Psychoimmunology, the Nocebo Effect and Psychiatry

©2018 Romesh Senewiratne-Alagaratnam (MD)

In the 5th century BC, the Athenian general and historian Thucydides wrote about how people who lost hope after contracting the plague were more likely to die from the deadly disease. His was the first description of what is now called psychoimmunology – the effect of the mind on the immune system. Another common manifestation of psychoimmunology is the well-known placebo effect, where belief in a treatment results in greater efficacy of the treatment, even if there is no active ingredient in the said treatment. The nocebo effect is the opposite of the placebo effect – when negative effects of an inert treatment occur due to expectations of harm.

The immune system is always subconsciously active, fighting off potential infections and cancers. It can also be over-active, as in allergic reactions, or become misdirected against the body’s own tissues, causing a wide range of autoimmune diseases. It is a common observation that mental stress can aggravate allergies and autoimmune diseases as well as cause depressed immunity.

The term ‘psychoimmunology’ was coined by George Solomon at UCLA in 1964. In 1975 Robert Ader and Nicholas Cohen coined the term ‘psychoneuroimmunology’ (PNI), emphasising the role of the brain and nervous system (neuro) in the processes by which the mind influences the immune system. This was initially viewed with scepticism since medical orthodoxy taught that the immune system was independent of the nervous system (despite knowledge of the placebo effect). There was less focus on how the immune system affects the brain and mind, although at times it obviously does (such as various types of inflammation of the brain). One of Ader’s interesting experiments was one where he conditioned rats to become immunosuppressed by pairing an immunosuppressive drug with saccharin. He found that he was able to stimulate immunosuppression by merely exposing the rats to saccharin after they had been conditioned to link saccharin with the immunosuppressive effects of the drug Cytoxan.

The placebo effect, and its converse, known as the ‘nocebo effect’ illustrate the effect of the mind on the immune system. How these effects arise and what neurological and physiological processes underpin them are partly unanswered questions, but are likely to involve many parts of the brain, especially those areas that affect emotional reactions (such as the amygdala and nucleus accumbens) and the hypothalamus, which affects the endocrine system via the pituitary and pineal glands as well as the autonomic nervous system. The role of the endocrine system in these effects is emphasised by the new term “psychoneuroendoimmunology” (PNEI).

An interesting thing about the placebo effect is that it operates even when the subject knows that it is a placebo. It has also been found that the colour and size of placebo tablets have a bearing on their effectiveness. Red tablets have been found to be more energising, while blue tablets are more calming. This indicates the role of the visual system on the placebo effect. Effective placebos are not just tablets, however. Injections of saline and ‘sham’ surgery have also been shown to be effective placebos. It has also been found that placebos are effective even when the subject knows that they are placebos and have no active ingredients in them. However, belief that an active drug is in the placebo makes the effect more powerful.

The converse effect, the nocebo effect, is the phenomenon by which a drug or treatment that is expected to cause disease does so. For example people become immunosuppressed, nauseated and lose hair if they think the placebo drug they have been given is a cancer chemotherapy drug (and they have been warned about possible side-effects). This indicates the possible negative, as well as possible positive effects, of suggestions.

Studies have shown that depressed mood is associated with impaired immunity and that a good mood promotes health of the immune system. The problem is that improved mood, especially if sudden and accompanied by insights and reduced need for sleep, is liable to be pathologised as hypomania or mania (and ‘elevated’, rather than improved, mood) and treated by dopamine-blocking drugs and lithium, often after locking the person up (which predictably causes the mood to come down). To complicate matters further, it has been reliably reported that people in a good mood (and those who are mentally relaxed) require less sleep. It is also known that meditation can lead to both insights and less need for sleep.

It is generally accepted that the amygdala, an almond-shaped nucleus located deep in the temporal lobes, plays an important role in the placebo and nocebo effects. The amygdala is activated by fear, alarm and anger responses. These emotions activate the hypothalamus and the sympathetic nervous system causing what the Harvard physiologist Walter Cannon termed the “fight or flight reflex”. Activation of the amygdala causes a cascade of hormonal changes via the hypothalamic-pituitary-adrenal (HPA) axis, causing stimulation of the heart, bronchodilation in the lungs, sweating and diversion of the blood flow away from the gut and towards the muscles (in preparation for fight or flight). Though the sympathetic nervous system is known to be involved in “flight and fight” (fear and anger) responses, this branch of the autonomic nervous system is also involved in positive excitement and healthy activation. As well as this, it innervates the pineal gland, where it regulates the synthesis of melatonin from serotonin (during the night).

The body’s response to stress, both physical and mental, is to secrete the hormone cortisol (from the adrenal glands) under influence of adrenocorticotrophic hormone (ACTH) from the pituitary. The ACTH is secreted in response to corticotrophin-releasing hormone from the hypothalamus, a structure at the base of the brain that is neurally connected with the amygdala and other emotion-related parts of the brain. In addition, neuropeptides such as Substance P, which have pro-inflammatory effects, are secreted by the brain and by immune cells such as macrophages and other white cells. The cortisol affects white cells in complex ways, including increasing some populations and decreasing others, causing apoptosis of some cells and chemotaxis of others. It has a generally suppressive effect on the immune system, for which it is often used therapeutically.

While this stress response is essential for escaping from danger, it is thought that in modern society there is often a chronic overstimulation of the stress pathways, leading to increased illness from a range of stress-related maladies (including heart disease, hypertension, autoimmune disease, headaches, peptic ulceration and irritable bowel syndrome).

The sympathetic nervous system is counterbalanced by the parasympathetic nervous system (associated with “rest and digest” physiology according to Cannon). This branch of the autonomic nervous system is associated with a range of physiological activities associated with healing and regeneration. Many stress-reduction techniques (including biofeedback and meditation) aim to increase parasympathetic activity over sympathetic activity in the autonomic nervous system, with the objective of increasing healing and regeneration.

The possible role of the pineal has not been discussed much, but the pineal’s main hormone, melatonin, is known to have effects on the secretion of pituitary hormones, and is thought to have effects on the immune system. In addition, melatonin is known to be a powerful antioxidant. Antioxidants counter oxidative stress and have positive effects on the immune system (and ageing) as well as beneficial effects on the cardiovascular system and nervous system. It is known that conversion of serotonin to melatonin in the pineal (which occurs mainly at night) occurs under the influence of sympathetic activation and the SNS neurotransmitter noradrenaline (norepinephrine).

There has been considerable study on the effects of neurotransmitters and neurohormones, cytokines and endorphins on the immune system. These studies illustrate the complexity of the brain’s effects on the immune system (especially the activity of white blood cells or leukocytes) and the effects of the immune system on the brain and mind (in such diseases as Multiple Sclerosis, AIDS, Parkinson’s Disease and Alzheimer’s Disease). Though complex and incompletely understood, it is clear that loss of hope and pessimism have negative effects on the immune system, as well as other physiological systems.


Implications for Psychiatry


The detrimental effect of loss of hope, written about by Thucydides 2500 years ago, has serious implications for doctors, especially psychiatrists. Psychiatry is a notoriously pessimistic area of medicine. Hundreds of “mental disorders” have been named, all incurable according to psychiatric orthodoxy. If the signs and symptoms of the “disorder” are no longer evident, the patient is said to have gone into remission, rather than cured. Labels of “personality disorder”, once applied, are never removed and all personality disorders are, according to psychiatric orthodoxy, permanent. This can be expected to depress the mood and the immune system. In addition there is an increasing tendency to regard the normal as abnormal. Excitement, for example, is seen as hypomania and normal sadness as “depression”, while a range of New Age beliefs and alternative science (and political) beliefs are regarded as signs of “schizophrenia”. This leads to self-fulfilling prophesies and partly explains the appalling life expectancy of people once they have been given a label of schizophrenia or bipolar disorder.

In the case of bipolar disorder (manic depression) a single episode of mania or hypomania is taught in psychiatric texts to herald a life-long condition of “mood disorder” requiring long-term mood stabilizing drugs like lithium. These drugs have terrible side-effects and shorten the life, explaining why a diagnosis of bipolar disorder is accompanied by a ten to twenty year shorter lifespan, on average. A diagnosis of schizophrenia shortens the life by 15 to 20 years, on average, and again is treated with long-term antipsychotic drugs that are known to shorten the life and make people lethargic, obese and prone to diabetes and heart disease in addition to causing neurotoxicity in the form of Parkinson’s Syndrome and Tardive Dyskinesia (a permanent condition characterised by involuntary spasms, grimaces and writhing movements that is caused by antipsychotic drugs). Lithium is notorious for causing kidney and thyroid failure.

Though the suicide rate is much higher in people given these diagnoses, most of the morbidity and mortality is not due to suicide. Besides, self-harm and suicide can be partly attributed to the pessimistic diagnosis (resulting in loss of hope), and social stigmatization resulting in loneliness, poverty and other social problems. These commonly lead to loss of motivation and depression, with negative effects on the immune system. The main cause of the shortened life span when on antipsychotic drugs is due the long-term effect of blocking essential neurotransmitters, causing metabolic problems and heart disease. They can also cause irreversible brain damage in the form of cognitive decline, cerebral atrophy and tardive dyskinesia. Though they can be effective in treating hallucinations, they should not be used for behaviour control or as chemical restraints, as they frequently are, especially in the elderly. Delusions are better treated by debate than drugs. The diagnosis of delusions can also be problematic in that the belief system of the interviewer is pitted against, and assumed to be superior, to that of the patient.

To maximise the potential of the body’s own healing mechanisms, and those mediated by the mind, is imperative that people reject labels of incurable mental illness and realise that just because they have been mentally unhealthy in the past does not mean they need to be mentally unhealthy in the future. It is also imperative that doctors and other health workers realise that implanting pessimism in the minds of their patients is a recipe for inducing chronic illness.

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