By Julian Lieb, M.D.

Stimulating immune function would transform the prevention, treatment, research and economics of infectious disorders, among them the acquired immunodeficiency syndrome (AIDS), hospital-acquired infections, antibiotic-resistant bacterial infections, resistant tuberculosis, a possible avian influenza pandemic and acts of bioterrorism. Immune stimulation is widely held to be beyond our reach, an unfortunate misconception, for as early as nineteen eighty-one published evidence showed that lithium (1) and antidepressants (2) have immune stimulating and antimicrobial properties (3).

In the early 1950’s physicians observed that patients treated for tuberculosis with the monoamine oxidase inhibitors isoniazid and iproniazid became animated and energized, the observation the first that drugs are capable of acting as antidepressants. That monoamine oxidase inhibitors have dual antimicrobial and antidepressant properties curiously failed to impact the pharmacology of infectious disorders. Remission of such manifestations of viral infections as sinusitis, bronchitis, frequent colds, sore throats, cold sores and genital herpes in patients taking lithium carbonate has been reported. In various studies chronic lithium therapy reduced the rate of recurrent labial herpes infections, while lithium and antidepressants reduced the rates of common, “flu-like” colds, and lithium reduced the frequency and duration of recurrences of genital herpes.

The white blood cells of a woman with recurrent staphylococcal and streptococcal skin infections were unresponsive to stimulation. Addition of lithium to her cells restored their response. After receiving lithium for five weeks she became free of infection, and relapsed when lithium was withdrawn. Lithium chloride prevents replication of type 1&2 herpes virus in baby hamster kidney cells, augments several immune reactions in laboratory settings, and enhances antibody synthesis in humans.

Antidepressants can remit tuberculosis, canker sores, cold sores, genital herpes, upper respiratory tract infections, plantar warts and reduce the frequency of recurrences of shingles, remit the pain of this disorder and prevent post-shingles pain. Antidepressants can destroy the organisms of various parasitic diseases, inhibit the growth of the intestinal parasite giardia lamblia, and have antimalarial properties. Antidepressants enhance susceptibility to chloroquine in resistant malaria, and can destroy such parasites as those of sleeping sickness. Antidepressants are lethal to disease causing fungi, remit recurrent vaginal candida, have antibacterial activity, and synergize antibiotics against several bacteria. Evidence to date shows that lithium has antiviral and antibacterial properties, while antidepressants have antiviral, antibacterial, antiparasitic, and fungicidal properties. While laboratory studies show that lithium and antidepressants have direct antimicrobial properties, their actions on the brain would seem to be responsible for their immune stimulating properties.

A therapeutic claim is reinforced when the mechanisms are known. Prostaglandins are ephemeral, infinitesimal and powerful lipid signalers that self-regulate every cell in the body, including those subserving mood and those subserving immune function, and differentiating between the function and dysfunction of every cell. Prostaglandins regulate the physiology, immunity, replication and toxicity of microbes, and the resistance of their hosts. When synthesized excessively prostaglandins depress immune function, allowing microbes to replicate. The failure of such anti-prostaglandin drugs as aspirin and ibuprofen drugs in infection led to the conclusion that prostaglandin inhibition has limited value in this context. The prostaglandin- inhibiting properties of lithium and antidepressants have been neglected, along with their unique immunopotentiating and antimicrobial actions. Lithium and every antidepressant tested inhibit prostaglandins in a more complex fashion than aspirin and ibuprofen, and act on a wider variety of enzymes. This probably accounts for lithium and antidepressants having powerful immune stimulating and antimicrobial properties, which aspirin and ibuprofen do not.

The relationship between prostaglandins and viruses has been studied intensively, especially the human immunodeficiency virus (HIV). Where HIV comes into contact with arachidonic acid, the precursor of prostaglandins, it converts it into prostaglandin E2, the most powerful, ubiquitous and immune suppressive of all prostaglandins, and possibly responsible for the immune suppression that is the hallmark of AIDS. An HIV protein powerfully induces prostaglandin E2 production, and humans with AIDS dementia have a marked increase in prostaglandin E2 in their spinal fluid.

Prostaglandins are present in high concentrations in the saliva of such blood-sucking insects as ticks. They are involved in parasite metabolism and physiology, facilitate feeding by increasing local blood flow, and prolong attachments of ticks by suppressing immune mechanisms. Release of prostaglandins by parasites plays a role in penetration, immune suppression, inflammation and modulation of blood clotting. Induction of prostaglandins is responsible for many of the symptoms of bacterial infection including the Immune suppression. Disease causing fungi produce and respond to prostaglandins. Prostaglandins regulate the physiology, immunity, reproduction and toxicity of microbes and the resistance of their hosts.

The depressive effect of bereavement and other stresses on immune function is well documented. Impaired immune function has been demonstrated in depressives, and antidepressants are known to stimulate immune function. While lithium is effective against some bacteria and viruses, evidence for its effectiveness against parasites and fungi is lacking. Antidepressants, on the other hand, are effective against various bacteria, viruses, parasites and fungi. As lithium and antidepressants have immunopotentiating as well as antimicrobial properties, they stand to be effective against a gamut of microbes. The response of infection to lithium and antidepressants mirrors the treatment of depression in which subjects respond to tricyclic antidepressants, specific serotonin reuptake inhibitors, monoamine oxidase inhibitors or lithium. An infection should not be labeled refractory to antidepressants until many, if not all have been tried. Many studies with antidepressants are biased by the generalization that “antidepressants” lack a specific property when the study involved only one. Antidepressants are highly specific and humans remarkably variable.

Developing a vaccine for pandemic influenza has the disadvantage of needing to know the strain of the virus, which may mutate from preparation to use. That problem would not exist with immunostimulants: once stimulated, an immune system should be effective towards all strains. The disadvantage with antidepressants as immunostimulants is matching drug to human: sertraline might be effective for one person, fluoxetine for another. Another advantage of immunostimulation would be its value in coinfection. Resistant tuberculosis, malaria and HIV are a common coinfection in the third world. Imagine the good that a daily dose of a generic antidepressant could do, along with its paltry cost.

Impaired immune function has been demonstrated in depression and stimulation of immune function by antidepressants. As lithium and antidepressants have immunostimulating properties, they are effective against a wide range of microbes. Response of infection to lithium and antidepressants mirrors that of response to depression, with subjects responding selectively to one or other antidepressant or to lithium. Antidepressants are highly specific and humans remarkably variable. When infection accompanies depression their response to lithium or an antidepressant is invariably simultaneous, suggesting that the actions of the drugs on the brain in infection are essential. Tolerance may complicate the treatment of depression, and paradoxical reactions induce or intensify symptoms. Antidepressants are, paradoxically, capable of activating dormant viruses. Elevation of mood and energy in subjects treated for tuberculosis ushered in the pharmacological treatment of depression. The wheel will turn full circle when lithium and antidepressants are integrated into the pharmacology and therapeutics of infection (4).

References:

1. Lieb J. Remission of herpes virus infection and immunopotentiationwith lithium carbonate: inhibition of prostaglandin E2 E1 synthesis by lithium may explain its antiviral, immunopotentiating, and antimanic properties. Biological Psychiatry 1981; 695-698
2. Lieb J. Remission of rheumatoid arthritis and other disorders of immunity in patients taking monoamine oxidase inhibitors. International Journalof Immunopharmacology 1983; 5(4): 353-357
3. Lieb, J.”The immunostimulating and antimicrobial properties of lithium and antidepressants.” J Infection (49) 2 88-93
4. Lieb, J.”Lithium and antidepressants: Stimulating immune functionand preventing and reversing infection.” Medical Hypotheses (2007) 69, 8-11