Depression in Autism – More Than Meets The Eye?

Jun 11, 2021Autism Science and Research News

High rates of depression and suicide in autism  

Depression is a common and serious problem in autism, and one of the main contributors to poor quality of life.

Both children and adults with autism experience high rates of depression and other mood disorders. One large population-based study carried out in Sweden found that about 20 percent of people with autism also had a diagnosis of depression, compared with 6 percent of the general population

When a separate group of researchers reviewed and analysed a large collection of data from thousands of other studies conducted in diverse countries and continents, they found that “compared to typically developing individuals, individuals with ASD are 4-times more likely to experience depression in their lifetime”.

If you suffer depression, mental health problems or have suicidal thoughts please seek immediate help. 

If you are in the UK here is who you can contact RIGHT NOW:

Emergency services
If you feel that you want to end your life, please seek immediate help from the emergency services on 999

Samaritans – call 116 123 (free from any phone)
Whatever you’re going through, a Samaritan will face it with you. We’re here 24 hours a day, 365 days a year.
If you don’t like talking on the phone you can email them on jo@samaritans.org or visit some branches in person. You can also call the Samaritans Welsh Language Line on 0808 164 0123 (7pm–11pm every day).
samaritans.org

Find a local NHS urgent mental health helpline – follow this link and type in your postcode for local NHS urgent mental health helpline. Anyone can call these helplines, at any time. nhs.uk/service-search/mental-health/find-an-urgent-mental-health-helpline

Shout 85258text “SHOUT” to 85258
A free, confidential, 24/7 text messaging support service for anyone who is struggling to cope
giveusashout.org

Saneline – call 0300 304 7000
Alternative number: 07984 967 708. Email: support@sane.org.uk
Confidential helpline for those aged 16 or over.
sane.org.uk

Papyrus HOPELINEUK  – call 0800 068 4141 (weekdays 10am-10pm, weekends 2pm-10pm and bank holidays 2pm–10pm). You can also text: 07860039967 or email: pat@papyrus-uk.org. For children and young people under the age of 35 who are experiencing thoughts of suicide, or anyone concerned about them.
papyrus-uk.org

The Mix – call 0808 808 4994
Support for under 25s. Here to help you take on any challenge you’re facing – from mental health to money, from homelessness to finding a job, from break-ups to drugs.
themix.org.uk

Campaign Against Living Miserably (CALM)
If you identify as male, you can call the Campaign Against Living Miserably (CALM) on 0800 58 58 58 (5pm–midnight every day) or use their webchat service.

C.A.L.L.
If you live in Wales, you can call the Community Advice and Listening Line (C.A.L.L.) on 0800 132 737 (open 24/7) or you can text ‘help’ followed by a question to 81066.

Helplines Partnership
For more options, visit the Helplines Partnership website for a directory of UK helplines.

If you are in the US call National Suicide Prevention Lifeline on 1-800-273-8255

Depression is commonly found in individuals with autism who have normal intelligence and verbal ability, in other words those belonging to the so-called ‘higher-functioning’ end of the spectrum.

It is not clear why higher daily functioning skills and/or intelligence would result in increased risk for depression in autism, and the reasons are likely complex, but one possible answer is that individuals with more severe forms of autism are simply not able to communicate how they feel and therefore their depression goes undiagnosed. If this is the case, the risk and rates of depression could actually be higher than those revealed by the studies. 

Rates of suicide are also increased in autism compared to the general population, with suicide being the leading cause of premature death in people with so-called higher functioning autism/Asperger’s syndrome.

Life expectancy of a person with severe autism is 39.5 years, rising to only 58 years for those with high-functioning autism, or Asperger syndrome.

The importance of recognising symptoms of depression in autism

It is important to be aware of the possible symptoms of depression in autism, especially where affected individuals are unable to clearly communicate.

Diagnostic and Statistical Manual of Mental Disorders defines depression as a ‘longstanding pattern of negative mood’. In addition to negative mood, symptoms of depression in adults can include

  • losing interest in activities
  • changes in sleep patterns, appetite or energy levels
  • feelings of worthlessness, sadness or hopelessness
  • angry outbursts, irritability, agitation
  • difficulties with attention
  • slowed thinking, speaking or body movements
  • feelings of worthlessness or guilt, fixating on past failures or self-blame
  • suicidal thoughts or actions

Most signs and symptoms of depression in children and teenagers are similar to the ones above. In younger children, symptoms of depression may also include clinginess, worry, aches and pains, refusing to go to school, or being underweight. In teens, symptoms may include poor performance or poor attendance at school, feeling misunderstood and extremely sensitive, using recreational drugs or alcohol, eating or sleeping too much, and self-harm.

Since many of the recognized symptoms of depression overlap with symptoms commonly experienced by people with autism, and since many individuals on the autism spectrum often have difficulties recognising and communicating how they feel, depression can be challenging to detect and diagnose.

The ‘Why’ — digging deeper and looking beyond the ‘common suspect’ causes of depression

Depression, like any other human condition, arises from an interplay between biological and psychological factors. The reasons and risk factors behind depression are complex and vary from individual to individual.

Psycho-social factors and risk of depression in autism

Some of the common psycho-social factors that predispose one to developing depression are now better understood and include a combination of adverse factors such as insecure attachment, childhood neglect, trauma, chronic stress, low self-esteem, bullying, feelings of loneliness, lack of social support, and lack of sense of belonging.

Individuals with autism are especially vulnerable to many of those risk factors, due to limitations in social communication and lack of peer bonding and support.

In addition, difficulties in the areas of cognition, executive functioning or emotional regulation can make it difficult for a person with autism to carry out tasks or to find and hold down employment in environments that offer little accommodation or understanding, further deepening feelings of inadequacy or worthlessness.

Additionally, communication impairments can make it especially challenging for a person with autism to communicate and to ask for help and receive early support and treatment.

But is there more to this story?

“Repeated investigations have found chronic inflammatory processes in multiple areas of the brain and cerebrospinal fluid of individuals with ASD, including increased inflammatory cytokine and chemokine production and consistent activation of astrocytes and microglia.” (Sala et al. 2020)

Genes, serotonin and other biological factors

Although genetic susceptibility was in the past believed to be the main predisposing factor for depressive disorders, decades of genetic research have failed to reveal any major ‘depression genes’ or, indeed, any clear-cut answers.

Contrasted with the lack of results yielded by genetic research, neuroscience has provided ample evidence of depression being strongly linked to disturbances in neurotransmitter pathways, especially the serotonin/tryptophan/kynurenine metabolic pathway.

Further strengthening those findings, experimental animal research has clearly shown that manipulating the levels and behaviours of those neurotransmitters leads to direct changes in depressive moods and behaviours.

In addition, strong links have been uncovered between depression and a wide range of biological disorders such as thyroid and other endocrine disorders, tumours of the central nervous system, traumatic head injury, and pro-inflammatory autoimmune disorders such lupus, rheumatoid arthritis, and coeliac disease.

This established and continually emerging research has led a growing number of scientists and doctors to call for a differential diagnosis for depression—in other words, ruling out all possible biological reasons for a person’s mood disorders, depression and possible suicidal tendencies, before  determining that it is ‘all in the head’.

close examination of possible causes of depression in autism

Photo by Michael Longmire on Unsplash

Inflammation & depression – the million-year old relationship between the nervous and the immune systems

Accumulating evidence shows that the immune and the nervous systems are interlinked and influence each other in myriad ways.  In general, the immune system supports the functioning of the brain, but it can also negatively impact the brain and other parts of the nervous system.

Inflammation is a natural defence response of the immune system against environmental insult, stress and injury, but too much inflammation can trigger diseases, including brain disorders.

One commonplace example which most people will have experienced: inflammation as a response to infection can lead to something called ‘sickness behaviour’, which slows the person down in order to preserve energy and to allow the immune system to fight pathogens.

When a person is unwell, their body’s energy is diverted away from what the organism perceives as ‘non-essential’ functions — for  example, higher-order cognition and processing of language and social clues — and  towards functions that are necessary for immediate survival, such as fighting the perceived threat from infection or injury.

Sickness behaviour is characterised by symptoms that mirror depression, including decreased social interaction, fatigue, disturbed sleep and appetite, anxiety, irritability, abnormal pain sensitivity, lack of motivation and interest in everyday activities.

We have all experienced sickness behaviour for a day or two while our body fights infection or injury. However, the cessation of sickness behaviour is predicated on inflammation returning to the baseline ‘normal’ levels after the body stops fighting the immediate threat.

“Normally, when the infection resolves, this presumed sickness system is turned off and physiology and behaviour are restored. However, if the inflammatory input is extremely high or prolonged, or if the neuroinflammation in the CNS is not resolved, behavioural dysfunction may follow.” (Karshikof 2015)

There are several biological mechanisms by which inflammation and immune response in the body can affect the brain and behaviours:

  • Cytokines and other inflammatory molecules can affect the synthesis and release of serotonin and other neurotransmitters that play a role in depression
  • Inflammatory molecules trigger and increase the levels of hormones involved in the stress response (via hypothalamic-pituitary-adrenal axis)
  • Excessive and prolonged inflammation impairs the ability of the brain to repair and regenerate neurons after injury or stress. In other words, even when excessive inflammation is not the primary cause, prolonged inflammation can make recovery more difficult.

For more than a century, researchers have explored whether infectious agents might trigger mental illness. Several late 19th century clinicians reported to have become ‘convinced of a link between acute infection and emergence of mental symptoms in their patients’ and several decades later researchers were intrigued by the observed peak in hospital admissions for psychoses during the influenza epidemic of 1918-19.

Modern studies have shown that having a serious infection more than doubles a person’s risk of developing depression later on. A large population-based study in Denmark reported that patients with a history of hospitalisation for infection had a 62 percent increased risk of developing a mood disorder at some point.

“The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease.” (Benros et al. 2013)

In addition to severe infections that require hospitalisation, it has been proposed that long-term, chronic inflammation produced in the presence of a persistent pathogen may be just as detrimental to the functioning of the brain. Persistent low-level infections can repeatedly stimulate the immune system and expose the brain to cytokines and other inflammatory mediators over long periods of time.

In other words, infections that do not cause visible symptoms, and thus go undetected, coupled with chronic inflammation, which may also go undetected, could be a risk factor for depression.

how inflammation affects tryptophan serotonin and leads to depression

What has autism got to do with links between inflammation and depression?

A large number of people with autism – over half according to many studies – present with immune dysregulation and neuroinflammation. (For a more complete discussion of immune dysregulation, neuroinflammation and other common comorbidities in autism, see the document Medical Comorbidities in Autism Spectrum Disorder)

Various human studies as well as experimental animal research point to abnormal immune function playing a major role in the emergence of many symptoms and behaviours related to autism.

While immune dysfunction and inflammation in autism are often dismissed as being caused solely by psychological stress, it is important to focus on the fact that  inflammation is found in autism very early in life, often before birth.

“Studies have consistently shown an association between prenatal infection/immune activation, maternal/infantile atopic diseases, food allergies/intolerances as well as family history of autoimmunity and risk of ASD… Repeated investigations have found chronic inflammatory processes in multiple areas of the brain and cerebrospinal fluid of individuals with ASD, including increased inflammatory cytokine and chemokine production and consistent activation of astrocytes and microglia…” (Sala et al. 2020)

Several large studies have found that exposure in the womb to a maternal infection and/or inflammation increases the risk for both autism and depression, pointing to the possibility of shared biological pathways and risk.

When researchers and doctors in Sweden analysed records of 1.8 million pregnant women and their children, they found that hospitalisation for infection during pregnancy significantly increased the risk of the child developing both depression and autism later in life.

The evidence from human data is further strengthened by experimental animal research, where one easy way of producing animals with abnormal social and exploratory behaviours is to expose them to excessive levels of inflammation during pregnancy.

“Prenatal immune activation significantly increased the levels of dopamine and its major metabolites…whilst at the same time it decreased serotonin…infection-mediated interference with early fetal brain development may predispose the developing organism to the emergence of neurochemical imbalances in adulthood.” (Winter et al. 2008)

Inflammation has a major effect on the levels of serotonin and the other neurotransmitters that play important roles in brain development during pregnancy, as well as in the development of depression in later life.

During pregnancy, various factors ranging from genes to the mother’s nutritional status, stress, medication, and immune activation in response to infections can raise the levels of inflammatory cytokines, which in turn affect the levels of serotonin in the unborn baby’s brain and lead to long-term changes in brain structure and functioning.

“Maternal and fetal inflammatory responses to infection may alter fetal neurodevelopment, as suggested in some children with autism, who display a chronic state of inflammation in the periphery as well as in the brain…. Overall, our findings provide evidence for a fetal origin of some portion of autism and depression across a spectrum of maternal infections in pregnancy.” (al-Haddad et al. 2019)

High levels of inflammatory molecules are found in newborns who are later diagnosed with autism, further adding to the evidence that extensive inflammation is an ‘intrinsic’ part of autism and not solely due to adverse psycho-social factors.

“Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.” (Heuer et al. 2019)

“Microglia are activated following infection with viral, bacterial, fungal, and protozoan agents through a complex and highly refined process…Microglial activation has been documented in a wide range of psychiatric disorders including schizophrenia, bipolar disorder, and autism.

Because the pattern of response to infectious agents is similar, microorganisms..can cause similar activation of immune processes and, hence, similar clinical pictures.
Yolken et al. ‘Psychiatric Disorders: Are Infectious Agents To Blame’

Interferon therapy, depression and suicide – what can hepatitis C and cancer patients teach us about autism?

Interferons (IFNs) are proteins produced by human cells in response to infections. These molecules are pro-inflammatory – they induce inflammation in the body as a way of fighting off infectious invaders.

IFNs are sometimes used as ‘clinical weapons’, administered in clinical settings as a treatment against viral infections, especially hepatitis C virus, multiple sclerosis, skin conditions, and some types of cancer.

Patients who receive IFN treatment, and in particular interferon alpha type treatment, frequently develop sudden new-onset depression and anxiety disorders:

“After 12 weeks of treatment 37.9% of (patients) had major depressive disorder and 46.6% had generalized anxiety disorder.” (Bassiony et al. 2015)

In extreme cases, such depression may lead to suicide or attempted suicide:

“While on therapy, all three patients developed a psychiatric disorder leading to their suicidal behavior. In a survey of 15 European hospitals, three cases of attempted and two of successful suicide during alfa-interferon therapy…were additionally reported. None of the patients had a psychiatric history. Alfa-interferon is known to lead to neuropsychiatric symptoms, and our observations strongly suggest that these mental disorders could lead to suicidal behavior.” (Janssen et al. 1994)

Other side effects frequently experienced by patients who receive IFN therapy include:

  • decline in verbal ability
  • decline in executive functioning
  • mood and personality changes, especially irritability
  • cognitive problems
  • sleep disturbances
  • increased fatigue
  • slow motor function

“It is of particular interest that large doses of interferon-alpha, a pro-inflammatory cytokine given to humans in cancer treatment, can cause symptoms that can mimic ASD. Symptoms include a decline in speech, executive functioning and cognition as well as motor coordination, anxiety and irritability issues.” (Sala et al. 2020)

It is also known that IFN triggers various immune responses that affect the levels and behaviours brain hormones and neurotransmitters. Some of IFN effects on brain function are linked to the effects these molecules have on microglia, the brain immune cells.

“These results indicate that the kynurenine (KYN) pathway of indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan metabolism plays a critical role in depressive symptoms associated with interferon alpha therapy.” (Murakami et al. 2016)

The mechanisms behind cognitive, mood and personality changes triggered by the presence of IFNs in the blood – either through natural production in response to an infection or through IFN therapies as described above – are manifold and beyond the scope of this article.

corona virus is one of the infections known to cause depression and psychiatric symptoms

What can COVID-19 and other pandemics teach us about autism and depression?

Viral pandemics have been associated with long-lasting neurological and psychiatric consequences, including depression. “Psychoses of influenza” was the term used in the eighteenth century to describe neuropsychiatric disturbances in the wake of influenza infection.

In addition to major pandemics, localised epidemics and sporadic infections with viruses as diverse as enteroviruses, borna disease virus, herpes type viruses, human immunodeficiency virus and hepatitis C have been linked to increased incidence of depression.

“The results suggested that children and adolescents with CNS EV infection were a susceptible group for subsequent depressive disorders.” (Liao et al. 2017)

One of the main mechanisms behind this is the detrimental effect of infection-triggered inflammation on the functioning of the brain, even in cases when the virus does not directly penetrate the central nervous system.

“Since the association of autism with congenital rubella infections was noted more than 50 years ago, numerous other infections have been connected to the incidence of autism in the intervening years. Epidemiological studies and case reports demonstrated the link between exposure of viruses such as rubella, measles and mumps, polyomaviruses, cytomegalovirus, and influenza to the risk of autism. Animal studies have also indicated that prenatal or early postnatal infections could result in both acute and persistent neurological and behavioural abnormalities in the offspring, displaying features reminiscent of autism and schizophrenia.” (Shuid et al. 2021)

In the past year, a growing body of evidence has pointed to links between COVID-19 virus infection and lasting neurological, cognitive and psychiatric symptoms. It has been suggested that severe COVID-19 infection could result in prolonged systemic inflammation in the body, which in turn could lead to the development of persistent depression.

“The link between inflammation and depression is well described and might explain some of the psychiatric morbidity (in severe coronavirus infections)…

Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term…

The immune response in SARS-CoV-2 infection is of interest and there might be a hyper inflammatory state”
(Rogers et al. 2020)

The largest study to date that investigated consequences of severe COVID infection found that up to a third of survivors develop long term cognitive and psychiatric symptoms and difficulties in the domains of:

  • verbal fluency
  • verbal memory
  • sleep
  • attention /focus
  • information processing
  • executive function
  • motor coordination
  • stress response
  • anxiety
  • depression

Most individuals with autism experience difficulties and impairments in almost all of the above areas.

Cognitive dysfunction and depressive symptoms in severe COVID-19 survivors are directly related to the level of inflammation that persists long after the infection has cleared.

In addition, when patients are given strong inflammation blocking agents they appear to be better protected against depression:

“We also observed a protective effect against depression of cytokine- blocking agents (anakinra, a recombinant version of the human IL-1β receptor antagonist, and tocilizumab, a monoclonal antibody targeting the IL-6 receptor), possibly associated with their effect in dampening (systemic inflammation), in hospitalized male patients surviving severe, life-threatening COVID-19.” (Mario Gennaro et al. 2021)

In other words, higher inflammation is associated with higher depression in COVID-19 survivors:

“Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, predicted self-rated depressive symptomatology and cognitive impairment at three-months follow-up; and changes of SII predicted changes of depression during follow-up.

Neurocognitive impairments associated with severity of depressive psychopathology, and processing speed, verbal memory and fluency, and psychomotor coordination were predicted by baseline SII.

We hypothesize that COVID-19 could result in prolonged systemic inflammation that predisposes patients to persistent depression and associated neurocognitive dysfunction.” (Mario Gennaro et al. 2021)

Bacteria and parasites change human personality & mood, can lead to suicidal behaviour

In addition to viruses, several types of bacterial infections have also been linked to incidence of major depression.

Exposure to Toxoplasma gondii parasite, even without the development of physical symptoms of Toxoplasmosis, has been shown to cause personality and behaviour changes in large number in infected people. Numerous studies have linked seropositivity to this bacterial infection with an increased rate of depressive disorders and suicide, and reports describe cases of patients whose long-standing severe depression, previously unresponsive to antidepressant treatment, disappears after toxoplasmosis-targeted treatment.

“Many neuropathic infectious agents have complex mechanisms that allow them to lie dormant within the brain for extensive periods with little evidence of classical inflammatory reactions. This concept is consistent with recent studies indicating that there is substantial immune activity in the brains and systemic circulation of individual with psychiatric disorders.” (Yolken et al. ‘Psychiatric Disorders: Are Infectious Agents To Blame’)

A recent study from Egypt noted that all patients who could be identified as asymptomatic typhoid carriers – individuals who are not showing any acute symptoms of infection but are instead carriers of ‘latent’ salmonella bacteria reservoir – presented with severe depression in addition to various physical symptoms:

Approximately, 2–5% of patients with typhoid fever turn into chronic carriers, who are asymptomatic but continue to excrete the organism for an ill-defined, prolonged period and act as reservoirs for the organism. (Bakeer et al. 2019)

Out of 60 individuals who were identified as asymptomatic typhoid carriers all suffered major depressive disorder in addition to fatigue, headache, indigestion and changes in bowel habits, chest pains, shortness of breath, heart palpitations, anorexia, erectile dysfunction and menstrual disruption, urination frequency, and myalgia (muscle pain).

Many of the identified patients also presented with pale skin, white coating on the tongue, as well as mild splenomegaly (enlarged spleen) and tenderness in right iliac fossa (lower right) part of the abdomen, “best explained by the local chronic inflammation in the terminal ileum”.

A course of antibiotic therapy with intravenous ceftriaxone led to significant and lasting reductions in both physical symptoms and as well as depression:

Statistically significant improvement was observed in their depression scale, solely after antibiotic treatment. The improvement in the depression scale was evident immediately after the completion of antibiotic courses and consolidated at the 6th-week post-antibiotic completion.” (Bakeer et al. 2019)

antibiotic therapy reducing depression symptoms in patients with salmonella infection

It was proposed that the mechanism behind chronic salmonella infection in the gut causing depression could be related to ‘the leaky gut hypothesis’ (see section below).

Many other types of bacteria have also been implicated as capable of causing long term depression including Streptococcal infections, Bartonella, Borrelia burgdorferi (Lyme disease) and Helicobacter pylori.

“These findings provide epidemiologic evidence that some pediatric-onset neuropsychiatric disorders, including OCD, tic disorders, ADHD, and Major Depressive Disorder, may be temporally related to prior streptococcal infections.” (Leslie et al. 2008)

Gut health, gut-brain axis and depression (and autism too)

The brain is not an isolated organ. While that statement may seem obvious, its significance cannot be overstated. A constant two-way communication exists between the brain and other systems in the body, including the gut.   

One of the major regulators of gut-brain axis signalling is gastrointestinal microbiota – the bacteria that reside in the gastrointestinal tract. Microbiota influence the functioning of the brain through several mechanisms.

The ‘leaky gut’ hypothesis of depression and other neuropsychiatric and neurological disorders describes how certain bacteria present in the gut can make the intestinal barrier more porous to bacterial toxins (endotoxins). Bacterial molecules and pro-inflammatory food proteins are in this way able to enter the blood, provoke the immune system and so influence the metabolism of hormones and neurotransmitters that regulate moods and behaviours.

“The ‘leaky gut’ hypothesis proposes a mechanism by which gastrointestinal bacteria may contribute to major depression…cytokines or other stressors may render the intestinal tract permeable to lipopolysaccharides (LPS) from gram-negative bacteria to activate the immune system.” (Canly, 2014)

“Supporting this finding, an elevated serum IgM and IgA was observed against lipopolysaccharides of the Gram-negative enterobacteria in depressed patients.” (Bakeer et al. 2019)

Multiple animal studies clearly show that manipulating the composition of gut microbiota directly influences the stability of the gut barrier, as well as the levels of inflammation in the blood and the nervous system, subsequently the levels of neurotransmitters and, ultimately, the behaviours of experimental animals:

“These findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.” (Bravo et al. 2011)

“There is ample evidence for an association between the gut microbiota and the pathophysiology of depression. Different stress (social or emotional, chemical, physical, a poor diet, etc.) have the potential to alter the taxonomic composition of bacterial communities in the gut, and, as a result, leads to changes in various metabolic pathways. This leads to a systematic inflammatory process…” (Averina et al. 2020)

Gut bacteria also directly influence the functioning of the brain via the vagus nerve, the long nerve that connects the brain with the insides of the gastrointestinal tract. Vagal nerve endings are sensitive to molecules and signals excreted by the gut bacteria.

Vagus nerve stimulation is one of the most effective non-pharmacological treatments for depression.

gut brain connection between inflammation serotonin and mood disorders

Gut dysbiosis, meaning disturbances in the composition of gastrointestinal microbiota, is also a feature of irritable bowel syndrome (IBS), a gut-brain axis disorder that is frequently accompanied by anxiety and depression.

Many psychiatric and neurological disorders, from Parkinson’s disease to multiple sclerosis to epilepsy, have been linked to changes in the composition of gut microbiome and vagus nerve signalling.

Compared to the general population, individuals with autism suffer higher rates of gastrointestinal disorders, including constipation, diarrhoea, indigestion and reflux, as well as Ulcerative Colitis and Crohn’s disease (inflammatory bowel diseases). Increased levels of bacterial endotoxins in the blood have been found by one study to correlate with the severity of autism.

“Other clinical findings appear to be overrepresented in ASD, including increased intestinal permeability, various digestive enzyme deficiencies and bacterial dysbiosis…Analyses of the GI bacterial composition as well as the identification of bacterial metabolic and biochemical markers in the urine of individuals with ASD have demonstrated the presence of atypical microbiota. Translocation of bacterial species to other parts of the GI tract and indeed, outside of it, has also been described.” (Sala et al. 2020)

Impaired digestion and absorption of nutrients, almost certainly a feature of gut dysbiosis and gastrointestinal disorders, is another factor that can cause and/or contribute to depression.

Vitamin B6, for example, is a cofactor in the dopamine serotonin pathway, and its deficiency may cause mood disorders and depressive symptoms. Similarly, low levels of folates, vitamin D, omega-3 fatty acids have all been associated with the risk of increased inflammation and depression.

Levels of many vitamins and nutrients, including B6, folates, omega-3 fatty acids and vitamin D, are often reported to be low in individuals with autism.

“Nature has already provided examples by which parasites, bacteria, or viruses can affect emotional behavior. The best-known example of a parasite that affects emotional behavior and that is relevant to human health is Toxoplasma gondii.” (Canly, 2014)

‘Hidden’ health issues and risk of depression in autism

Autoimmune and allergic disorders and depression

Autoimmune disorders are strongly linked to depression. Patients suffering from autoimmune disorders such as multiple sclerosis, lupus and rheumatoid arthritis have much higher rates of depression compared to the general population. Autoimmune conditions are highly prevalent in families of individuals with autism.

Coeliac disease (CD) is an autoimmune disorder in which the body triggers an immune reaction to gluten, a protein found in wheat, barley and rye. This immune reaction damages the body’s own tissue, notably the lining of the intestine, often resulting in decreased absorption of nutrients. Other possible consequences of undiagnosed and untreated coeliac disease can include weight loss, bloating, anaemia and diarrhoea.

More than half of CD sufferers have signs and symptoms unrelated to the gastrointestinal system, including:

  • Depression
  • Anxiety
  • Lack of focus/hyperactivity
  • Seizures
  • Itchy, blistery skin rash
  • Headaches and fatigue
  • Mouth ulcers
  • Joint pain
  • Balance problems
  • Cognitive impairment
  • Peripheral neuropathy

In some cases, there is a total absence of gastrointestinal pathology or symptoms, with the only manifestation being neuropsychiatric ones:

“In this large database, patients with CD are at increased risk of having multiple psychiatric diseases including anxiety, depression, bipolar, attention-deficit hyperactivity disorder, eating disorder, and childhood autism.” (Alkhayyat et al. 2021)

“Gluten elimination may represent an effective treatment strategy for mood disorders in individuals with gluten-related disorders…We performed a systematic review of prospective studies for effects of gluten on mood symptoms… A gluten-free diet (GFD) significantly improved pooled depressive symptom scores in GFD-treated patients.” (Busby et al. 2018)

Gluten sensitivity, food allergies and depression

Non-coeliac gluten sensitivity (NCGS) is a syndrome diagnosed in patients responsive to gluten-free diet after coeliac disease has been ruled out. As with CD, NCGS symptoms can also include psychosis, anxiety and depression.

“(The patient, 14-year-old girl) presented with severe abdominal pain…slowed speech, depression, distorted and paranoid thinking and suicidal ideation… the correlation of psychotic symptoms with gluten ingestion and the following diagnosis of NGCS were well demonstrated; the girl was, indeed, not affected by celiac disease (CD), because she showed neither the typical CD-related autoantibodies…nor the signs of intestinal damage… double-blind gluten challenge, currently considered the gold standard for the diagnosis of NCGS, clearly showed that the elimination and reintroduction of gluten was followed by the disappearance and reappearance of symptoms.” (Lionetti et al. 2015)”

Food allergies and sensitivities, and allergic disorders in general, are very prevalent in autism, and appear to be directly correlated to the severity of core autism symptoms and autism-related behaviours:

“Our study showed that the majority of children with ASD had food intolerance. The most common food intolerance items were eggs, milk, and wheat…stereotyped behaviors of preschool children with ASD…correlated with food-specific IgG antibody levels, which may have implications for exploring the immune mechanism of ASD.” (Li et al. 2020)

Individuals with autism and a history of allergy and atopic disease are more likely to suffer from NCGS.

Allergic disorders such as atopic dermatitis/eczema, allergic rhinitis, asthma and food allergies have strong links to mood disorders and suicidal behaviours. The relationship between allergic disorders and depression is especially strong in children and younger adults.

“Allergic rhinitis (AR) negatively affects emotions and behavior, leading to cognitive deficits, memory decline, poor school performance, anxiety, and depression. Several cellular and molecular mediators are released in the inflammatory process of AR and activate common neuroimmune mechanisms, involving emotionally relevant circuits.” (Yang et al. 2018)

“This article reports on a 34-year-old female patient with Major Depressive Disorder whose symptoms improved in response to a dietary intervention involving the elimination of common food allergens. Reintroduction of the foods on several occasions was associated with a worsening of mood symptoms. Serum IgG testing reported results consistent with the reintroduction challenge.” (Aucoin & Bhardwaj, 2019)

Sleep apnoea in autism and depression

Sleep apnoea is a sleep disorder characterised by pauses in breathing or periods of shallow breathing during sleep. The lack of oxygen caused by untreated sleep apnoea, and subsequent increase in systemic inflammation in the body, can cause or contribute to the severity of depression.

“Co-morbid depression is prevalent in patients with obstructive sleep apnea…We found that chronic intermittent hypoxia significantly increased the MAO-A expression… The MAO-A upregulation resulted in increased 5-hydroxyindoleacetic acid/serotonin ratio, oxidative stress, leading to NF-κB activation, inflammation and apoptosis. Also, the expression of cytokine-responsive indoleamine 2,3-dioxygenase-1 (IDO-1) was significantly augmented in hypoxia, resulting in increased kynurenine/tryptophan ratio and lowered serotonin level.” (Lam et al. 2017)

Several investigations on the prevalence of obstructive sleep apnoea (OSA) in children found that it more commonly occurs in children with autism compared to typically developing children. There have been no studies on the prevalence of OSA in adults with autism. Several studies reported that treatment of OSA in children with autism resulted in significant improvement in autism-related behaviours:

“Three months after adenotonsillectomy, her mother observed continued improvements in socialization, with her daughter playing with other children. She no longer covered her ears to loud sounds. She expressed an interest in helping other people, and continued to notice when her mother was upset and reassure her. Her spinning in circles had resolved.” (Malow et al. 2006)

“Behavioral problems were significantly improved following AT in ASD children with OSA. Early detection and treatment of children with OSA is essential to prevent behavioral problems and to support mental development.” (Murata et al. 2017)

Further consideration for differential diagnosis of depression and suicidal behaviours

Various other physical health disorders have been linked to increased risk of depression and/or suicidal behaviours including:

  • Exposure to pesticides and environmental toxins
  • Endocrine disorders – diseases of the adrenal, thyroid and parathyroid glands
  • Tumours of the pituitary gland
  • Type 2 Diabetes / Hypoglycaemia
  • Post-concussion syndrome
  • Anaemia

Chronic stress, psychological trauma and inflammation

As mentioned previously, the immune system and the nervous system are closely interlinked, and affect each other in numerous ways. The early development and lifelong functioning of the brain are regulated and directed by the immune system and vice versa – the neurotransmitters and hormones stemming from the central nervous system affect the functioning of the immune system.

It is known that prolonged and increased levels of stress-hormone cortisol negatively affect the ability of cortisol to regulate the inflammatory and immune response to psychological and physical stress and trauma. In other words, chronic or severe stress interferes with the body’s natural ability to shut down its own pro-inflammatory immune response after it is triggered.

In this way, chronic stress especially when experienced by children and youth may activate a harmful immune response and predispose to depression and anxiety disorders, even in the absence of infection.

“There is evidence that post-traumatic stress disorder (PTSD) is underpinned by the presence of a systemic low-grade inflammatory state. This inflammation may be the mechanism associated with increased risk for chronic disease in the PTSD population. From this, future research should focus on interventions that help to reduce inflammation, such as exercise.” (Speer et al. 2018)

Conversely, just as stress affects the functioning of the immune system, the immune system largely determines the body’s response to stress and trauma. Major predisposing genetic risk factors for dysregulated stress responses and PTSD are found amongst the genes that regulate the immune response.

A recent prospective study by Michopoulos and colleagues explored the links between the immune responses and the risk of developing PTSD following a traumatic event. The study demonstrated that peripheral immune markers measured in blood samples collected in an emergency department immediately after trauma exposure can predict later chronic development of PTSD.

This is especially pertinent in the light of the recent findings showing lower threshold for trauma and higher rates of PTSD in individuals with autism compared to general population:

“Adults with ASD described a wide range of life events as being experienced as traumatic. Findings indicate that adults with ASD may be at increased risk of PTSD development following both traumas meeting DSM-5 PTSD Criterion A and non-DSM-5 traumatic events that do not meet Criterion A… A broader range of life events appear to be experienced as traumatic and may act as a catalyst for PTSD development in adults with ASD.” (Rumball et al. 2020)

It should be noted here that prolonged stress induces pathological states in the body that can be self-perpetuating and hard to heal. Inflammation and hormonal changes induced by biological or psychological stress can remain in place long after the initial trigger is gone.

It is therefore believed that in order to successfully treat stress-related psychological and physical disorders, multi-factorial approaches should be employed:

“To improve stress condition, reduction of psychological and physical stress should be put on the agenda of the patients with a wide variety of the chronic multifactorial stress-related diseases. Furthermore, interventions targeting stress risk factors, especially stress-induced inflammation, would be beneficial for the treatment of diseases (mainly aiming at specific inflammatory factors)” (Lie at al. 2017)

mental health and depression in autistic person

Treatment implications for depression and inflammation in autism

Current evidence points to inflammatory mechanisms playing a major role in depression.

Almost one third of patients with depression do not experience lasting relief from symptoms with standard antidepressant drugs such as serotonin reuptake inhibitors (SSRIs). About one-third of them do not respond to this treatment at all.

Results of preliminary research suggest that patients with increased inflammatory cytokines in the blood are less responsive to antidepressant treatment. This has led to a growing number of clinicians and researchers searching for further answers in relation to the role of inflammation in depression, in order to guide treatment decisions.

Several large studies and recent meta-analysis show that anti-inflammatory treatments, when used both as single therapies and when added to existing antidepressant therapy, have a strong beneficial effect in depression.

Considering that some cases of depression in autism could be at least partially related to chronic inflammation, strategies and treatments aimed at reducing inflammation offer promising therapeutic options.

Some of the therapeutic strategies that have so far shown promise for reducing depression:

  • anti-inflammatory medication, e.g. pentoxifylline, minocycline
  • anti-inflammatory dietary supplements, e.g. sulforaphane, curcumin, N-3 polyunsaturated fatty acids
  • vitamin D, vitamin E, vitamin B6, biotin, folates
  • vagus nerve stimulation
  • transcranial magnetic stimulation
  • transcranial direct current stimulation
  • ketogenic diet
  • exclusion diet/s, where indicated, for example coeliac disease and/or gluten intolerance
  • psychedelic medicine
  • statins
  • metformin
  • probiotics, prebiotics and microbiota transplant therapy
  • reducing stress: aerobic exercise, yoga, meditation, mindfulness and breathing exercise

“Psychiatric conditions, such as schizophrenia, depression, bipolar disorder…are neurometabolic diseases that share several common mechanistic biopathologies. These include glucose hypometabolism, neurotransmitter imbalances, oxidative stress and inflammation. There is strong evidence that ketogenic diets can address these four fundamental diseases, and now complementary clinical evidence that ketogenic diets can improve the patients’ symptoms.” (Norwitz et al. 2020)

“Probiotics + FOS intervention can modulate gut microbiota, SCFAs and serotonin in association with improved ASD symptoms, including a hyper-serotonergic state and dopamine metabolism disorder.” (Wang et al. 2020)

“Replacing inflammatory foods, such as sugar, gluten, artificial trans fats, chemical additives, taste enhancers, and preservatives with anti-inflammatory foods, such as berries, avocado, broccoli, olive oil, cocoa, and green tea, can be a huge step towards mitigating the heightened inflammatory response of the immune system… There is enough evidence showing that diet is a powerful modulator of the immune response and a determinant of social behavior in patients with depression.” (Averina et al. 2020)

treatments for depression in autism providing new hope for autistic people

Photo by Daniel Joshua on Unsplash

Conclusion – what can be done to reduce the problem of high rates of depression and suicides in autism?

Getting to the root of the problem is never easy. Especially when going to the root means digging deep and possibly disturbing and uncovering some long held ‘truths’ as being merely unproven assumptions. Suicide is the leading cause of death in people with autism without intellectual disability, and depression is a major factor in the poor quality of life experienced by individuals and their families.

Without doubt, psychological and social problems experienced by people strongly contribute to poor mental health. This might be particularly true for people with autism and without doubt, greater acceptance, understanding, accommodation and social support are sorely needed.

But at the same time, we are also obliged to step back and look at the whole picture.

The whole picture includes these facts:

Increasing evidence indicates that inflammatory processes can cause or contribute to the development of depression and can trigger or worsen suicidal behaviours and inflammation is a more common and serious problem for people with autism than the general population (where it is also a common medical problem).

In other words, we need to start considering and addressing possible biological contributors to depression in autism. Differential diagnosis for depressive and suicidal symptoms and behaviours in autism should be sought in every instance.

Reluctance to engage with research which shows that certain physical conditions, if properly identified, treated, and ameliorated might hold the key to reducing or even alleviating depression is leaving many people with autism without the help they might need and instead placing a greater burden on them by attributing their depression exclusively to the realm of their mind.

The attainment of strong mental health, better quality of life, and longer average lifespan in autism is the ultimate goal. If we fail to consider all of the causes of depression and fail to work to ameliorate each of them, we will  fail to reach that goal.

In order to rise to the challenge of finding effective interventions for depression no stone must be left unturned.

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DISCLAIMER The purpose of this site is to provide information. No information on this website should be construed as medical advice. Neither article authors, associated charities, nor individual contributors take any responsibility or liability for any decision taken by site visitors as a result of the information contained herein or the external links provided. If you need medical advice, please seek it from a suitably qualified practitioner.

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