多巴胺含量异常？精神分裂“新选择”UZEDY新鲜出炉！疗效如何？

The global population suffering from schizophrenia accounts for about 1%, and nearly 7 million people in my country have schizophrenia. As a classic old drug against schizophrenia, risperidone has firmly occupied the position of first-line medication due to its minimal extrapyramidal systemic reactions and excellent efficacy. So, what is the efficacy of its subcutaneous injection UZEDY? Let’s take a look!

Uncovering the "mystery" of schizophrenia

From the ancient methods of burning with iron tongs, tying up and whipping, and soaking in cold and boiling water, to the modern drug treatment, human beings have never given up the dream of curing schizophrenia. So is schizophrenia really that scary?

Schizophrenia is a chronic, progressive, and severely debilitating mental disorder that affects a person's way of thinking, feeling, and behavior. In severe cases, it is difficult to engage in normal social interactions. It is still the leading cause of mental disability.

The pathogenesis of schizophrenia is not very clear, but it is currently recognized in the world that the cause of schizophrenia is abnormal levels of dopamine, a neurotransmitter, in specific areas of the brain. Simply put, this is mainly reflected in two neural pathways: one pathway is from the midbrain to the prefrontal cortex. Reduced dopamine content reduces the function of this pathway, causing negative symptoms. Common negative symptoms include social withdrawal, apathy, sleep changes, etc.; the other pathway is from the midbrain to the limbic system. Excessive dopamine content makes this pathway hyperfunctional and causes positive symptoms. Common positive symptoms include hallucinations, confusion, and abnormal behavior.

The “new choice” for schizophrenia—what is UZEDY?

In April 2023, Teva Pharmaceuticals and MedinCell announced that the U.S. Food and Drug Administration had approved UZEDY [(Risperidone) extended-release injectable suspension] for the treatment of adult schizophrenia.

Risperidone is a potent dopamine receptor antagonist that can improve the positive symptoms of schizophrenia, and it causes less motor function suppression and catalepsy than classic antipsychotics. In addition, the antagonism of 5-HT and dopamine in the central system of this drug can reduce the occurrence of extrapyramidal side effects, so its therapeutic effect can be extended to the negative symptoms and affective symptoms of schizophrenia.

“New Choice” for Schizophrenia—How Effective is UZEDY?

In August 2015, "JAMA Psychiatry" published a pilot study aimed at comparing the clinical efficacy of long-acting injectable preparations of risperidone and oral preparations in the early stages of schizophrenia. The primary efficacy endpoint was psychosis exacerbation or recurrence.

The researchers recruited 83 patients who had either recently experienced a psychotic episode or had their first major psychotic episode within the past 2 years. In the end, only 57 patients completed the trial, and these patients were randomly divided into the experimental group and the control group at a ratio of 1:1. Among them, 30 patients were assigned to the experimental group and received injections of risperidone with an average dose of 26.3 mg/day; 27 patients were assigned to the control group and received oral risperidone with an average dose of 3.6 mg. The patients were followed up for 12 months, and the rate of mental illness exacerbation or recurrence was recorded.

In the control group, 12 of 14 relapses (86%) occurred within the first 6 months after randomization, while only 2 relapses occurred in the experimental group, occurring approximately 4 and 8 months after the start of treatment. The rate of psychosis exacerbation or relapse in the experimental group was significantly lower than that in the control group. Details are shown in Figure 1:

Figure 1: Rates of exacerbation or relapse of psychosis in the experimental and control groups

As time went on, the exacerbation or recurrence rate of psychosis in the experimental group was significantly lower than that in the control group, indicating that the risk of mental illness was significantly lower than in the control group.

To sum up, the long-acting injection preparation of risperidone is more effective in treating psychosis than the oral preparation, and can more effectively inhibit the exacerbation or recurrence of psychosis!

Global research and development of schizophrenia drugs

Currently, there are 539 drugs for schizophrenia, in addition to the marketed UZEDY, 395 are currently not in the research stage, 30 are in the preclinical stage, 12 are in the drug discovery stage, 4 are in the clinical application stage, 5 are in unknown clinical stages, and 3 are in early clinical phase 1. There are 39 kinds of drugs in clinical phase 1, 4 kinds in clinical phase 1/2, 34 kinds in clinical phase 2, 4 kinds in clinical phase 2/3, there are currently 23 kinds in clinical phase 3, and 3 kinds have been applied for marketing. I believe they will meet us in the near future. In addition, there are 56 kinds of drugs that have appeared in front of you. Today I will briefly introduce two kinds for you:

Figure 2: Global research and development map of schizophrenia drugs

Epipiprazole

On July 10, 2015, the U.S. FDA approved Brexpiprazole, a new molecular entity drug for schizophrenia and depression produced by Japan's Otsuka Company, with the trade name Rexulti.

Epipiprazole oral formulation is an atypical antipsychotic. According to the current specific mechanism of action, experts have analyzed that it may work by partially activating 5-HTIA receptors and D2 receptors and blocking 5-HT2A receptors. Epipiprazole can be used as an auxiliary drug for the treatment of adult patients with severe depression; it can also be used for the treatment of adult patients with schizophrenia.

iloperidone

On May 6, 2009, the US FDA approved the marketing of iloperidone (Fanapt) successfully developed by the US company VandaPharma. It is mainly used clinically to treat schizophrenia in adults.

Iloperidone is a dual antagonist of 5-HT2 and D2 and has a significant effect on both positive and negative symptoms of schizophrenia patients. Compared with current antipsychotic drugs, iloperidone does not induce diabetes in patients and has fewer extrapyramidal symptoms. However, iloperidone can increase the risk of death in patients with Alzheimer's disease, so it is contraindicated in patients with Alzheimer's disease.

"UZEDY exemplifies Teva's commitment to bringing innovative advances to patients, providing people living with schizophrenia an important new treatment option designed to address certain treatment challenges and potentially reduce the risk of relapse," said Richard Francis, president and CEO of Teva.

Teva President and CEO Richard Francis, picture from Google, deleted if infringement

References

[1]Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, Marder S, Nuechterlein KH. Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry. 2015 Aug;72(8):822-9. doi: 10.1001/jamapsychiatry.2015.0270. PMID: 26107752; PMCID: PMC5065351.

[2]Emsley R, Oosthuizen P, Koen L, Niehaus DJ, Medori R, Rabinowitz J. Oral versus injectable antipsychotic treatment in early psychosis: post hoc comparison of two studies. Clin Ther. 2008;30(12):2378–2386.

[3] Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic drugs for schizophrenia: a critical systematic review and meta-analysis of randomized long-term trials. Schizophr Res. 2011;127(1–3):83–92.