Antibiotic minocycline shows potential for treating panic disorder symptoms

A study supported by FAPESP shows that small doses of the antibiotic minocycline may help treat panic disorder. Experiments conducted at São Paulo State University (UNESP) in mice and at the Federal University of Rio de Janeiro (UFRJ) in humans showed that minocycline has a similar effect to clonazepam, the most commonly prescribed anti-panic medication and best known by its brand name, Rivotril.

The study was published in the journal Translational Psychiatry.

The antibiotic doses required to treat panic attacks in the study were lower than those used to treat bacterial infections, reducing the likelihood of developing bacterial resistance.

"In our experimental model, which uses carbon dioxide [CO₂] inhalation to induce a panic attack, the mice treated with minocycline for 14 days prior to the experiment showed a reduction in one of the panic-inducing responses. In humans, the treatment reduced the intensity of panic attacks triggered by CO₂ inhalation," says Beatriz de Oliveira, the first author of the study. Oliveira conducted the study during her undergraduate research with a FAPESP scholarship at the Faculty of Agricultural and Veterinary Sciences (FCAV) at UNESP in Jaboticabal.

The study is part of the project "Physiopathology of CO₂ Sensitivity: Role of the Locus Coeruleus", which is supported by FAPESP and coordinated by Luciane Gargaglioni, a professor at FCAV-UNESP.

It's well known that some psychiatric conditions result from nerve cell inflammation. Since minocycline has an anti-inflammatory effect at low doses but not necessarily an antibiotic effect, the improvement in symptoms likely occurs through the reduction of inflammation. It's a different mechanism than that used by clonazepam, which acts by inhibiting specific receptors in the brain." 

Luciane Gargaglioni, Professor at FCAV-UNESP

While some responses to antibiotic treatment differ from those to clonazepam, which was used as a control in the human study, minocycline may be an alternative for patients who do not respond to psychiatric medications. These medications account for about 50% of cases.

"Clonazepam potentiates the action of GABA [gamma-aminobutyric acid, a neurotransmitter] by binding to the receptor of the same name. These receptors are present throughout the brain. Therefore, using clonazepam also reduces heart and respiratory rates, impairs decision-making ability, and causes other side effects, such as dependence, which makes it a controlled substance," Gargaglioni explains.

Since minocycline is already used for another purpose, it is safe for humans. Therefore, clinical trials could proceed directly to Phase 2, which includes an increase in the number of patients, testing of different doses, and evaluation of possible side effects, among other assessments conducted in this type of study.

This research also paves the way for searching for other drugs with anti-inflammatory action on microglia that could have a similar or even more satisfactory effect than minocycline in treating panic disorder.

Experiments

The researchers observed that patients who took minocycline had reduced levels of pro-inflammatory cytokines, such as interleukin (IL)-2sRα and IL-6, and increased levels of IL-10, which promotes an anti-inflammatory response. Additionally, there was a reduction in TNFα, a cytokine linked to various inflammatory processes.

A total of 49 patients diagnosed with panic disorder were analyzed. At the start of the study and again after seven days of taking clonazepam or minocycline, they inhaled air enriched with 35% carbon dioxide. On both occasions, trained psychiatrists measured anxiety symptoms using standard methods for this type of study.

"Neither that concentration of CO₂ nor the 20% concentration used in the mice is found in nature. However, excess carbon dioxide causes the same sensation of suffocation as a panic attack. Since it's a very unpleasant sensation, the control group took clonazepam. It wouldn't be ethical to have a group take a placebo in this case," says Gargaglioni.

Although the scientific literature has reported differences in cytokine levels in mice undergoing different treatments, these differences were not detected in the current study, likely due to methodological limitations.

Following treatment with minocycline, however, significant behavioral responses were observed in the animals, including a reduction in jumping – one of the responses after they were induced to have a panic attack by enriching the air with 20% CO₂.

Analyses of the locus coeruleus, a CO₂-sensitive region of the brain, showed a decrease in microglial density in the mice six hours after gas exposure. This finding reinforces the role of this part of the brain in panic attacks.

"We tested different intervals during which changes in the brain could be observed and concluded that six hours after 15 minutes of CO₂ exposure is ideal, which is an important finding for future studies," says Oliveira.

Further studies are needed before minocycline can be adopted for this purpose. The current study opens the door to a new way of treating this and other psychiatric conditions related to increased inflammation in nerve cells.