Release date: 2014-08-14
On the Experience Project website, a young woman named "Blueberry Octopus" talked about her experience with antidepressants. She has been taking antidepressants for more than three years, mainly to suppress anxiety and panic. She initially took Paxil, a very popular selective serotonin reuptake inhibitors (SSRIs). However, she had to stop using it after one year because the side effects of the drug made her lose her sexual desire. So she switched to another anti-anxiety drug, Xanax, which, while regaining her sexual desire, did not help her symptoms. She then re-administered paroxetine and then tried citalopram (another SSRIs drug) and a serotonin and norepinephrine reuptake inhibitor (SNRIs). - Go to Pristiq. When posting on the website, she was taking Zoloft (another SSRIs drug) and bupropion (Wellbutrin, which is similar to SNRIs and can affect both dopamine and norepinephrine activity). Taking bupropion is a side effect of "neutralizing" Zoloft - loss of libido. “I didn’t feel any difference after taking bupropion, but I’m using the lowest dose now,†she wrote. “I’m going to see my psychiatrist next week, maybe he will give me more dose. Who knows?"
This prescription is a typical trial-and-error method. In addition to treating depression, this method is also used to treat other similar mental illnesses. Andrew Solomon wrote in his book The Noonday Demon that this way of trial and error "makes you feel like a dart board."
The nerve-wracking side effects are not the only cause of "dart-dish therapy." Since SSRIs and SNRIs have been used in the treatment of the antidepressant market since they were used in the 1880s and 1990s, they have not helped every patient – ​​more than one-third of patients take it completely after taking it. No effect. A drug that is effective today may expire tomorrow. Sometimes, a drug has to wait a few weeks before it starts to work, and in a few weeks waiting, the patient can be very dangerous. According to a report in the American Journal of Psychiatry in 2006, elderly people (age 66 and older) who use SSRIs have a risk of suicide in the first month of the second month. Times.
Obviously, patients are in desperate need of faster and better antidepressants, but the development of new drugs has stagnated. In fact, in the past few years, pharmaceutical giants such as GlaxoSmithKline have issued statements stating that they will abandon the development of psychotropic drugs because the cost of research and development of these drugs is too high, too difficult, and the success rate is too low.
Some scientists in government departments, research institutes, and small pharmaceutical companies are trying to solve this problem, but their success is still unknown. However, it is not currently possible to develop new drugs to meet approximately 15 million people with depression in the United States. Many patients still have no treatment. They are eager to try any possible method to alleviate mental pain and even try some extreme experimental methods, such as inserting electrodes into the brain or burning holes in the brain tissue.
Seeking quick results
In order to find fast-acting antidepressants, some researchers are investigating some mood-regulating agents that can work immediately, such as ketamine. They want to figure out why these compounds work faster than SSRIs.
Ketamine is an anesthetic that can relieve pain and bring pleasure, commonly known as K powder (Special K). It can influence people's consciousness and make people illusion. Animal experiments have shown that this drug poisons nerve cells and is therefore not an ideal antidepressant. However, this is a great medicine for studying how to quickly relieve the symptoms of people with depression. Ronald Duman and George Aghajanian of Yale University in the United States found that only two hours after the injection of ketamine in rats, their prefrontal cortex It produces the proteins needed to form new synapses (synapses are the point of contact between nerve cells). In many people with depression, this area of ​​the brain just behind the eyes is abnormal. After 24 hours of ketamine injection, new dendritic spines begin to appear on the dendrites of rat nerve cells - these are used to receive signals from other nerve cells. The more dendritic spines, the faster the signal transmission between nerve cells. In the experiment, Duman and Agajyanyan found that the more dendritic spines, the more mild the symptoms of depressiveness in animals (such as not participating in activities that would normally participate in normal conditions).
“In the past decade, many studies have shown that the prefrontal cortex and hippocampus are shrinking in a state of depression,†said Duman, now head of the molecular psychiatry laboratory at Yale University. “Ketamine can quickly reverse atrophy. ", the prefrontal cortex and hippocampus area returned to normal. The speed at which ketamine is effective is the research topic of Yale University scientists. A few hours after they injected ketamine into the rats, they began to study the rat brain to see if new dendritic spines would form within 24 hours.
Another study in depressed rats has revealed the mechanism by which ketamine promotes synapse formation by activating an enzyme called mTOR in neurons. This mechanism was discovered after Duman and colleagues used mTOR inhibitors. They first gave rats a drug that inhibits mTOR and then injected ketamine. It was found that these rats did not form new dendritic spines and the symptoms of depression were not alleviated. This means that when mTOR is inhibited, ketamine is ineffective. In other words, ketamine needs to pass mTOR in order to promote the formation of dendritic spines.
Given the high risk of ketamine use as a drug, scientists are looking for other mTOR activators. They know that ketamine activates mTOR by preventing the binding of glutamate, the most important excitatory neurotransmitter in the brain, to the N-methyl-D-aspartate (NMDA) receptor on the neuron surface. To achieve. Therefore, they tested another NMDA blocker and found that this NMDA blocker also activates mTOR and rapidly promotes dendritic spine formation and alleviates depressive symptoms in rats. Doman said that they are currently investigating other drugs that block NMDA receptors, hoping to find safe, effective antidepressants.
Another drug like ketamine, which can quickly relieve mood, has already been marketed for other effects. The drug, called scopolamine, is usually sold as a plaster to treat a variety of motion sickness. The effect of scopolamine on the brain circuit is different from ketamine: it blocks acetylcholine, a neurotransmitter associated with attention and memory, and muscarinic receptor, a class of acetylcholine that is widely distributed in the brain. Combination of body).
As early as the 1870s, researchers noticed that artificially altering the activity of acetylcholine in the brain may lead to depression. The mood of bipolar patients usually shifts back and forth between mania and depression. When they are arrogant, if they take medications that increase acetylcholine levels, they may show symptoms of depression within an hour, such as sadness and listlessness. When people with depression take medications that increase acetylcholine levels, their depressive symptoms worsen.
Seeing this, you may be thinking that researchers who develop new antidepressants should find ways to prevent acetylcholine from functioning. However, at that time, the researchers' attention was distracted by the most important neurotransmitter at the time, serotonin. In fact, many psychiatrists have argued that SSRIs are so effective because they do not affect the neural circuits in the brain that work through acetylcholine. Thus, acetylcholine has not received much attention because doctors believe that previous antidepressants were not as effective as SSRIs and had many side effects because they affected the choline system, especially the muscarinic receptors.
Therefore, if someone says that he has found a drug that specifically acts on muscarinic receptors, not only has fewer side effects, but it also works quickly, which is simply challenging traditional thinking. However, some scientists have achieved this effect with scopolamine.
In a clinical trial involving 22 patients, Maura Furey of the National Institute of Mental Health (NIMH) Laboratory Therapeutics and Pathophysiology found that veins Injection of scopolamine can relieve depressive symptoms within three days. Frei said that in fact, the next morning, the patient basically felt better. At the end of the four-week trial, nearly two-thirds of the patients improved significantly, and half of the patients' symptoms completely disappeared. This good condition lasts for two weeks after the last dose. In another experiment involving 22 patients, the researchers got the same results.
NIMH hopes to find a pharmaceutical company to conduct the necessary tests and clinical trials to bring scopolamine to the market as a fast-acting antidepressant. There are no pharmaceutical companies that are willing to take over, and Frey is "very disappointed", she said, "this drug is really effective in patients."
The route of administration of scopolamine is a stumbling block. It is unrealistic to inject scopolamine intravenously, like some anesthesiologists inject anesthesia mixture. When made into a skin plaster, the concentration of the drug in the blood cannot reach the desired level. As an oral medication, most of the scopolamine is cleared by the digestive system. Frey is now working on finding a viable and effective route of administration.
Focus on invalid people
In addition to taking a long time to work, another major drawback of existing antidepressants is that they are not effective for everyone. To solve this problem, scientists are focusing on several new mechanisms of action. Some people are studying another type of acetylcholine receptor, the nicotinic receptor, which is named for its ability to bind to nicotine. Scientists at Targacept, a small US pharmaceutical company, are working on an experimental drug called TC-5214 that blocks a specific nicotine receptor. Scientists hope to bring the drug to the market as a helper drug. When a single drug alone does not alleviate the symptoms, they hope that adding it will help.
In an initial trial involving 265 participants, patients taking Citalopram alone as an ineffective SSRIs supplemented with TC-5214 or placebo. In 2009, Targacept reported that patients who took citalopram and placebo at the same time scored 7.75 on the Hamilton Rating Scale for Depression, while those taking citalopram and TC at the same time. Patients with -5214 improved by 13.75 points.
Soon after, AstraZeneca signed a contract with Targacept to prepare a larger-scale efficacy study, phase II clinical trials. In Phase II clinical trials, subjects took a placebo, or TC-5214, in addition to the original antidepressant. 614 people participated in the first two experiments and the results were disappointing: compared with the placebo group Compared with the TC-5214 group, there was no improvement in depressive symptoms after 8 weeks. However, Targacept and AstraZeneca still decided to conduct two additional drug efficacy trials as planned, which will be completed at multiple test centers around the world, with more than 1,300 subjects, and new clinical trials will test drugs. Long-term security. They expect to submit a new drug application for TC-5214 to the US Food and Drug Administration (FDA) in the second half of 2012.
Because TC-5214 is a nicotine receptor antagonist (antagonist), its mechanism of action is not affecting serotonin or norepinephrine, so this drug is mainly used to help those with depression who have no effect on existing drugs. Another approach to these people will lead to more radical changes: instead of affecting the signaling pathway through receptors, it acts on another biological process—neurogenesis (new neuron production and growth). Especially in the hippocampus. The hippocampus is a small structure at the bottom of the brain. It is generally believed that the regeneration of nerves in the brain of adults mainly occurs in two parts, and the hippocampus is one of them.
Long ago, people thought that the structural changes in the hippocampus were related to depression. An autopsy of the brain of a depressed patient showed that the hippocampus of the depressed patient atrophied and the volume became significantly smaller. SSRIs and SNRIs drugs can alleviate depression, in addition to their ability to modulate serotonin concentrations, but also to promote the growth of new hippocampal cells. However, this growth process is very slow, which may be the reason why the above drugs take a long time to function. Scientists at Neuralstem, a small US pharmaceutical company, believe they have found another way to promote nerve regeneration and maintain nerve regeneration after stopping the medication.
To find new drugs, scientists at Neuralstem used in vitro cultured neural stem cells derived from human hippocampal cells. According to the company, only they are doing this in vitro culture. Based on the effects of drugs on hippocampal cells cultured in vitro, scientists first screened approximately 10,000 drugs. Karl Johe, the company's chief scientist, said their goal was to see which drugs could increase cell proliferation rates after seven days. He said that fewer than 200 compounds met this requirement. On this basis, Neuralstem's research team designed 12 chemical molecules that are likely to promote nerve regeneration in the hippocampus. In 2004, researchers began animal experiments to inject these alternative drugs into normal mice. Then, select the best-performing drug and inject it into mice with depressive symptoms. After such an experiment, the most promising drug came to the surface.
Now, Neuralstem is conducting an initial safety test (Phase I clinical trial) to test whether this drug tablet, named NSI-189, is safe for humans. If it goes well, Neuralstem hopes to begin testing for drug efficacy at the end of 2012, such as using magnetic resonance imaging to detect whether the drug promotes nerve regeneration, and through other tests to detect whether depressive symptoms can be alleviated. Even if NSI-189 is useful, it is unlikely to be effective in a short period of time. "Unlike epileptic seizures, you can stop him with a single pill," Joe explained. "This therapy requires genetic changes at the genetic level." The shrinkage of the hippocampus has only occurred after many years. "It takes a long time to reverse this process." However, he hopes that the effect will last for a long time, so that only NSI-189 should be taken intermittently. The idea has yet to be proved, but Joe said, "This possibility is exciting."
Further research
Studies have found that chronic inflammation is associated with many diseases, such as cancer, atherosclerosis and diabetes. Recently, scientists have realized that depression is also associated with chronic inflammation, and this connection has opened up new therapeutic approaches.
Inflammation is often thought of as the body's response to foreign body invasion. Multiple studies have shown some links between inflammation and depression. Some studies have shown that people with depression have high levels of cytokines in their blood. These cytokines are small molecules that coordinate the inflammatory process, such as interleukin-6 and tumor necrosis factor alpha (TNF-α). ). In addition, about a decade ago, scientists observed that skin cancer patients became depressed after receiving inflammatory cytokines.
Andrew Miller, director of the Department of Psychiatry and Oncology at the University of Emory, at the University of Emory, said: "In the early years, I interviewed one of these cancer patients, his depression, and what I encountered as a psychiatrist. I am very surprised that the symptoms of depression are very similar."
Cytokines are particularly bad, and they interfere with the process by which SSRIs and SNRIs promote nerve regeneration. "Destruction of nerve regeneration is almost a fight against depression," Miller said. This effect helps explain why those with chronic inflammation who are very severely depressed are the most difficult to cure. In 2006, scientists reported in the Lancet that etanercept was able to reduce depression in 618 patients who tested Etanercept for psoriasis. This is true even in patients who are not effective against psoriasis. It seems that this seems to be due to the neutralizing effect of etanercept on the inflammatory molecule, tumor necrosis factor alpha. One member of the research team, Ranga Krishnan of Duke University, said, “At present, patients can't ask doctors to prescribe this medicine to treat depression.†Etanercept antidepressant The result is still only an anecdote, "However, this result is really exciting."
Miller also thought the study was very interesting. He contacted Krishnan to discuss how to use an cytokine antagonist, Remicade, to conduct an antidepressant experiment. Infliximab is an already marketed anti-inflammatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. After more than five years, Miller and his colleague Charles Raison at Emory University finally received funding from NIMH for the experiment. They have used infliximab to experiment with 60 patients with depression who are ineffective in general therapy, and will soon announce some gratifying results.
Some researchers are turning their attention to serotonin, but they are experimenting with a new way to increase the activity of this neurotransmitter by increasing the number of serotonin receptors on the synaptic surface. There are also scientists who have proposed more radical programs that aim to achieve this through gene therapy.
When you mention gene therapy in front of biologists, you are likely to see their disdainful look. However, scientists have recently announced the initial success of gene therapy for a Parkinson's disease patient. A scientist involved in the treatment of Parkinson's disease hopes to treat depression in a similar way.
The candidate gene for gene therapy is called p11, and when some serotonin receptors migrate to the cell surface, the protein encoded by the gene (p11 protein) is required. Without p11, the serotonin receptor is trapped inside the cell and the cell's response to the serotonin signal is diminished. In 2006, Paul Greengard of Rockefeller University in the United States and others demonstrated that p11 protein was rare in mice with depressive symptoms (such as no longer doing the previously preferred activities). Previous autopsy tests showed that p11 protein was lower than normal in patients with depression.
Greengard's laboratory produced a mouse lacking the p11 gene by gene knockout, and these mice did show signs of depression. The next step in the study was done by Michael Kaplitt, head of the Molecular Neurosurgery Laboratory at Cornell University's Will Medical School, and colleagues: re-inserting these mice into functioning P11 genes, see if their symptoms will be alleviated. Capril has been using gene therapy to treat Parkinson's disease. He also used the defanged adno-associated virus to deliver the p11 gene directly to the nucleus accumbens of mice lacking the p11 gene. As a result, the depressive symptoms of these mice were alleviated.
Every neuroscientist has his or her favorite brain area, and Capulet loves the nucleus. He said: "I like the nucleus accumbens, because it is a very important center in the brain, responsible for reward and satisfaction, which is the area of ​​action of dopamine, a neurotransmitter." Capulet said. There is a common depressive symptom called anhedonia, which patients do not realize the joy of life. This highly destructive symptom is likely to be related to the dopamine signaling pathway. He also likes the nucleus accumbens for another reason: functional magnetic resonance imaging (fMRI) studies of animals and humans have shown that many brain areas associated with depression are connected to the nucleus accumbens.
The third reason he likes the nucleus accumbens is that the nucleus accumbens has become the target of another experimental depression therapy called "deep-brain stimulation" (DBS). The therapy is permanently implanted in the nucleus accumbens and then periodically pulsed with electrical stimulation through the electrodes.
In Capract's view, gene therapy directly on the brain is simpler than DBS because "DBS requires an electrode, and gene therapy requires only a small catheter and does not leave anything in the brain" (DBS not only It is necessary to permanently place the electrodes in the brain, and it is necessary to implant a neurostimulator like a pacemaker for generating electrical impulses at the clavicle). In the study of Parkinson's disease therapy, Kaplit et al. have demonstrated that the viral vector is safe and that the correct gene can be delivered to the target brain area through a catheter to improve symptoms.
At NIMH, Elisabeth A. Murray at the Neuropsychology Laboratory and Pam Noble at the Primate Experimental Center are testing the safety of p11 gene therapy in monkeys. Efficacy. If the experiment is successful, it will lay the foundation for human experiments of this gene therapy.
For "blueberry octopus", better treatments do not appear soon. “Antidepressants have really changed my life,†she wrote on the “Experience Talk†website. “But, I regret that I paid a lot of money and my sexual life was affected.†. She is less than 25 years old. "Finally, I may give up antidepressants and return to normal sex. I just feel that I am not ready yet." Life should have better choices, and no one should be confronted with sexual and desperate choices. For any patient with depression, even if many kinds of treatments have failed, we should not tell them hope. If a new generation of antidepressants is successfully developed, it may not be so cruel to trade off the pros and cons.
Source: Global Science
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