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Trimetazidine(?) for bipolar depression (2023study

Posted by PeterMartin on June 5, 2024, at 11:39:15

Came across this Dec 2023 study that sought to find drugs to repurpose for bipolar depression (something I suffer from greatly). The drug they found most likely to be effective is Trimetazidine, a drug for angina that was never approved for use the USA.

It's an old medication w/ a very good safety profile. It doesn't seem like it would be extremely difficult to pick up some from a "nootropic" type online vender. Any thoughts on potential benefits or pitfalls? Anyone ever heard of this medication?

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression

Objectives: The aim of this study was to repurpose a drug for the treatment of bipolar depression.

Methods: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats).

Results: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test.

Conclusion: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.



Trimetazidine (IUPAC: 1-(2,3,4-trimethoxybenzyl)piperazine) is a drug sold under many brand names for angina pectoris (chest pain associated with impaired blood flow to the heart).[1] Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and marketed by Laboratoires Servier (France). It is an anti-ischemic (antianginal) metabolic agent of the fatty acid oxidation inhibitor class, meaning that it improves the heart muscle's ability to use glucose as a fuel by inhibiting its use of fatty acid metabolism. It has become controversial for its use as a performance-enhancing drug, with several scandals involving its use erupting at successive Olympic games.

Medical uses
Trimetazidine is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for tinnitus and dizziness. It is taken twice a day. In 2012, the European Medicines Agency (EMA) finished a review of benefits and risks of trimetazidine and recommended restricting use of trimetazidine-containing medicines to just as an additional treatment of angina pectoris in cases of inadequate control by or intolerance to first-line antianginal therapies.[2]

Controlled studies in angina patients have shown that trimetazidine increases coronary flow reserve (thereby delaying the onset of ischemia associated with exercise), limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.[citation needed]

However, a 2020 placebo-controlled, randomized trial in over 6000 patients who had recently had a percutaneous coronary intervention or heart surgery found that adding timetazidine to typical anti-anginal therapies alone led to no significant difference in cardiac death, hospital admission for a cardiac event, recurrence or persistence of angina, or the need for repeat coronary angiography.[3] This study therefore calls into question the clinical utility of trimetazidine in the treatment of angina.

It improves left ventricular function in diabetic patients with coronary heart disease.[citation needed] Recently, it has been shown to be effective in patients with heart failure of different etiologies.[4][5]

As of 2023, it is in clinical trials to determine if it is effective in treating bipolar depression.[6]

Adverse effects
Trimetazidine has been treated as a drug with a high safety and tolerability profile.[29]

Information is scarce about trimetazidine's effect on mortality, cardiovascular events, or quality of life. Long-term, randomized, controlled trials comparing trimetazidine against standard antianginal agents, using clinically important outcomes would be justifiable.[29] Recently, an international multicentre retrospective cohort study has indeed shown that in patients with heart failure of different etiologies, the addition of trimetazidine on conventional optimal therapy can improve mortality and morbidity.[30]

The EMA recommends that doctors should no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo, or disturbances in vision.[2] The recent EMA evaluation also revealed rare cases (3.6/1 000 000 patient years) of parkinsonian (or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, restless leg syndrome, and other related movement disorders; most patients recovered within 4 months after treatment discontinuation, so doctors are advised not to prescribe the medicine either to patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome, or other related movement disorders, or to patients with severe renal impairment.[2]

Mechanism of action
The mechanism of action of trimetazidine involves its effect on cellular energy metabolism, specifically the metabolism of fatty acids and glucose.

One of the primary ways that cells generate energy is through the process of oxidation, where molecules such as fatty acids or glucose are broken down to produce ATP (adenosine triphosphate), the main energy currency of cells. In a healthy cell, both fatty acids and glucose can be oxidized to produce ATP.

However, in certain situations such as ischemia (reduced blood flow) or hypoxia (reduced oxygen supply), the cell's ability to generate energy becomes compromised. In these conditions, the cell may experience a shortage of oxygen, which is necessary for the complete oxidation of fatty acids. This can lead to a decrease in ATP production, affecting the cell's ability to maintain its normal functions.

Trimetazidine works by inhibiting a specific enzyme called long-chain 3-ketoacyl-CoA thiolase, which is involved in the beta-oxidation process of fatty acids. By blocking this enzyme, trimetazidine reduces the oxidation of fatty acids and promotes the oxidation of glucose instead. Glucose oxidation requires less oxygen consumption compared to the beta-oxidation of fatty acids.[31] Therefore, by enhancing glucose oxidation and reducing the reliance on fatty acid metabolism, trimetazidine helps to optimize cellular energy production in conditions where oxygen supply is limited.

By preserving energy metabolism and promoting glucose oxidation, trimetazidine prevents a decrease in intracellular ATP levels. This is important because ATP is essential for various cellular processes, including the functioning of ionic pumps and the maintenance of transmembrane sodium-potassium flow. By ensuring adequate ATP levels, trimetazidine helps to maintain cellular homeostasis, or the balance of different ions and molecules within the cell.[32]




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