Schizophrenia drugs may have been off target for decades, study finds

Same study discussed previously:<p><a href="https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=37057135">https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=37057135</a><p>(50 points&#x2F;3 days ago&#x2F;51 comments)

The brain is really complicated, and all psychiatric medications affect multiple receptors and subsystems. Framing this study as &quot;antipsychotics were off target&quot; is an editorial choice. The title could just as easily have been &quot;Improved understanding of antipsychotic action means we may be able to design better antipsychotics.&quot;<p>Edit: It also ought to be noted that the study was on mice that had been given amphetamines to mimic psychosis. Which is interesting and good science, but seems far from enough evidence for the press to write stories with headlines like &quot;Everyone Was Wrong About Antipsychotics&quot; or &quot;Schizophrenia Drugs May Have Been Off Target For Decades, Study Finds.&quot;<p>This sort of internet story bothers me because I&#x27;ve spent time around schizophrenics who are recovering from a psychotic episode. Schizophrenia can get really, really bad, in a way that I don&#x27;t think most people who haven&#x27;t had contact with the psychiatric medical system understand. Antipsychotics have awful side effects, but for many people the alternative is uncontrolled psychosis, which can be vastly worse.<p>There&#x27;s a decent chunk of people who inherently and vocally dislike psychiatric medication, and these media stories are in that tradition. But the only people who ought to be involved in the decision about using antipsychotics are the patient, their family, and their medical providers. Writing headlines that are too broad for the evidence that supports them does not help improve the lives of people with schizophrenia.

Situation normal.<p>Consider the discovery of valproic acid:<p>&quot;Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a &quot;metabolically inert&quot; solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.&quot;<p>To this day, nobody knows exactly how it works, apart from the fact that it hits more than a few targets. (And it&#x27;s a particularly potent inhibitor of the epigenetic modulator histone deacetylase.)<p>Apart from a subset of very clear-cut cases -- steroid hormones, peptide hormones, and certain aggressive chemotherapeutic drugs -- there&#x27;s no clear model for most small molecule drugs. Even really mundane ones like metformin and paracetemol are very imperfectly understood.

The study used a mouse model where amphetamine is used to simulate schizophrenia. Obviously, it&#x27;s not guaranteed to map to real humans having real schizophrenia.<p>That doesn&#x27;t mean it&#x27;s a useless result, but everyone should remember that research is an accumulation of decades of many little pieces of information. This is another clue, not a &quot;nail in the coffin&quot; of old theories.<p>The ultimate evaluation of medication is how well it actually performs in studies. If someone can develop a new medication that is more selective for D1 and show that it performs better and&#x2F;or has fewer side effects then this would be a great result.<p>However, don&#x27;t get too excited. The pharmaceutical industry is often 10 steps ahead of public findings like this. A selective D1&#x2F;D5 antagonist with negligible D2 affinity has already been trialed for schizophrenia without good results: <a href="https:&#x2F;&#x2F;en.wikipedia.org&#x2F;wiki&#x2F;Ecopipam" rel="nofollow noreferrer">https:&#x2F;&#x2F;en.wikipedia.org&#x2F;wiki&#x2F;Ecopipam</a><p>Many of the most prescribed schizophrenia medications already have significant D1 affinity, too, so it&#x27;s not really correct to say that we&#x27;re &quot;off target&quot;<p>These findings tend to be very aggravating to computer scientists who are familiar with systems that (mostly) obey clear-cut rules and can examined in extremely fine detail with enough equipment and motivation. Neuroscience is not so simple, but that doesn&#x27;t mean it&#x27;s all wrong. Each finding is one more piece of the puzzle.

So I&#x27;ve tried half a dozen antipsychotics, here are my 2 cents:<p>The only things those drugs did to me were making me comatose, poop my pants, sleepy, dumb and hungry.<p>You can&#x27;t be declared psychotic or paranoid, when the only thing you can do is sleep, drool, poop yourself, and make 3 words sentences, so lazy doctors think these drugs work.<p>But they don&#x27;t, there was zero change in my beliefs, fears, anxieties, I was the exact same person, only slower, dumber, and sleepier.<p>And at some point, when you&#x27;re exhausted from being a zombie, you end just lying to your doc and pretending everything is fine, even when you believe doctors should always know the truth, because it&#x27;s the only way to stop yourself from staying a brain dead zombie for life and causing irreversible damage.

I know someone who has diagnosised but untreated schizophrenia. She was admitted to the hospital after she started having thyroid problems and they also administered schizophrenia medication while she was in. The change in her behaviour was positive and dramatic and allowed her to start accepting help after being scared that men in white coats would take her away if she ever let on about her illness to anyone. Now she has been out of hospital for a while, unmedicated again and back to her old behaviour including talking to people who aren’t there and having bad episodes. Maybe some medications are off the mark but whatever they used for her absolutely worked.<p>I realise a sample size of one anecdotal piece of evidence is hardly scientific, but I’m getting rather tired of the constant mouse model studies, with barely related parameters.<p>I wish there was a better way to do medical research, in actual human beings. Unfortunately it seems historically that actual human medical research is mired in the suffering of the (generally unwilling) participants.

I was diagnosed with schizophrenia, given some strong antipsychotics, it was a disaster I could barely talk or hand-write properly, gained 15kg. Fortunately I didn&#x27;t listen the advices and stopped after 4 months, my therapy now is just walking, running, cycling, outdoor, trees, vegetable, minimalism

Link to the actual paper: <a href="https:&#x2F;&#x2F;www.nature.com&#x2F;articles&#x2F;s41593-023-01390-9" rel="nofollow noreferrer">https:&#x2F;&#x2F;www.nature.com&#x2F;articles&#x2F;s41593-023-01390-9</a>

My Schizophrenic friend tells me the difference between schizophrenics and normal people is that normal people can hear their own thoughts whilst schizophrenics can hear other peoples.<p>Serious point, maybe schizophrenic symptoms are cause by a disruption in REM sleep. As in the suffers are experiencing a waking dream. Some time back they did an experiement on students and kept them awake for days-and-nights on end. Eventually they couldn&#x27;t tell the difference between the dreaming and the real world.

The entire paradigm for treating schizophrenia and other chronic mental states is flawed.<p>Mental distress&#x2F;disorder cannot be treated properly because of the strong for-profit motive (unrestricted greed) that these privately-owned (sometimes publicly traded) mental hospitals and pharmaceutical companies have.<p>Mental hospitals are effectively a prison. Locked doors, removal of rights once committed, coercive and sometimes forced treatment and restraints, being told that you have a lifelong disease (with no measurable physical damage -- fMRI scans are not indicative of damage) that needs drugs for the rest of your life, and getting billed an exorbitant amount - to name a few things that are wrong.<p>If your rights are violated and you are declared incompetent (which is pretty common if you are unstable or in crisis), it&#x27;s an uphill battle in special courts called Mental Health Courts. It&#x27;s difficult to get a second opinion from a third-party psychiatrist, or to contest treatment orders (such as mandatory intramuscular antipsychotic injections or ECT which respectively have a very potent and long-term effects).<p>The conversation needs to be shifted towards the Soteria House paradigm.<p>This article sums this model of care pretty well: <a href="https:&#x2F;&#x2F;www.madinamerica.com&#x2F;2019&#x2F;09&#x2F;soteria-house-heal&#x2F;" rel="nofollow noreferrer">https:&#x2F;&#x2F;www.madinamerica.com&#x2F;2019&#x2F;09&#x2F;soteria-house-heal&#x2F;</a><p>They have very impressive results, particularly in regards to schizophrenic and psychotic patients, and do not use life-long tranquilizer prescriptions to achieve their results. It needs more study, it needs more implementation, but the core of the model is that it builds a supportive community around vulnerable people -- instead of caging and viciously profiting off of these people.<p>I spoke on this matter in the past, and you can read my thoughts here: <a href="https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=34029719">https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=34029719</a>

One of the more popular Schizophrenia drugs also cause diabetes :(

It&#x27;s amazing how far the medical world has come in treating ailments of the body, but we&#x27;ve made comparatively little headway in ailments of the brain.

I have a theory. Antipsychotic medications just need to make the person more &quot;manageable&quot; to be considered effective. It doesn&#x27;t need to eliminate the psychosis directly, it could just make the person more sedated, and it would appear to be &quot;working&quot; properly.

The pharmacodynamics of antipsychotics is such a rich topic, yet this article is so crap!<p>Surprised no mention of pimavanserin (which doesn&#x27;t act on dopamine useful in those with Parkinson&#x27;s and psychosis) and that L-dopa can reliably induce psychosis (used on Parkinson&#x27;s).

Schizophrenia is a strange illness. We&#x27;ve had two successes (by some metrics) in psychiatric treatments because the science aimed at schizophrenia but hit something else: lithium and electroshock.

<a href="https:&#x2F;&#x2F;archive.ph&#x2F;sZerh" rel="nofollow noreferrer">https:&#x2F;&#x2F;archive.ph&#x2F;sZerh</a>

Strictly speaking, psychosis is more strongly related to excess serotonin, &#x27;the molecule of stress and inflammation&#x27;. Doctors sometimes recognize &#x27;Serotonin Syndrome&#x27; in their ER patients: &quot;too much serotonin causes signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures).&quot; Usually the Serotonin Syndrome is caused by a combination of prescriptions, or street drugs.<p><a href="https:&#x2F;&#x2F;www.mayoclinic.org&#x2F;diseases-conditions&#x2F;serotonin-syndrome&#x2F;symptoms-causes&#x2F;syc-20354758" rel="nofollow noreferrer">https:&#x2F;&#x2F;www.mayoclinic.org&#x2F;diseases-conditions&#x2F;serotonin-syn...</a><p>All the effective anti-psychotics seem to have anti-serotonin properties, in addition to their anti-dopamine effects. For example: &quot;there are also recent studies that &#x27;stumbled upon&#x27; the &#x27;shocking&#x27; evidence that anti-dopamine drugs commonly used for treating schizophrenia such as haloperidol are actually potent serotonin antagonists as well.&quot; - <a href="http:&#x2F;&#x2F;haidut.me&#x2F;?p=1297" rel="nofollow noreferrer">http:&#x2F;&#x2F;haidut.me&#x2F;?p=1297</a><p>One of you quoted my essay <i>Cargo Cult Psychiatry</i> in a comment on Sunday, on a submission of Feynman&#x27;s <i>Cargo Cult Science.</i> I responded, then thought to submit my link to the original at Mad In America again: <a href="https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=37110874">https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=37110874</a><p>This paragraph from that comment is essential for helping anyone diagnosed with the label of &quot;schizophrenia&quot;:<p>&quot;The good news from the mental health world is that Chris Palmer, M.D. published Brain Energy [0] last year. I haven&#x27;t read more than excerpts from google books [1]. My understanding is Dr. Palmer was a conventional palliative psychiatrist, then he had a patient whose schizophrenia improved on a ketogenic diet. The patient was able to discontinue antipsychotics: Dr. Palmer&#x27;s mind was blown. Then he discovered the 70+ years of research establishing that mental health conditions are metabolic problems that can be successfully treated with pro-metabolic therapies.<p><pre><code> Perhaps the most bold and disruptive aspect of Brain Energy is understanding precisely how and why medications that harm metabolism might reduce mental health symptoms. The long-term consequences are of great concern and require the urgent attention of the psychiatric community. </code></pre> -Chris Palmer, MD - <a href="https:&#x2F;&#x2F;twitter.com&#x2F;ChrisPalmerMD&#x2F;status&#x2F;1687850270602981376" rel="nofollow noreferrer">https:&#x2F;&#x2F;twitter.com&#x2F;ChrisPalmerMD&#x2F;status&#x2F;1687850270602981376</a> [...]<p>[0] <a href="https:&#x2F;&#x2F;brainenergy.com&#x2F;" rel="nofollow noreferrer">https:&#x2F;&#x2F;brainenergy.com&#x2F;</a> &#x2F; [1] <a href="https:&#x2F;&#x2F;books.google.com&#x2F;books?id=FoxlEAAAQBAJ&amp;pg=PT233&amp;dq=B" rel="nofollow noreferrer">https:&#x2F;&#x2F;books.google.com&#x2F;books?id=FoxlEAAAQBAJ&amp;pg=PT233&amp;dq=B</a> &quot;

It&#x27;s important to keep in context that none of hepsteens clients were persecuted or even publically named, and the people connected to them take a percentage of every profit you work to generate. Don&#x27;t call them out on that though, these sedatives will fuck you up.