Lots of people complain of memory and other cognitive problems on or after taking medications, whether psychotropic drugs such as serotonin reuptake inhibitors, cholesterol lowering statins or fluoroquninolone antibiotics.
The term “brain fog” refers to the experience of a general cognitive impairment that can include deficiencies in memory, concentration and ability to think clearly.
These issues are different to the known memory problems:
- Benzodiazepines have clear and easily demonstrable effects on episodic memory.
- Antipsychotics have effects on set-switching and the memory problems that might be linked to set-switching such as the ability to remember the right phone number for the right person.
- The statins are linked to Transient Global Amnesia [1,2].
- Anticholinergic drugs are linked to memory impairments, and extensive work has gone into the development of choline esterase inhibitors aimed at enhancing memory functions in patients with dementia. For the most part the hope has been to find agents that stop or reverse the impairments of episodic, declarative or semantic memory found in dementia.
In contrast to these cognitive difficulties, a wide range of skills are retained in dementia where the behaviours are learnt, such as piano playing. These are based on procedural rather than declarative memory.
It is possible in many instances to demonstrate conclusively normal or degraded functioning in aspects of memory predicated on the normal operation of higher executive functions. This can most clearly be done in patients with gross neuropsychological injuries, where a specific function may be compromised.
But many other people complain of problems, in whom it has proven more difficult to provide an objective demonstration of cognitive impairment. The assessment problems include the clearly brain injured patients where deficits in functioning can be demonstrated, but who complain of problems beyond those that are demonstrable. This has given rise to the notion of metamemory problems, which accepts that the person is affected but holds out the possibility that the problem has more to do with the way we experience memories than with actual memory failures.
At the other end are patients who are in withdrawal from antidepressants who complain of brain fog, but whose complaints are all too likely to be dismissed as neurotic because the problem cannot be objectively demonstrated. The fact that this complaint is deemed neurotic contributes to views that complaints of dependence and withdrawal are in general neurotic, which reinforces the difficulties for patients in getting their experience recognized.
In addition to patients either on or withdrawing from antidepressants, several other groups of patients complain of brain fog, most notably those on statins or fluoroquninolone antibiotics.
There are very clear descriptions of brain fog for these three treatments. Typical descriptions point to difficulties with routine tasks, so that these require greater concentration and attention than usual, making work and much else seem more effortful than usual (See Appendix). However, when tested on attentional tasks, working memory, or almost any tests of cognitive or mnemonic function, patients with brain fog will ordinarily do well. There is no specific diagnostic test that can validate their complaints of the syndrome.
This article proposes an origin for the experience of brain fog and other metamemory problems in established models of cognitive functioning.
Muscle memory impairments?
The books don’t mention memory problems on SSRIs, but looking at adverse event reports in FDA’s adverse event report database on RxISK shows that memory problems are linked to serotonin reuptake inhibiting drugs.
These problems likely occur both on treatment and in withdrawal – FDA’s database does not distinguish between these options. The RxISK database does distinguish between these events and makes it clear that brain fog can occur both on and for months after stopping treatment and is more common in the withdrawal state.
One group of patients who complain of memory problems in both the FDA and RxISK databases are those taking the fluoroquinolone antibiotics – levofloxacin and ciprofloxacin. The cognitive difficulties linked to these drugs can be severe enough to give rise to frank disorientation [3,4]. More generally, very high numbers of patients reporting problems on fluoroquinolones to FDA have reported memory problems while 25% of those reporting problems on fluoroquinolones to RxISK have reported memory problems.
In addition to memory problems, patients on fluoroquinolones report muscle wasting, muscle pain, and tendonitis. These drugs are the commonest cause of ruptured Achilles tendons.
But the curious thing is that almost everyone who has reported muscle and tendon problems to RxISK complains of memory problems also.
Patients taking statins are a further group who complain of both muscle and memory problems. The muscle destruction (rhabdomyolysis) linked to statins is uncontested, so that research in this area centers on finding a genetic marker to predict those at risk of this problem with a current focus on the SLCO1B1 T521C marker (Constantinos et al 2014).
But in addition to muscle problems, lots of people on statins have cognitive problems. FDA’s database shows numerous reports of memory problems on commonly prescribed statins such as simvastatin, atorvastatin, or rosuvastatin for instance. One of the problems with FDA’s adverse event database is that it is difficult to be certain just what is being reported in some cases. This is certainly the case for memory problems where the coding default will often be to memory impairment, and especially if a memory problem cannot be supported by formal cognitive test abnormalities.
On the RxISK database, as with patients on fluoroquinolones almost all patients on statins complaining of memory problems also report muscle problems.
Aside from clear cases of Transient Global Amnesia on statins, however, it has been difficult to bring statin related cognitive problems into focus.
In 2004, Muldoon et al reported on a controlled trial tracking cognitive function in patients randomized to placebo or high or low dose simvastatin . There were no abnormalities on tests of executive functioning or declarative memory. But, patients on statins showed an impairment of learning compared with those on placebo, when retested after 6 months.
These findings are consistent with an effect of these drugs on procedural memory. Procedural memory underpins the learning of skills, such as piano playing or typing. In the case of piano playing, music teachers commonly refer to muscle memory. Skills like this can be disrupted by muscle injuries to the extent of requiring new learning. In contrast these skills can be retained in dementia. Procedural memory impairments of this sort therefore stand in contrast to the abnormalities found in dementia which involve executive function.
The combination of muscle injury and cognitive complaints found in fluoroquinolone and statin patients opens the possibility that procedural memory has been affected. The memory in this case in some sense lies in muscles, as the phrase muscle memory suggests, or perhaps more accurately in movements that cannot now be undertaken or have to be relearnt, and is more generally better termed learning.
The experience of piano players who have injured an arm is that they have to relearn skills. They do not complain of brain fog.
In the case of patients on statins and fluoroquinolones however there is more extensive and subtle injury to a range of muscles affecting a wide range of skills. This will result in the unsettling experience of getting things wrong that should be second nature and as a result having to pay more attention than usual and having to concentrate more than usual. This is far more effortful. This combination of effortful performance and apparent poor performance despite clearly concentrating more can be expected to give rise to many of the features of brain fog and maps well onto the descriptions offered below.
Patients who complain of impaired memory or poor cognitive function and attentional difficulties will in fact have normal performance on all tests of executive memory function, and in addition, normal function on tests of attention and concentration. The one set of procedures that might detect effects across a group of patients are those employed by Muldoon et al , but even these will not be diagnostic for an individual patient.
Just as there is a problem demonstrating autobiographical memory deficits, so also there is inevitably a difficulty demonstrating autobiographical learning impairments post hoc, when new learning may be relatively intact.
The serotonin reuptake inhibiting antidepressants are not linked to rhabdomyolysis or snapped tendons in the way statins or fluoroquinolones are. But serotonin was discovered in gut walls and its action as a neurotransmitter was also first demonstrated on gut muscle contractility. There is much more serotonin in gut than brain and the role of serotonin in voluntary and involuntary muscle contractility has been repeatedly demonstrated [6,7]. There is abundant evidence for a range of muscle changes on SSRIs from dystonias of voluntary muscles to altered gut function both on treatment and in withdrawal.
There is conflicting evidence for a role for serotonin in executive functions and in learning but agreement that there is extensive serotonergic input to the hippocampus which has roles in both memory and learning . There are indications from some studies that drugs with agonist effects at S1 receptors can cause learning problems, while antagonists at S3 receptors can produce improvements in learning based performances. This latter point opens the possibility that S-3 antagonists might enhance new learning in the presence of activity and might on this basis lead to a dissipation of brain fog over time.
If this hypothesis has any merit, it is a moot point whether the changes in procedural memory are more likely to follow changes in voluntary or involuntary muscle function. Visceral changes have a greater input to vigilance systems based in the locus coeruleus than do voluntary muscles .
There are a range of disorders and treatments across medicine that give rise to conditions variously termed chemo brain or brain fog by patients. These have resisted delineation. The apparent mismatch between the findings from research and the experience of patients in these states might be explained if the effects of these drugs are on the substrates of procedural memory rather than on executive functions.
The experience of errors and increased effort can be expected to give rise to anxiety and such combinations could for instance underpin the difficulties experienced in the menopause.
In instances of gross muscle damage, some of the cognitive problems that arise are not likely to be amenable to drug treatment. In some cases of dysregulated motor or gut function, treatment with drugs may be more successful. The role of a drug treatment however need not be aimed at reversing the original dysfunction; it might rather help if it produced compensatory changes. In either case pinpointing the nature of the problem might still be of benefit, and might be therapeutic in its own right.
Just as piano players can relearn skills, so also a recommendation to relearn in order to restore muscle memory and the cognitive function that goes with it might be helpful. Recognizing that the non-specific complaints in these clinical syndromes are neither neurotic nor the result of irremediable brain damage may offer a roadmap for a range of therapists from physiotherapists to occupational and fitness therapists to come up with programs that may be of benefit.
Appendix: Brain fog
Case 1: SSRI withdrawal
I have difficulty finding words or names whilst in conversation. I have to consciously think about what shape my mouth should be making, try and picture the word, its length and what I think it begins with. Sometimes I have to opt out of a conversation because I just get stuck. I may construct the thought in my head, but when it comes to speaking, I’ll completely forget what I was going to say. My brain has to work overtime to recollect the words and point of what I was saying. It doesn’t always come out how I want and is often simplified or doesn’t make any sense, but I can’t rectify any of it, I just feel really confused.
Asked to speak on local radio, answering questions, I have felt I speak nonsense but have been told I still do it well which is surprising to me. Having to consciously find words and what I want to say makes my head feel heavy.
I also have problems focusing on things like a flower. Almost of having the high definition vision I am used to, everything is more pastel and less defined. I have to consciously blink, open my eyes wide and focus in on things to see something clearly, but then its only momentary. Seeing the details in things was a strength in my art work. I was a person of detail.
I get irritated when I’m trying to watch something and someone talks at the same time. I think because it takes me so much energy to focus on one thing, if someone breaks that flow I feel I’ve lost where I’m at and it takes me time to re-focus. When I research things, I find that instead of reading something and making sense of it I have to re-read things to get a grasp of it and deconstruct a sentence so I understand the relation each word has to the other. Information doesn’t seem to stick in my mind very well anymore.
When walking the dog, doing housework, driving, going round the supermarket, it often feels like I’m living in a dream. I am aware of the general goings on but nothing really comes into focus.
I can be driving knowing one minute where I am going but the next moment I forget. Sometimes in supermarket I have to stop in my tracks because I’ve forgotten what I’m there for. I can be making a cup of tea and forget what stage I’m at – have I put the water in the kettle, has it been switched on? I’ve put cold water on a teabag a couple of times. I have to do a check list for menial tasks.
When watching television I often find I can’t focus on what’s happening. I may have to rewind it so I can try to make sense of it.
Social situations are distressing because I don’t always ‘hear’ what people are talking about, I know they are talking but I can’t absorb or make sense of what they are saying. Even more so when there’s more than one conversation going on at once, it takes energy to focus on one person.
I have sung for most of my life. I am good at picking up a song quickly; the tune and the lyrics. I am one of the singers in the band we have at church but have found that I have to remind myself more often the lyrics and if I’m harmonising where I’m meant to go on songs I’ve done loads of times.
I had been very good at multi-tasking at work. I can have several queries at a time and routinely do all at a fast pace, but now I struggle. I also make errors, despite my best efforts to take my time and double, even triple check things.
I can put a wash load on and forget temporarily which slot the detergent and which the conditioner goes in to.
Case 2: Statin linked
My first experience of brain fog was when my secretary handed me a piece of paper with the new location and room number of a seminar class I was teaching. I read the piece of paper and the information disappeared instantly. By the time I got to the room, I had looked at the paper several times but could not remember what I had read each time – it just won’t go into my head. Had she not written the information down, I would have been lost.
The landscape seems cluttered and you can’t pick out things of importance you are looking for on your monitor, on a page. I can’t organize things in sequence. I can’t do subtraction in my head, or recall common words, people’s names, or birth dates. I cannot figure out how to draw or read a sketch map – trying to give or remember directions is almost impossible
I have great difficulty concentrating. It is very hard to read something all the way through, the eye moves along in a non-disciplined way and it is hard to read things in sequence.
It is very hard to keep track of things, put something down and it is gone one second later
All of this is associated with a low grade anxiety and fatigue because you can’t quite grasp what is going on.
This inability to concentrate or to think clearly makes it impossible both to follow a recipe in the kitchen or to teach or administer large classes, which involves coordinating with several teaching assistants. I couldn’t insure accuracy of lecture schedules, exam dates and contents and of course could not figure out what exactly was going on or why I couldn’t do the things I had been doing for years.
- Wagstaffe, LR, Mitton, MW, McLendon, B, et al. Statin associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003; 23: 871–80
- Healy D, Morgan R, Chinnaswamy S (2009). Unexpected outcome (positive or negative) including adverse drug reactions. Transient global amnesia associated with statin intake. BMJ Case Reports 2009, doi:10.1136/bcr.06.2008.0033.
- Kiangkitiwan B, Doppalapudi A, Fonder M, Solberg K, Bohner B (2008). Levofloxacin induced delirium with psychotic features. General Hospital Psychiatry 30, 381- 38
- Raj L, Murthy TV (2013). Levofloxacin induced delirium with psychotic features in a young girl. Medical J Armed Forces India.
- Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB (2004). Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Medicine 117, 823-829.
- York B, Twarog B (1973). Evidence for the release of serotonin by relaxing nerves in molluscan muscle. Comp biochem physiol 44, 423-430.
- Bendtson L, Jensen R, Olesen J (1996). Amitriptyline, a combined serotonin and noradrenaline reuptake inhibitor, reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension type headache. Electroencephalography and Clinical Neurophysiology 101, 418-422.
- Cowen P, Sherwood AC. The role of serotonin in cognitive function: evidence from recent studies and implications for understanding depression.. J Psychopharmacology 27, 575-583.
- Svensson TH (1987). Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: putative implications for psychiatry and psychopharmacology. Psychopharmacology (Berl.) 921–710.1007/BF00215471