Does Herpes Virus Cause Mood Disorders?

Research published in Frontiers in Microbiology shows remarkable links between herpes virus infection and mood disorders.  Dr Bhupesh Prusty and his team conducted post-mortem brain biopsies. They investigated bipolar mood disorder (BMD), major depressive disorder (MDD), and schizophrenia. They also included a control group of patients with no history of psychiatric illness.  Signs of herpes virus infection are more common in the brains of deceased MDD and BMD sufferers compared to schizophrenia and controls.

Amazingly, hospitalisation for infection during childhood increases the risk of developing schizophrenia, MDD and BMD.  This applies irrespective of whether the infection was viral or bacterial. Why should this be the case? Does herpes provide clues about the underlying microbiology?

Inflammation and Depression

There is an growing body of evidence that shows a relationship between inflammation and depression.  Cytokine concentrations increase in the plasma of depressed patients. This applies to interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor (TNF). The antidepressant, fluoxetine, reduces interleukin-6 levels in the blood of depressed patients. 

Selective serotonin reuptake inhibitors (SSRIs) are the most common type of antidepressant. Curiously, depressed patients who do not respond to SSRIs, continue to demonstrate raised IL-6 levels after commencement of treatment.  Increased levels of IL-1, IL-6 and TNF appear in BMD.

The behaviour of depressed patients is very similar to the sickness behaviour of patients with acute infection.  Both groups show alterations in sleep cycle, changes in appetite, hightened sensitivity to pain, irritability, reduced sexual activity, and reduced interest in getting out (exploratory behaviour).  Even the cognitive changes, such as impaired concentration, poor short-term memory and executive dysfunction, are similar.

An interesting proposition is a biological pathway that could provide a link between inflammation and mood disorders.  One such possibility may be the role of indoleamine 2,3-dioxygenase (IDO). IDO is present in immune cells, including microglia in the brain, and is ubiquitous in the organs of the body.  IDO increases in animals with sickness behaviour. 

Tellingly, we can deactivate the IDO gene in mice. When we do so, those mice do not manifest sickness behaviour in the face of immunological challenge.  IDO activation and inflammation could cause depression by tryptophan depletion or by kynurenine toxicity.

Roseoloviruses include Herpes

Of course, there are multiple factors that might cause inflammation in the brain, but viral infections are one of the most common causes.  Prusty et al focused on a common type of virus that infects a large percentage of the human population, the roseolovirus genus.  Specifically, they investigated two forms of the human herpes virus (HHV), HHV-6A and HHV-6B.  There are more than a 130 types of herpes virus, of which nine infect humans.  More than 90% of people have been infected with at least one of these herpes viruses. 

As is the case with viruses, a latent form remains in most people with the potential for reactivation.  Roseoloviruses have a tissue tropism for immune cells, such as T cells, B cells, natural killer cells, monocytes and macrophages.  Respiratory particles transmit these viruses, not sexual behaviour.

The Cerebellum in Mood Disorders

Perinatal viral infection causes long-term anatomical changes in the cerebellum. It also results in behavioural disturbances in adult animals. Animal research has established these facts. Dr Prusty therefore chose to investigate the cerebellum.

Of relevance, cerebellar dysfunction has been associated with a number of psychiatric conditions, autism being perhaps the best-known.  We know that corticocerebellar tracts are abnormal in schizophrenia, and that the cerebellum tends to be a bit smaller in patients with MDD and in BMD.

The images above (from Alalade et al.) show reduced cortico-cerebellar connectivity in depressed geriatrics, compared to healthy geriatrics.  The seed region for the connectivity trace is in the cerebelum and is shown in the bottom row.  Compare especially the leftmost and middle columns and notice that there is almost no frontal connectivity in the depressed group.

Herpes, the Cerebellum and Mood Disorders

Late proteins form after replication of a virus and are therefore a marker of active infection.  Prusty et al looked for late proteints. They were able to detect signs of active HHV-6A and HHV-6B infection in the Purkinje cells of the cerebellum in MDD and BMD cadavers.

Compared to controls, statistical significance was greatest in the MDD group, slightly less in the BMD group, and absent in the schizophrenia group.  Additionally, there was occasional staining of GABAergic interneurons of the molecular layer, and astrocytes and microglia in the vicinity of positively stained Purkinje cells.  These results provide unambiguous evidence for a strong and specific effect of herpes virus, HHV-6 in particular, on Purkinje nerve fibres.

So, does herpes cause MDD and BMD?  No, not directly at least, but via the effects of inflammation on brain function, herpes is setting the scene for depression.  It would seem that perinatal HHV-6 infection is the first step.  In adulthood, reactivation of latent HHV-6 sets in motion inflammation that may lead to MDD and BMD.  Whether this requires an emotional trigger or not requires clarification.  Some patients are unable to identify an obvious emotional cause of their depression and perhaps their illness is entirely biological and without a psychological cause.