To a collective sigh of relief from across the US, Mr Musk took his leave from his peculiar post as head of DOGE, the department that doesn’t actually exist (only Congress can establish government departments). Once again, he gave a bravura performance as rising ego-to-watch at what looked like a full cabinet meeting, marred only by reports that he had pissed himself. Being foreign-born, of course, he can’t rise to the top of the US political ladder but that doesn’t stop him collecting lot of enemies along the way. In fact, reports he had wet himself are just the sort of thing his enemies need, so it’s possible the only top he’ll be rising to will be the Potomac River. What’s it about? Well, ketamine of course. He’s long been known for abusing Special K, as the rave crowd know it, as well as other drugs. In a recent video interview, he said he takes it for “negative chemical states of the brain, like depression.” It’s obviously effective, he hasn’t shown a trace of depression for the last 17 years I know of.
One of the lesser-known effects of chronic abuse of ketamine is serious damage to the urinary system. Whether it’s the drug itself or a metabolite, I don’t know, but abusers start to have trouble passing urine, with frequency, pain and bleeding, fibrotic contraction of the bladder wall, retention, infections etc., eventually proceeding to kidney damage and even renal failure. Part of the trouble is that ketamine is an anaesthetic agent which, unsurprisingly, produces anaesthesia for all pain, including bladder pain, so, hoping to kill the pain caused by a chemical, the unhappy user takes more and more of the chemical that’s causing it. FAFO, you say, and I agree, except mainstream psychiatry is eagerly promoting ketamine as an all-purpose, all-comers cure promising a bright future for sufferers of the relatively new condition of “treatment-resistant depression.”
Two points there, what and why is treatment-resistant depression (I have to use the brutalising abbreviation “TRD”), and is an anaesthetic drug derived from the party drug angel dust (phencyclidine) the proper form of management? Without starting on an encyclopaedia article, “TRD” is a modern invention, it didn’t exist 40 or 50 years ago. Before the era of so-called “antidepressant” drugs (they’re not, but that’s another small book), there was only ECT. Some people ended up with “maintenance ECT,” meaning they came in once a week or a month for another shot. There weren’t many of them and, predictably, it was used a lot more in private hospitals than in public. The few people I saw who were knocking up their hundredth attack of ECT showed decidedly abnormal personalities, meaning they were unhappy as a result of who they were. Since then, the notion of “TRD” has exploded. People are deemed “treatment resistant” if they don’t respond to two or three drugs, but that assumes drugs are the correct management and not adding to the problem. What we see is that familiar graph from the early studies on smoking, where the condition accurately tracks the social phenomenon but about 10-15 years later:
[Doll and Hill, BMJ, 1950].
At this stage, it’s impossible to whether the exponential rise in diagnoses such as “TRD,” the infamous bipolar disorder, ADHD of course (which, like obesity, definitely didn’t exist when I went to school), and so-called ASD, are or are not caused by the preceding rise in consumption of psychoactive drugs (psychoactive means any drug that acts on the mental state; it doesn’t just mean hallucinogenic). It also correlates neatly with the deskilling of psychiatrists in the field of psychotherapy, not that the majority were ever much chop, and the flood of drug company money into academic psychiatry. However, and despite the careers and fortunes made on the back of antidepressant drugs (“depression pills,” as Peter Gotzsche calls them), it’s becoming clear that they’re not actually very good. In fact, it may well prove that they have done more damage than they have ever resolved but that could take decades to emerge, by which time psychiatry will have dropped them into its justly-famous memory hole and jumped on another magic cure bus, if it still exists.
We see this happening now. Twenty years ago, you couldn’t open a psychiatric journal or go to a conference without being besieged by the wonders of SSRIs and SNRIs and the others, with ECT panting in the rear. One after the other, speakers lined up to talk up their prowess in manipulating brain chemistry but somewhere, that faded away. Today, it’s hallucinogenics, hallucinogenics, all the way to the bank, especially as the “serotonergic model” of depression is itself headed for the memory hole [1]. A lot of the excitement surrounding these drugs comes from Australia and New Zealand but, typically, researchers organise projects with their friends overseas as people believe that “a 4-week, randomised, double-blind, active-controlled, parallel-group, international multicentre phase 3 trial” trial carries more weight than a small group, and certainly more than a single author. It’s rubbish, of course: we can all organise a group of like-minded friends to push a particular point of view, while the weaknesses of that point of view are almost always exposed by one or two independent investigators – if it ever gets published.
Anyway, the ketamine bandwagon is just pulling out, so we’ll need to see who’s driving it. And, surprise surprise, it’s the usual team from the so-called “Black Dog Institute” at the University of New South Wales, in Sydney. In a paper published in the British Journal of Psychiatry in 2023 [2], Prof. Colleen Loo and 37 co-authors from half a dozen places around Australia and New Zealand collected 174 patients with “TRD” i.e. 2 previous forms of treatment, drugs or ECT, hadn’t worked. Half were given subcutaneous injections of ketamine twice a week for four weeks and half got an injection of another psychoactive drug. After the first trial, there was no effect of either drug so they changed the protocol and had another go. Ketamine produced some improvement (they were still depressed) so it was declared a success.
At the usual press conference the Institute organised to announce their results (they maintain very close links with the scribblers and stenographers of the mainstream media), the lead author announced:
There was a 10-fold treatment advantage for ketamine treatment compared with placebo medication. This corresponds to a 20% remission rate for the treatment group, versus only 2% for the placebo group … It can lift mood incredibly quickly. You can go from being severely depressed to completely well in one day. But you can also go the other way in one day and then that’s not just depression but also suicidality.
Another researcher added a subdued warning:
Ketamine is used as a party drug, it does have abuse potential. One of the things we were very careful to watch out for was whether participants might become addicted to ketamine during the study (but there may be potential for oral use and self-administration at home).
Another researcher was reported as saying: “… research into ketamine for severe depression was a long time coming … we are entering a ‘new world’ for treatment-resistant psychiatric illness.”
Where to start? Possibly with the idea that “depression” is an “illness” that needs/only responds to drugs and other physical treatment. They have no proof of this at all. The historical evidence is that, historically, depression used to be mild and transitory (David Healy has written extensively on this, using records from his former mental hospital in North Wales). Second: for all the talk about “brain chemistry,” none of this was known when the drugs were developed. The great majority were discovered by chance to have a calming effect on disturbed people, so they were approved and prescribed. Much later, some sort of scientific-sounding justification was discovered, a classic example of seeing where the arrow has landed and then painting a bulls eye around it.
Third, and for this study, four weeks is nothing. What happens a month after it’s stopped? If, after a four week trial, the drug is approved in this form then, within five weeks of approval, people will be taking it permanently. If they have a biological disease of the brain called “chronic depression,” they won’t be able to stop because their “disease” will come roaring back, like diabetes when the patient runs out of insulin. But they won’t stop, just because ketamine is addictive. Or course nobody in the trial became overtly addicted in four weeks, it takes longer. It it’s approved for home use, people will soon realise they can easily buy more on the black market, while plenty of clever souls will realise they can make a lot of money selling it into the black market, as happens with all the ADHD drugs. The other thing is that serious side effects rarely start within four weeks, the urinary effects take 3-5 years to develop.
But more important is the fundamental question: “What are you actually doing?” What is the nature of depression that a hallucinogenic drug is the correct treatment? Or, why talk of “treatment-resistant depression” when the person has simply been given a couple of unpleasant psychoactive drugs with no attempt to sort out the nature of the problem? How do I know that? Because people who use hallucinogenic drugs to relieve mental distress have a singular view of the nature of mental distress. It's chemical. End of story, so chemicals are needed to rectify it.
I completely disagree. My lengthy experience is that the overwhelming majority of cases of recurrent or persistent depression are due to (a) an unsuspected anxiety state (unsuspected because nobody asked), (b) major personality difficulties, directly related to early life experiences, and (c) further adverse life circumstances. Or some or all of the above in some unholy mixture. All of which requires the psychiatrist to take a detailed history which may take weeks to emerge. All too often, I had patients say to me: “I’ve been seeing psychiatrists for 10 years but none of them ever asked me those questions.” I could give hundreds of examples (other psychiatrists can give more, I’m sure) but that’s not the point. The point here is that the anaesthetic agent, ketamine, was invented in 1962. It was always known to be a very difficult drug to use but it had real advantages. I recall it being used when I worked in a burns unit, for cleaning and stripping the wounds or for painful skin grafts. It has since been found to work on a range of neurotransmitter systems which weren’t discovered until years later. Nobody has a clue how they relate to the experience of sadness and despair now called depression.
Ketamine is an NMDA receptor antagonist that produces a trance-like state, anaesthesia (suppression of pain) and amnesia, as well as hallucinations and a variety of physical effects. NMDA receptors were discovered in the late 1960s but their role as neurotransmitters wasn’t explored for 20 years, when the technology became available. The major role for NMDA appears to be in connection with neuronal survival and death but there are so many variants with different roles in different cells that we may never know what it does. The notion that it is somehow specific to depression is pure pseudoscience. Does that say there is something wrong with psychiatry’s model of depression? It would if they had one but they don’t. Perhaps, then, it’s all wrong, perhaps depression should be seen as a human reaction to adverse life events? Is there one available? Indeed there is, but we’ll start with anxiety, as we all know about it. What follows is lifted from my little monograph on anxiety [3].
First point: Anxiety is the universal reaction to the perception of a threat. All animals have some sort of threat response, otherwise they wouldn’t survive. In our area, we have giant earthworms which like to come out for a stroll after rain. They’re as thick as my index finger and about 30-40cm long stretched out. Unfortunately, they often stroll across the road and get squashed so if I see them, I pick them up and put them in the wet grass. As soon as they’re touched, they get shorter and thicker and exude a sticky mucus so they actually look like little penises frantically wriggling across the road. That’s their response to the perception of a threat and it works, as the ravens leave them alone.
Our threat response is all too familiar: shaking, sweating, heart racing, short of breath, churning stomach, feeling faint, dry mouth, stammering, unable to think or concentrate, and feeling that something terrible is about to happen. Unlike worms that don’t respond until they’re touched or feel vibration, we don’t need an external stimulus, we can trigger a threat response from within by thinking of something scary. The threat is always in the future, it’s coming at us and we have to get ready to deal with it, either fighting or running away. That’s it: anxiety is not a “disease” or “chemical imbalance” or any of that other crap, it is the body doing precisely what it is told to do, get ready to deal with a threat.
What sets humans apart from other animals is that because of our capacity for language, we can react to threats that we expect are going to happen, such as an exam or a court case tomorrow, money worries, fear of illness, the threat of a visit from an awful relative, and so on. We can also respond to threats within us: if the threat we perceive just is a symptom of anxiety, like a racing heart, we are immediately trapped in a vicious circle where anxiety causes the feared symptoms, and the feared symptoms intensify the anxiety. The trigger can be anything but people aren’t scared of the actual triggers, they’re scared of how they will feel if they go near the feared object. Fear of frogs is very common. People often say: “I know they can’t hurt me but I’m terrified of frogs.” The answer is: “No, you’re not scared of frogs, you’re scared of how you will feel if you go near a frog, which is completely different.”
The steps in the sequence are quite clear: The mental perception of a threat triggers activating signals to the brain centres that control the state of arousal (because that’s all anxiety is). The reaction to a minor fright is just a brief bout of feeling a bit edgy whereas the reaction to a major threat is paralysing fear because it keeps sending signals to stay on edge. The body reacts accordingly; the person either deals with the threat (“fight or flight” response) or falls in a heap and can’t do anything. The reaction to a minor threat is a brief shiver of apprehension; the reaction to a life-threatening danger can be prolonged and disabling terror because the continued thought of the threat sends a constant barrage of signals until it is removed. The initiating event is always a mental perception or idea of danger. Anxious people misinterpret neutral events in the environment as a threat and react accordingly. To deal with the anxiety, deal with the idea that something is dangerous.
Depression is quite similar: it is the reaction to the perception of a loss. Most higher animals have a standardised loss reaction, which involves withdrawal, low levels of activity, reduced responsivity to environmental events, and no signs of interest or wanting to play or explore. We know there are “pleasure centres” in the brain; what we don’t know is how they function and interact with the rest of the brain, especially with the cognitive brain but, in practice, we don’t have to. All we need know is that misery parallels anxiety: “The perception of a loss sends blocking signals to a the brain centres that control the state of pleasure and interest. The reaction to a minor loss is just a brief bout of reduced pleasure whereas the reaction to a major loss is paralysing because the continued thought of the loss sends a barrage of signals that prevent the experience of pleasure.” The final outcome will be determined by additional matters such as a sense of guilt, unworthiness, self-hatred and other personality factors, anger toward others or the world in general, suspicion and so on, all of which are signposts for the therapist to follow but are usually not the primary issue.
The initiating event in depression is always a mental perception or idea of loss. This can be in the past, the present or may relate primarily to the future. It can be outside me, as in “Our house has burned down, we’ve lost everything” or inside, as in “This anxiety is destroying me, I can’t see any future like this. Nobody does anything to help, I may as well end it now.” To deal with the sadness, deal with the idea that is causing the sense of loss. The role of the treating therapist is to bring to full awareness the nature of the loss and help the sufferer to adjust to it. That’s it, so simple. Nothing complex about it at all, no brain disease, no abnormal chemicals, no genetic influences, etc.
The idea that anything so complex as a human emotion could be reduced to a single pointer on a gauge, such as high or low serotonin, is laughable. There are over 100 known neurotransmitters, most likely with more to come. Each can have up to a dozen different receptors, meaning each chemical may be excitatory or inhibitory, depending on where it acts. The whole affective system is so complex that we may never fully understand it, but then we don’t have to. All we have to do is talk to the experts, meaning the people suffering miserable moods. They know what causes their misery, their neurotransmitters are just the mechanism. Biological psychiatry just doesn’t get that simple point. Instead, it pokes around until it finds a chemical that seems to improve matters, then constructs a “theory” of depression around it. It’s one of the fallacies of classic logic: Argumentum ex iuuantibus, or arguing backwards from a treatment effect. But it’s all rubbish, all pseudoscience, designed to fool the unwary:
The first benefit of psychiatric training is to equip students with a vocabulary that enables them to talk with apparent authority about subjects they don't understand, the better to quell critics. The second is to give them principles that reinforce their ability to withstand any amount of criticism or disconfirming evidence, sufficient to prevent them ever seeing they may be doing damage. The third is to give them a ticket to a well-paid job where they can gain experience in their trade at the expense of the general public and to the cost of their patients. Finally, they are given a sense of power that allows them to see all criticism and questioning as malicious and needing to be curtailed, but under the pretext of “needing treatment.” Psychiatry is a veneer of hustle concealing a lack of scientific standing.
BTW, that well-known expert on all things medical, RFK Jr, is in bad odour as it seems some of the many papers cited in his initial report (see last week) don’t actually exist, while others were misquoted or misrepresented. In a normal country, the “responsible” minister or secretary would sneak off to commit hari-kari, but the US at present is not a normal country. Far from it. Watch for more sparks from the project, and maybe even a full-scale meltdown.
References:
1 Moncrieff, J., Cooper, R.E., Stockmann, T. et al. (2022) The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry Published online July 20th 2022. https://doi.org/10.1038/s41380-022-01661-0
2 Loos C et al (2023). Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. Brit. J. Psychiat. 223: 533–541. doi: 10.1192/bjp.2023.79
3 McLaren N (2018). Anxiety: The Inside Story. Ann Arbor, MI: Future Psychiatry Press.
TRD what about RRD that psychiatry has - Resistance to Reality Disorder. Resistance to behaving ethically and heed the rigours of medical science.
First Psychiatrist use. They use the patients pain, fear, trauma and misfortune to feather their own nests, they use the patients Medicare card like their own private credit card and if in private practice they get the co payment too.
Second the minute patient becomes intellectually suspicious re failed treatments that make them worse, psychiatrists will start accusing patient of paranoia, non compliance and start throwing the DSM numbers around.
Third psychiatrists abuse. Spiteful appointment scheduling. Involuntary treatment orders and then the dismissal - refusing to see patient, not ensuring continuing care with another practitioner. When trouble arises, the psychiatrist will cowardly hide behind the skirts of their office staff. Whose only advise to patient is to present at their local hospital emergency department. Patient and family left without scripts left to detox with no help.
Thank you, Niall, I agree with you about TRD, it did not exist until recently and in my many years of practice I have never made that diagnosis. These days the chronic refractory cases of depression that I see are invariably on antidepressants and have been for years or decades so it is difficult to avoid the conclusion that the treatment is causing the illness. Carolyn