Antibiomania

Any medication can cause side effects, ranging in severity from trivial to life-threatening. There can also be psychiatric side effects, such as depression, mania, confusion, or even psychosis. Some medications are well known culprits. Elderly people are particularly susceptible to confusion from medications that block the neurotransmitter, acetylcholine, in the brain. Such anticholinergic medications include some antihistamines, medications for bladder control, and anti-motion sickness medications. The older, so-called tricyclic antidepressants are strongly anticholinergic and should be avoided in the elderly.

Corticosteroids, such as prednisone, can cause depression, mania, or psychosis.  Anabolic steroids, often used illegally by body builders, can cause agitation, anger, and paranoid thoughts. Finasteride, which blocks conversion of   testosterone to dihydrotestosterone, treats both baldness and enlarged prostates.  It can cause loss of sex drive and sexual function. However, the drug also blocks another important steroid conversion in the brain. That is, the conversion of progesterone into allopregnanolone. Lack of  allopregnanolone can lead to anxiety and depression.

Medications for Parkinson’s Disease often produce psychiatric symptoms. Most increase the activity of dopamine in the brain. High doses can cause paranoid delusions and hallucinations. Other medications with reputations for producing psychiatric side effects are the acne treatment, isotretinoin; the malaria drug, mefloquine; the opiate, pentazocine; and the hepatitis treatment, interferon-alpha.  Unfortunately, some psychiatric medications can themselves produce unintended psychiatric side effects. Most notably, antidepressants can cause mania if what is diagnosed as Major Depression is actually bipolar depression. 

While some medication-induced psychiatric side effects are well known, others are rare and unexpected. Many doctors, including psychiatrists, are unaware that some antibiotics can induce agitation and mania. This phenomenon, called antibiomania, was first described in a 2002 paper by Dr. Ahmed Abouesh, with whom I served as a fellow resident at the University of Virginia Medical Center. Abouesh then discussed about 100 cases.  Most involved the antibiotics isoniazid, clarithromycin, and ciprofloxacin.

That isoniazide, used to treat tuberculosis, could cause mania is understandable. Isoniazide prevents the growth of the Mycobacterium tuberculosis bacteria by blocking the production of mycolic acid, a substance essential for the bacteria. However, the drug also blocks the activity of an enzyme in the brain called monoamine oxidase, or MAO. MAO inactivates the neurotransmitters serotonin, norepinephrine and dopamine. In blocking MAO, isoniazide enhances the activities of those neurotransmitters, which is how most antidepressants act. In fact, the serendipitous observation of improvements in mood of patients being treated for tuberculosis with isoniazide led to the discovery of antidepressants in the 1950’s. As noted above, antidepressants, including MAO inhibitors, can induce mania in patients that  suffer forms of bipolar disorder. Also of concern, isoniazide and linezolid, a newer antibiotic that also inhibits MAO, can cause the potentially fatal condition, serotonin syndrome, if given to patients already taking antidepressant medications.

The mechanisms by which clarithromycin and ciprofloxacin produce mania are more surprising. Clarithromycin and other so-called “mycin” antibiotics, such as erythromycin and azithromycin, fight bacteria by blocking their ability to produce proteins necessary to grow and reproduce. However, entirely unrelated to that antibacterial action, they also have ability to decrease activity at the GABA-A receptor.  GABA is a neurotransmitter in the brain that has a calming effect on neural activity. Anti-anxiety medications, such as the benzodiazepines Xanax and Valium, act by enhancing GABA-A receptor activity.  Thus, clarithromycin can have effects opposite to those of the anxiolytic benzodiazepine drugs. Rather than calming and relieving anxiety and agitation, clarithromycin can cause agitation, mania, and insomnia. It has even been used successfully to treat idiopathic hypersomnia, a condition of extreme daytime sleepiness. Ciprofloxacin and other “floxacin” antibiotics, such as levofloxacin and moxifloxacin,  work by inhibiting the enzyme, DNA gyrase, that is essential for maintaining the bacteria’s DNA. However, similar to the mycin antibiotics, they can also block GABA activity. The effects of the floxacins on GABA may be different than those of the mycins, as they appear to mostly block activity at a subtype of GABA receptor called the GABA-B receptor. However, the floxacins may also enhance the activity of neurotransmitter glutamate in the brain. Glutamate tends to have effects opposite to those of GABA. 

Other antibiotics that have been reported to cause mania are amoxicillin, ceftazidime, and imipenem, all of which can antagonize activity at GABA-A receptors. There have also been reports of mania caused by  metronidazole and Bactrim, which is a combination of sulfamethoxazole and trimethoprim. Metronidazole antagonizes GABA-A activity, but only mildly so. It is unclear how Bactrim might cause mania.

It is fascinating to consider that drugs designed to interact with the biology of bacteria can also interact with receptors and enzymes of the human brain. Many medicinal molecules are pleiomorphic, that is, they can randomly bend and twist, change shape, and occasionally hit unanticipated targets. However, early in the evolution of life on Earth, organisms incorporated molecular structures that were well suited for certain types of biochemical reactions. Many have been part of terrestrial organisms since life began.  Thus, we share  more biochemical machinery with bacteria, invertebrates, reptiles, rodents, and even plants than may be comfortable to consider.  Unexpected effects can happen.