In the Beginning
The sulfonamides transformed medicine in the 1930s. They were the first effective antibiotics and they gave rise to the first diuretics, antihypertensives and hypoglycemics.
The latest medical miracle, Semaglutide – Novo-Nordisk’s Ozempic – is touted not just as an effective hypoglycemic (anti-diabetic) medicine but also a Holy Grail drug that licensed as Wegovy produces extraordinary weight loss and mind-boggling profits. Companies, like Eli Lilly with tirzepatide, Mounjaro for diabetes and Zepbound for weight loss, are rushing to cash in.
The Dawn of the SSRIs
Before it came onstream for depression, Prozac, fluoxetine, commonly incorrectly thought of as the first SSRI, had a hinterland of note. Lilly hoped it might be an antihypertensive. They investigated it and nearly marketed it as a weight loss drug. Launched as an antidepressant, a key selling point was that it will lift your mood – and cause you to lose weight.
There is, on average, some weight loss in the early weeks of treatment, primarily because SSRIs cause nausea. But when taken for months or longer, most people gain weight.
SSRIs also cause dependence and many have wondered if this has any link to blood sugars. There are reported changes in blood sugar – sometimes up, sometimes down – and some talk of cravings.
Epidemiological studies point to an increase in the risk of aggravating Type-2 Diabetes (T2D) but it is not clear if this links to a direct effect on blood glucose or indirectly to weight gain.
There is an interaction between SSRIs and Estrogen. The SSRIs have had an illness specially created for them when what was PMS or PMT was converted into Pre-Menstrual Dysphoric Disorder (PMDD). The data for SSRI benefits in PMDD are not compelling, but it seems some women can benefit, perhaps because of a numbing effect.
Quite at odds with both this old and politically incorrect cartoon and the advert for Prozac rebranded as Sarafem, SSRIs in P-states overall increase irritability and aggression.
SSRIs were also marketed for women with menopausal Hot Flashes, especially when HRT came under a cloud. Some women are helped but in my experience these women with no prior nervous problems seem to find it particularly difficult to get off treatment because of a dysregulation SSRIs cause.
Finally, a condition called Persistent Genital Arousal Disorder (PGAD) is linked to a combination of SSRI withdrawal and the menopause/perimenopause. This is a state in which persistent genital irritability, caused by SSRIs, leads to painful and distressing orgasms triggered often by stimuli as minor as the vibration of a car. The genital changes in PGAD are often called genital dysesthesia but could be called genital akathisia. PGAD is so distressing that women have resorted to clitoridectomy to control it.
PGAD has a mirror image in Post-SSRI Sexual Dysfunction (PSSD), which is characterized by genital numbing, muted or absent orgasms and loss of libido. A key feature of both PGAD and PSSD is that they often begin on stopping treatment and can persist for decades after stopping. There are at present no known cures.
A Visual Snow Reporter
In the last decade a new condition Visual Snow Syndrome (VSS) has been described. VSS has a host of visual symptoms from snow, to nyctalopia, palinopsia, excessive floaters, entoptic phenomena, photophobia or light sensitivity, visual blurring, starbursts and other light distortions, along with a link to dizziness, tinnitus and vestibular or inner ear problems.
Initially linked to migraine, VSS can be triggered by medicines, in particular medicines acting on serotonin systems. Cases have likely been happening since the early 1960s when the first antidepressants were introduced and noted to cause visual problems from dry eyes, blurred vision and gritty eyes to glaucoma.
Until recently, these problems, along with every other problem in all bodily systems linked to older antidepressants, were attributed to an anticholinergic action these drugs have. There were no grounds other than marketing to make this link – many early antidepressants were potent serotonin reuptake inhibitors.
There is an overlap between the sexual and visual effects in that both can emerge on starting treatment but are more obvious on stopping and can persist for years after stopping.
In 2013 RxISK carried a post, Keeping an Eye on the Ball, on SSRI triggered visual problems before any link had been made between SSRIs and visual problems and before Visual Snow Syndrome (VSS) had been formally described. The person in question has now had these problems for over two decades.
Problems like these can be triggered by medicines that also act on the serotonin system but not through reuptake mechanisms.
A more recent patient with SSRI triggered visual snow and headaches was diagnosed with migraine – with which Visual Snow is also linked. The treatment of migraine and VSS typically turns to anticonvulsants. He tried most of these with no benefit but when put on Topiramate there was a benefit – See Visual Weird.
Topiramate is commonly thought of as the anticonvulsant with the most side effects, including one notable one which is weight loss. It is also linked to a number of perceptual distortions sometimes termed hallucinations but also called Alice in Wonderland syndrome, where objects can change size and shape, appearing bigger or smaller than they are ‘known’ to be.
Why might it help in a VSS case? In addition, to having a range of effects other anticonvulsants do not have, Topiramate has an action they do not have. Other anticonvulsants block sodium currents, or act on GABA systems or have both these actions. Topiramate has both of these actions and a third – it is also a Carbonic Anhydrase Inhibitor (CAI).
The relevance of this is that SSRIs are Carbonic Anhydrase Activators, and this action leads to increased fluid production in the eye which raises intra-ocular pressure and can cause glaucoma and gritty eyes. Our RxISK reporter’s experience suggests there are a number of VSS linked SSRI triggered symptoms Topiramate can help. It may also help manage the risk of glaucoma and gritty eyes.
When people mention gritty eyes they often mean dry eyes but some RxISK reporters do not have dry eyes and the grittiness is linked to raised eyeball pressure, tension and headache and may essentially be a form of akathisia.
Carbonic Anhydrases
Topiramate is a ‘dirty’ CAI – it does lots of other things. Acetazolamide, an older sulfonamide, is a pure Carbonic Anhydrase Inhibiting anticonvulsant, – it does not act on GABA receptors or Sodium currents.
Pursuing this RxISK reporters lead led to the following. Acetazolamide is used for:
- Partial epilepsy.
- Migraine, especially menstrual migraine.
- Periodic paralyses, especially linked to high potassium levels.
- Altitude sickness where the general view is that its action is to reduce edema. Many of those climbing in the Himalayas take it. And it seems SSRIs do not work at altitude – perhaps a combination of both SSRIs and altitude increasing edema.
- Visual vertigo – experienced as agoraphobia or car-sickness or visual processing issues thrown up by complex screen presentations – where SSRIs haven’t helped – see Balancing Our Bodies and our Selves and Ondine’s Curse,
- Glaucoma as it reduces fluid production in the eye, lowering intra-ocular pressure, including linked to SSRIs.
And
- PMT/ PMDD especially for people who do not respond to an SSRI.
This action to reduce localized fluid collections (edema) may link to an overall mild diuretic action. It blocks the reabsorption of sodium in kidneys but not as potently as other diuretics. Other diuretics seem better at removing overall excess bodily fluid but CAIs seem to have more local effects – as in Eyes and perhaps wherever fluid in menstrual linked states accumulates leading to what is experiences as irritability or tension.
Sexual Effects
PGAD was first noted 40 years ago with a first publication over 20 years ago. No successful treatment has been established to date. Against this background, very recently a woman with PGAD reported to her PGAD support group and research network that she had marked relief of her PGAD from Eli Lilly’s Mounjaro – tirzepatide.
Mounjaro did not cure in that as the injection wore off 8 weeks later her PGAD returned but this was immediately relieved by a further injection.
Tirzepatide (Mounjaro/Zepbound) and semaglutide (Ozempic/Wegovy) are also CAIs. Their CAI action may be of some benefit in terms of weight and glucose but this is not the primary mechanism for glucose or weight control. Is, however, this CAI action a factor in relieving PGAD symptoms by an anti-edematous effect that reduces irritability in key tissues?
The only way to find out is for some people with PGAD, PMT, Visual Grittiness and/or Snow syndromes to try it for a few days and see if there are any hints of a benefit.
Acetazolamide
Acetazolamide has an easy and safe to use reputation but here are some of the risks. The lowest dose pill in most places is 125 mg and there is probably no need to go above this although 250 mg should also be safe – it’s the routine dose for altitude. It lasts all day so only one pill in the morning is needed.
Fatigue, drowsiness, tingling of limbs, loss of appetite, altered taste and diarrhea are listed as rare and disappearing within a few days – although folk I know who have been to Everest report lots of mentions of altered taste.
Skin reactions, mainly allergic, are normally not serious but some severe allergic skin reactions or trouble breathing have been reported.
It can lower potassium levels, raise glucose, affect thyroid function, and increase uric acid which can lead to gout and kidney stones – these are all more likely on chronic use.
Confusion has been reported. On the other hand it has been reported as helpful in psychotic states characterized by dreamy states or confusion – the picture somewhat of puerperal psychosis.
As with many pills, the greatest risks often lie in interactions so anyone trying Acetazolamide for this purpose will ideally not be taking anything else.
Acetazolamide is a vastly less expensive and a safer bet than trying to access to Mounjaro or Ozempic, Wegovy or Zepbound.
The goal here is to get people with PGAD or any form of akathisia to test Acetazolamide and see if it helps.
A curious twist
Sodium Valproate (Epilim. Depakote and about 10 other brand names) is today’s most well-known anticonvulsant. It began life as a diluent in which other drugs were mixed until Georg Carraz in Lyon suspected that the diluent might have anti-convulsive properties – see Juggling Our Selves.
DMSO, Dimethyl Sulfoxide, began life as a diluent for sulfonamide drugs including acetazolamide. It is now recognized as a medicine in its own right. It appears to have an action to prevent nerve damage and may assist in nerve regeneration.
Just as Carraz reported that Valproic Acid was not just a diluent but also a drug, a US group reported that DMSO, a diluent, had local analgesic, anti-inflammatory and bacteriostatic effects. When applied to skin, it could penetrate to the tissues below and be useful in pain states like arthritis. Merck removed it from the market, supposedly to establish it’s safety profile.
Another research group tested it in what at the time was called interstitial cystitis, a condition that may be quite different now but today often co-occurs with PGAD. It was also tested in other genito-pelvic pain syndromes, apparently in all cases by applying it to external skin. Not surprisingly this did not produce convincing results but the authors did mention that some cases appeared to respond well – they had no idea why.
Merck decided DMSO was safe and it is now widely available.
A year ago news outlets reported the First Signs of Life elsewhere in the universe. The James Webb telescope had discovered DMSO on a planet 120 light years away. DMSO is a marker for living processes.
My understanding is that DMSO may have been tried in PSSD. There are no reports of it helping but now that we know it has local anaesthetic properties this is not surprising. This profile however might help PGAD.
annie says
A study known as FOCUS…
Can Ozempic Affect Eye Health? Here’s What Ophthalmologists Want You to Know
https://www.aao.org/eye-health/news/can-ozempic-affect-eye-health-here-s-what-ophthalm
The diabetes drug semaglutide has been making headline news ever since the medication received FDA approval to help with blood sugar control and obesity treatment. Semaglutide medications include Ozempic, Wegovy, and Rybelsus.
Results of the Ozempic studies show semaglutide can significantly help people control their blood sugar. But the studies also showed it can cause vision changes, including blurred vision, worsening of diabetic retinopathy and macular complications. So, do the benefits outweigh the risks?
What Is Semaglutide and How Does It Affect the Eyes?
Semaglutide helps people lose weight and control their blood sugar by releasing the hormone that makes us feel full while eating. This hormone, called GLP-1, also prompts the body to create more insulin, which reduces blood sugar.
When the body experiences a change in sugar level, it can affect the shape of the eye’s lens. This change is what causes blurry vision, a side effect of semaglutide.
Older patients are more likely to experience blurred vision when beginning the medication, said retina specialist Raj Maturi, MD. This is because the eye’s lens becomes less flexible as we age, so vision takes longer to stabilize when the body experiences these changes in blood sugar levels.
“The good news is that this is a temporary side effect, usually subsiding after three or four months,” said Dr. Maturi.
Can Semaglutides Cause Blindness?
One new study suggests there may be a connection between semaglutide use and increased risk for a blinding eye disease called non-arteritic anterior ischemic optic neuropathy (NAION). But experts say there isn’t enough data yet to suggest patients should be concerned or should stop taking their medications. People who have diabetes are already at risk for NAION, whether they use semaglutide or not.
“It is premature to conclude that the association is a causal association. More research is necessary to test the hypothesis. Until then, patients should be aware of this information and, in consultation with their care team, make a careful, informed choice based on their individual risk profile,” said neuro-ophthalmologist Andrew Lee, MD.
If patients are already taking semaglutide and have not experienced any symptoms, they should continue to do so as instructed and discuss any questions or concerns with their primary care physician. People interested in starting to take semaglutide for blood sugar control or for weight loss should ask their physician if this medication is right for them.
Will Ozempic and Other Semaglutides Make Diabetic Retinopathy Worse?
People with diabetes sometimes experience abnormally high blood sugar levels, which can cause blood vessels in the eye to leak. This is what causes diabetic eye disease, a leading cause of vision loss.
“It may seem strange that a drug made to help control diabetes could make your eyesight worse, but it’s something we’ve known about for a while. A large clinical study suggested that there is an association between blood sugar control and worsening of diabetic retinopathy,” said Dr. Maturi. “For the majority of people, this won’t be a problem and symptoms are manageable. Make sure to let your ophthalmologist know of any medications you are using, and get your eyes checked regularly. He or she will track for any vision changes and recommend potential treatments.”
Should I Use Ozempic for Weight Loss?
A primary care physician can help patients decide if Ozempic or other dieting medications are right for them. While semaglutide can help avoid overeating, ophthalmologists emphasize that this is not a substitution for taking care of your overall health.
“You still need to live a healthy lifestyle—eat well, exercise, and show up to your medical appointments as advised. For patients who really struggle with their diet and controlling their blood sugar, this drug can powerfully influence the desire to eat and help improve their life,” said Dr. Maturi. “My suggestion for a patient who discussed this with their doctor and decides to use the drug is to make sure that they are using it as instructed and to be patient with any known side effects, including blurry vision.”
Researchers are working to learn more about the long-term effects of semaglutide on diabetic retinopathy in people with type 2 diabetes. A study known as FOCUS will evaluate the effects of semaglutide in addition to diabetes medication on diabetic retinopathy. The study is expected to conclude in February 2027.
Dr. David Healy says
Annie
Good to get all details but this risks confusing things. In this case the interest is in looking at the eye effects of carbonic anhydrase inhibitors in people who do not have diabetes. Diabetes introduces its own eye problems that take months or longer to reverse and things – not just eye problems – getting temporarily worse is reasonably common and well-known.
In people who have SSRI linked problems the effects seeing what a carbonic anhydrase inhibitor does is much more clearcut and in treating glaucoma which SSRIs can cause the effects can be pretty immediate.
When it comes to antipsychotics phenothiazines are Carbonic Anhydrase Activators so will cause SSRI like problems but it looks like haloperidol and risperidone are not. Trouble is there are 7 different CA enzymes and the binding of drugs to them can be competitive or non-competitive but we don’t know which one is key and what kind of binding Acetazolamide has
D
annie says
Although this was spurred by ‘Diuretics’ exam questions; his investigations of Acetazolamide did bring up some pointers –
Acetazolamide does not do anything interesting to enzymes and its clearance is boring and uninstructive. The real meat and potatoes is where it inhibits carbonic anhydrase. If a single article was needed for quick revision, the best would have to be Kassmali & Sica (2011), “Acetazolamide: a forgotten diuretic agent”.
On a completely different topic, acetazolamide is related to, and itself a member of, antiepileptic drugs. According to Reiss & Oles (1996) it has been approved for use in epilepsy since 1953, and the mechanism of effect is related to CNS acidosis:
However, acetazolamide has a far higher affinity and its CA-inhibitor effects are dominant, whereas for other drugs they are lost as a minor side-effect amid their primary mechanisms of action.
In spite of this small-seeming VOD, this drug seems to get everywhere, including the central nervous system.
https://derangedphysiology.com/main/cicm-primary-exam/required-reading/renal-system/Chapter%20023/acetazolamide
tim says
After reading Vision Weird, Vision Blurred and Visual Snow, I commented:
This has been truly fascinating. A Masterclass in Pharmacology.
Yesterday, I read Complex Sensory Imbalance: New Remedies. This was also absolutely compelling.
I found myself eagerly making written notes for future reference.
I have just read it for the second time and made more detailed notes.
Two concepts have emerged:
1) My Medical School and Post-Graduate Training in Pharmacology emphasised one single action of a drug.
It is clearly of great importance to understand as many different actions of a drug as possible.
2) This scientifically and precisely explained pharmacology seems so important and so logical, yet I wonder if it could be accepted by current prescribers?
Perhaps the palpable difference in this information delivery is due to the scientific purity in these RxISK presentations; compared with the marketing-based motivation in day to day CME? (Continuing Medical Education)?
chris says
I have watery eyes since the drugs I was made to take.
But the main issue I have at the moment is this mini heatwave we are having – it’s been trying to keep my body cool at night, hopefully it will be over in a few days. It was never an issue before the drugs.
It is fascinating to read about a realisation of akathisia in localised areas, even eyes. Am going to be thinking about this, doubt there are any references or anyone else having these thoughts on akathisia.
tim says
I wonder if the degree of distress and the suffering resulting from psychotropic drug damage to human thermoregulation is widely recognised by prescribers?
It is prolonged, intense and restricts many aspects of life, yet I can’t imagine how I might try to describe this aspect of our loved one’s suffering if we were able to consult a GP.
(Not an option after such absolute destruction of trust following misdiagnosis of akathisia).
Many years ago, I was taught that the brain centre in which thermoregulation is controlled is the hypothalamus.
I ask myself: Is the loss of body temperature control due to chemical injury to this centre?
Might it result from damage to peripheral fine nerve fibres or sensors, a failure of blood vessel dilation/widening to disseminate heat?
Is it multifactorial in causation?
I do know that it causes yet another hidden, drug induced, significant disability.
Like you, I was intrigued by the observation that ophthalmic/optical adverse reactions, and PGAD may be conceptualised as localised manifestations of akathisia.
Chris says
(Not an option after such absolute destruction of trust following misdiagnosis of akathisia).”
Absolute destruction of trust
Yes this was how I felt especially after realising through my own experience of making a complaint that there is no real regulation. We have heard just last week the CQC is not fit for purpose well this was said 10 plus years ago. Nothing will be done because if it was an awful lot of people would be prosecuted for major human rights abuse due to serious adverse drug reations inducing major harm including death as a result of forced poly drugging in a prison – there are at least two locked doors to the outside world in a psych ward – called a mental “hospital”.
Another thing, the definition of akathisia should – in my view -include the affect on others such as yourself…. those who have a close realative with ongoing affected issues.
Anne-Marie says
Chris there is nothing worse than being too hot and you can’t cool down. I’ve been suffering unbearable heat at work (they have no aircon) and the place is stuffy, dry and hot. I started having icecream at work half way through the day and it is heaven. It cooled me down and saved me from flaking out.
I wonder if this could help releave your suffering for a short while.
chris says
Spend over £1000 on a small quiet portable air conditioner for my bedroom. Works like a fridge with a fan to blow cooled air and requires a heat outlet which I rigged up through a window. It works but you can’t sleep with it on so I can cool it down before I go to bed but it warms up again during the night.
Another problem recently presented itself in that due to the heat outlet neighbours assumed I was growing canabis and in formed the police. Can you imagine the stress….
Love to be able to solve the problem with an ice cream.
I would not be able to work under your circumstance and hope things improve for you.
Anne-Marie says
One last thing Chris make sure you drink plenty of fluids when it’s hot as dehydrated can make you feel worse. I have to keep reminding myself to drink more water as I have in the past felt very ill in the heat for not drinking enough.
Lany says
I have had visual issues/ear pressure like described here since I took psychedelics as a teenager (I now know these also act on serotonin), & now i have akathisia from SSRIs/benzos. I am clearly very sensitive to serotonergic drugs.
I would be willing to try since I have multiple issues listed here. This has effected my life greatly for the last 11 years & I am only 26.
chris says
Anybody read this:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651045/
I just laughed. If they spend a year in a psych “hospital” as I have they would have to fill themselves full self delusion of the drugs ‘uncovering a psychosis’ not to see the AP akathisia. It’s just incredible.
annie says
Three laughs for you –
Robert Howard reposted
Jesus Ramirez-Bermudez@JRBneuropsiqAug 4
It’s true! Being a clinical psychiatrist is not only about reducing symptoms. It involves understanding the person, caring about their overall life perspective, their sense of purpose & values, & their struggle to construct or recover their own meaning of life.
Allen Frances@AllenFrancesMD
Hard to have psych symptoms (especially severe ones) without becoming demoralized/losing hope/doubting value. Clinicians primarily treat symptoms- but also can help patients regain perspective/joy/meaning in life. Essential part of the recovery model.
If I ever needed ‘meaning in life’, to a psychiatrist I would not go.
You live and learn, but ‘they’ seem to live in some sort of utopia, self-indulgent claptrap –
Having failed at advancing psychopharmacology, ‘meaning of life’ seems malevolent and saintly…
chris says
Thankyou very much Annie I sure need a laugh or three today!
Harriet Vogt says
Pharmacological bravura. Iatrogenically harmed patients need this kind of clinical thinking – and hope.
I’ve been following up on PGAD. Never suffered anything so horrendous. But, as I expect most women have (much more common for us than biological males), I can empathise from past (thankfully) occasional and easily treated experiences of cystitis – when a normally painless, physical function morphs into a horrorshow. A constant, uncontrollable urge to pee, a urethra that feels like it’s been set alight, swollen, tender and almost gasping in pain with every compulsive trip to the loo – to pass a drip – at most.
You zeroing in on the anti-edematous effects of CAIs/semaglutide makes a lot of intuitive sense. If you examine the problem from an aesthetic rather than biochemical perspective, one of the undesirable adverse effects of semaglutide, as well as ‘Ozempic butt’ and ‘Ozempic face’, is apparently ‘deflation of the vaginal lips’ and I’d guess erectile clitoral tissue and genital zone generally.
https://www.drtahery.com/ozempic-vagina-what-are-the-side-effects-of-semaglutide
https://aayla.com/patient-resources/how-ozempic-wegovy-and-mounjaro-zepbound-can-affect-your-labia/
Needless to say the cosmetic surgeons in the US have jumped on this new marketing opportunity – and are promoting not just labiaplasty to tidy up deflated bits, but ‘labial puff’, aka fillers.
Extrapolating from these aesthetic issues, it does sound like what might have happened to your patient afflicted with PGAD on Mounjaro, is that her swollen, congested, hyper-aroused, genitals my have shrunk, literally deflated – and with that deflation calmed down a bit? Could this be the anti-edematous effects of the CAI component of tirzepatide in action – and/or … And we know that semaglutide stops working fast unless you keep up the jabs.
One of the most significant effects of semaglutide is apparently dehydration – and patients are counselled to keep up their water intake. Is this connected or?
https://www.slimtransformation.co.uk/post/stay-hydrated-the-importance-of-water-when-using-ozempic