant in the gut and peripheral tissues but low in the brain.
This discovery revealed that TPH2 is the main enzyme responsible for serotonin synthesis in the central nervous system.
TPH1 and TPH2 share 71% sequence identity, but differ in their regulatory domains – the region that controls enzyme activity.
While the structure and regulation of TPH2 remain poorly understood, its brain-specific expression makes it an exciting potential target for antidepressant drugs.
TPH2 Defects Implicated in Depression
Further evidence for TPH2’s central role in depression comes from studies on genetic mutations.
Over 300 single nucleotide polymorphisms in the human TPH2 gene have been identified.
Some specific TPH2 mutations have been associated with increased risk and severity of major depression. For example:
- R441H: Linked to early-onset depression and suicidality. Causes decreased TPH2 stability.
- P206S: Associated with major depression and bipolar disorder. Reduces thermal stability.
- S41Y: Identified in patients with bipolar and peripartum depression. Impairs serotonin production.
The effects of these mutations on TPH2 folding and activity demonstrate that defects in this enzyme can contribute to depression’s neurobiology.
Targeting TPH2 to Boost Brain Serotonin
Since TPH2 controls serotonin synthesis specifically in the brain, activating this enzyme could increase serotonin in relevant areas like the raphe nuclei selectively, avoiding peripheral side effects.
Considering the evidence linking TPH2 dysfunction to depression susceptibility, a subset of patients may particularly benefit from treatments aimed at enhancing their deficient TPH2 activity.
Possible approaches for harnessing TPH2 therapeutically include:
- Transcriptional activation to increase TPH2 expression. Issues with specificity.
- Gene therapy to overexpress TPH2 in certain regions. Technically challenging.
- Increase tryptophan/BH4 levels. Lacks regional specificity, affects TPH1.
- Develop small molecule activators that bind TPH2 selectively. Most promising option.
Small molecule compounds targeted to TPH2’s unique regulatory domains could enhance catalytic activity.
This novel strategy would boost serotonin neurotransmission specifically in circuits relevant to depression.
Future antidepressant development should consider moving beyond indirect effects on reuptake/degradation and towards directly stimulating serotonin synthesis itself via TPH2 activation in the brain.
This personalized approach based on neurochemistry could make treatment faster and more effective for many patients.
Challenges and Limitations with TPH2 Targeting
Despite its potential promise, this novel therapeutic strategy does come with some potential limitations and challenges:
- Little is currently known about TPH2’s structure and physiological regulation. Considerably more research is needed to design targeted drug compounds.
- Even if TPH2 is selectively activated, increasing serotonin neurotransmission can still cause side effects like nausea and insomnia.
- Other neurotransmitters like dopamine and glutamate are also involved in depression – serotonin is not the full story. Multifactorial treatment will still be needed.
- It is challenging to develop drugs that enhance enzyme activity rather than inhibit it like most conventional pharmaceuticals.
- Individual genetic testing would help personalize treatment, but this poses cost/access barriers currently.
- Depending solely on manipulating neurochemistry likely won’t address root psychological or environmental factors underlying depression. Holistic care is ideal.
In Summary: TPH2’s Potential for Serotonin Boost
In conclusion, directly enhancing brain serotonin synthesis by pharmacologically activating TPH2 represents an exciting new avenue for future antidepressant development.
This personalized, neurobiology-based approach could lead to faster-acting treatments with improved efficacy and fewer peripheral side effects.
However, considerable research is still needed to better understand TPH2 structure/function and design optimally targeted drug compounds.
TPH2-focused treatment would complement, not replace, existing options.
Holistic, multifactorial care integrating pharmacological, psychotherapeutic, and lifestyle approaches will remain the ideal standard.
But given the pressing need for better antidepressant medications, the time is right to start rethinking therapeutic strategies.
Boosting brain serotonin production specifically by targeting TPH2 holds substantial promise as one piece of that puzzle.
Though not a total solution on its own, selectively activating TPH2 could open the door to better outcomes for many suffering from depression.
References
- Study: Boosting serotonin in the brain: is it time to revamp the treatment of depression?
- Authors: Mariana P Torrente et al. (2012)
