Scientists at Queen Mary University of London and the University of Roehampton, London, have discovered that patients suffering from obsessive-compulsive disorder (OCD) have increased levels of a protein called Immuno-moodulin (Imood) in their lymphocytes, a type of immune cell.
Mice with high levels of this protein were also found to exhibit behaviours that are characteristic of anxiety and stress, such as digging and excessive grooming.
When the researchers treated the mice with an antibody that neutralised Imood, the animals’ anxiety levels reduced.
The findings have led the researchers to file a patent application for the antibody and they are now working with a drug company to develop a potential treatment for human patients.
“There is mounting evidence that the immune system plays an important role in mental disorders,” said Professor Fulvio D’Acquisto, a professor of immunology at the University of Roehampton and honorary professor of Immunopharmacology at Queen Mary University of London, who led the research.
“And in fact people with auto-immune diseases are known to have higher than average rates of mental health disorders such as anxiety, depression and OCD.
Our findings overturn a lot of the conventional thinking about mental health disorders being solely caused by the central nervous system.”
Professor D’Acquisto, whose findings are published in the journal Brain Behavior and Immunity, first identified Imood by chance while studying a different protein called Annexin-A1 and the role it plays in autoimmune diseases such as multiple sclerosis and lupus.
He had created transgenic mice to over-express this protein in their T-cells, one of the main cells responsible for the development of autoimmune diseases, but found the mice showed more anxiety than normal.
When he and his team analysed the genes expressed in the animals’ T-cells, they discovered one gene in particular was especially active.
The protein produced from this gene was what they eventually named Immuno-moodulin, or Imood.
When the anxious mice were given an antibody that blocked Imood, their behaviour returned to normal in a couple of days.
The researchers tested the immune cells from 23 patients with OCD and 20 healthy volunteers.
They found Imood expression was around six times higher in the OCD patients.
Other recent research by scientists elsewhere have also found the same protein may also play a role in Attention-Deficit/Hyperactivity Disorder.
Professor D’Acquisto believes Imood does not directly regulate brain functions in a classical way, for example by changing the levels of chemical signals in neurons.
Instead, it may influence genes in brain cells that have been linked to mental disorders like OCD.
“This is work we still have to do to understand the role of Imood,” he said.
“We also want to do more work with larger samples of patients to see if we can replicate what we saw in the small number we looked at in our study.”
In the meantime, Professor D’Acquisto and Dr Dianne Cooper, a Senior Lecturer at Queen Mary University of London, are working with the biopharmaceutical company UCB to develop antibodies against Imood that can be used in humans and to understand how this could be used to treat patients with mental disorders.
“It is early still, but the discovery of antibodies – instead of the classical chemical drugs – for the treatment of mental disorders could radically change the life of these patients as we foresee a reduced chance of side effects,” he said. Professor D’Acquisto estimates it could take up to five years before a treatment can be taken to clinical trials.
Obsessive-compulsive disorder (OCD) is often a disabling condition consisting of bothersome intrusive thoughts that elicit a feeling of discomfort. To reduce the anxiety and distress associated with these thoughts, the patient may employ compulsions or rituals. These rituals may be personal and private, or they may involve others to participate; the rituals are to compensate for the ego-dystonic feelings of the obsessional thoughts and can cause a significant decline in function.
In The Diagnostic and Statistical Manual of Mental Disorders (DSM)-5, which was published by the American Psychiatric Association (APA) in 2013, Obsessive-Compulsive Disorder sits under its own category of Obsessive-Compulsive and Related Disorders. Within that are the following subcategories were placed:
- Obsessive-compulsive disorder (OCD)
- Body dysmorphic disorder (BDD)
- Hoarding disorder
- Excoriation (skin-picking) disorder
- Substance/medication-induced obsessive-compulsive and related disorder
- Obsessive-compulsive and related disorder as a result of another medical condition
- Other specified obsessive-compulsive and related disorder
- Unspecified obsessive-compulsive and related disorder
A. Presence of obsessions, compulsions, or both:
Obsessions are defined by (1) and (2):
- Recurrent thoughts, urges, or images that are experienced, at some time during the disturbance, as unwanted, and that in most individuals cause marked distress
- The individual attempts to suppress such thoughts, urges, or images, with some other thought or action (i.e., by replacing with a compulsion).
Compulsions are defined by (1) and (2):
Repetitive behaviors or mental acts that the person feels driven to perform in response to an obsession.
The behaviors or mental acts aim at reducing anxiety or distress or preventing some dreaded situation; however, these behaviors or mental actions do not connect in a realistic way with what they are designed to prevent or are clearly excessive.
B. The obsessions are time-consuming or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C. The obsessive-compulsive symptoms do not arise from the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.
D. The symptoms of another mental disorder do not better explain the disturbance (e.g., excessive worries, as might be found in a generalized anxiety disorder; preoccupation with appearance, as seen in a body dysmorphic disorder; difficulty discarding or parting with possessions, as found in a hoarding disorder; hair pulling, as in trichotillomania a hair-pulling disorder; skin picking, as appears in excoriation [skin-picking] disorder; stereotypies, as found in a in stereotypic movement disorder; ritualized eating behavior, as found in eating disorders; preoccupation with substances or gambling, as seen in a in substance-related and addictive disorders; preoccupation with having an illness, as found in illness anxiety disorder; sexual urges or fantasies, as found in a paraphilic disorders; impulses, as seen in a disruptive, impulse-control, and conduct disorders; guilty ruminations, as occurs in a major depressive disorder; thought insertion or delusional preoccupations, as found in schizophrenia spectrum and other psychotic disorders; or repetitive behavior patterns, as found in an autism spectrum disorder).
Obsessions are defined as intrusive thoughts or urges that cause significant distress; the patient attempts to neutralize this distress by diverting thoughts or performing rituals.
Compulsions are actions the patient feels pressured to do in response to the anxiety/distress producing obsessions or to prevent an uncomfortable situation from occurring. These compulsions may be illogical or excessive.
The most common obsessions include fears of contamination, fears of aggression/harm, sexual fears, religious fears, and need to make things “just right.” The compensatory compulsions for these obsessions include washing and cleaning, checking, reassurance-seeking, repeating, and ordering, and arranging.
As OCD has the possibility of hindering one’s social grown and development, the WHO lists OCD as one of the ten most disabling conditions by financial loss and a decrease in quality of life.
Termed “obsessional neurosis” by Freud in 1895, OCD has had acknowledgment for centuries. However, only recently has the DSM listed OCD as less of an “anxiety” disorder, and more of a disorder similar to hoarding, body dysmorphia, trichotillomania (hair-pulling disorder) and excoriation (skin-picking) disorder.
The use of modern technology has allowed us to map areas of the brain that have been affected by this disorder. These areas of the brain do not typically correspond with anxiety and fear as previously thought and further separate OCD as an “anxiety” disorder.
The exact cause of OCD remains unknown, but it is likely multifactorial. There is a genetic predisposition, as 45 to 65% of the variance of OCD is attributable to genetic factors. In mice and human experiments, mutated NMDA mutated can cause an increase in OCD-like behavior. For example, mutations in the NMDA subunit “NR2” has been linked to fears of contamination and compulsive cleaning.
An inability to cope with uncertainty, an increased sense of responsibility as well as magical thinking seem to predispose those to obsessive-compulsive habits.
Earlier onset of sudden OCD that is preceded by a Streptococcus infection has been known as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).
Just as Sydenham chorea can present as a sequela from Streptococcus infections, the theory behind OCD is similar in that the strep infection, through molecular mimicry, causes autoimmune antibodies against the basal ganglia leading to obsessive thoughts and compulsive habits.
However, the term PANDAS is falling out of favor in lieu of childhood acute neuropsychiatric symptoms (CANS), which allows the development of OCD in the pediatric population to be attributable to other sources than Strep, such as metabolites and toxins.
OCD does appear to be heritable, confirmed by both twin and family studies. Research has shown that the heritability to be as high as 45 to 65% in children and 27 to 45% in adults. Having a family with OCD increases the risk of developing OCD. OCD has links with other neurological disorders, particularly those that affect the cortico-striato-thalamo-cortico circuitry, such as Parkinson disease, Sydenham chorea, traumatic brain injury (TBI), Tourette syndrome, Huntington disease, and epilepsy, to name a few.
The lifetime prevalence of OCD is 1.6 to 2.3% in the community; point prevalence is 1%. The average age of onset is 19.5.
About 50% of those with OCD have the onset of symptoms in childhood and adolescence. It is unusual to have OCD initially present over the age of 40.
The average time-to-treatment is 11 years. There is speculation of delay in treatment, as those with OCD may be embarrassed with their intrusive thoughts, such as inappropriate sexual beliefs or ritualistic behavior.
Roughly 90% of those with OCD have coexisting psychiatric diagnoses, most commonly are anxiety disorders.
Males present earlier, but in adulthood, more females are affected. Postpartum females are up to 2 times as likely than the general female population to develop OCD.
Treatment / Management
The mainstay of OCD treatment is SSRIs and cognitive behavioral therapy (CBT) with Exposure and Response Prevention (ERP).
Historically the tricyclic antidepressant (TCA) clomipramine was used as first-line for OCD due to its strong predilection for serotonin. However, given the side effect profile, SSRIs have gained favor.
ERP involves exposing the patient to their fears and having the patient resist the urge to perform a compulsion. The goal is to restructure the mind and alter the habituation created by participating in the compulsion. Success rates vary.
OCD is most commonly treated with SSRIs, and at much higher doses than used to treat anxiety or depression. FDA approved SSRIs include fluoxetine, fluvoxamine, paroxetine, and sertraline.
Two primary neurotransmitters are thought to contribute to OCD: serotonin and glutamate. The serotonin hypothesis arose after OCD symptoms abated with the use of serotonergic antidepressants.
Glutamate has been gaining support as more data comes to light. The use of d-cycloserine (DCS), a partial NMDA receptor agonist (a glutamate receptor), has gathered attention as research has shown DCS to enhance extinction learning in animal studies.
This information could potentially be useful in augmenting CBT. Other medications currently investigated include memantine, lamotrigine, N-acetyl cysteine, ketamine, topiramate, glycine, and riluzole, though more studies are necessary to prove their efficacy.
Antipsychotics have been entertained as an adjunct therapy. Aripiprazole, haloperidol (finding based on only one trial), and risperidone were significantly superior to placebo. In contrast, olanzapine, paliperidone, and quetiapine could not differentiate from placebo as measured by mean Y-BOCS total improvement.
There have been instances of refractory cases having treatment with ablative lesion neurosurgery; however, there are no controlled trials. Deep brain stimulation has also been considered for severe cases of refractory OCD. Transcranial magnetic stimulation (TMS) has not proven successful in treating the disorder.
In 1989 fluvoxamine was shown to be an effective treatment for OCD. Since the 1980s, there have been over 20 studies conducted to support the efficacy of SSRIs for the treatment of OCD. Thus far, they have found that fluvoxamine is not superior to other SSRIs as monotherapy.
The following are appropriate drugs and doses typically used to treat OCD: fluoxetine 80 mg, escitalopram 40 mg, 300 mg fluvoxamine, and 100 mg paroxetine. Citalopram is no longer a recommended agent, given the risk of QTc prolongation in higher doses. Those treated with an SSRI for OCD will need a longer trial of 8 to 12 weeks on the medication as they typically take longer to respond than those receiving treatment for depression for a reason still unknown.
Clomipramine was approved for OCD in the late ’80s but is no longer the first line to treat OCD, given its complicated side effect profile and the potential to elicit arrhythmias, seizures, and anticholinergic side effects, to name a few. Treatment with SSRIs can be augmented with the use of NMDA receptor antagonist Memantine.
In a double-blinded controlled study in Iran, Memantine was beneficial; after eight weeks of treatment, there was a 100% response with 89% remission. Other medications that have been tried for OCD modulation via the NMDA receptors include topiramate, lamotrigine, ketamine, and riluzole, but so far, data has been inconclusive.
Other medications being explored as augmentation therapy include ondansetron, tramadol, and amphetamines; however, no conclusive evidence can be drawn at this time.
Deep brain stimulation is still a novel treatment, and due to the high costs and invasive nature of the procedure is not yet in routine use. Over the past 20 years, only 200 to 300 patients with OCD have received treatment with DBS. In an Amsterdam study published in October 2019, they found that DBS aimed at the ventral anterior limb of the internal capsule makes those with OCD more open to environmental change and can engage in more activities than their compulsions. In that study, they surmised that DBS is similar in theory to cognitive flexibility.
CBT aims at altering malicious and harmful thoughts. In addition to CBT and ERP, the patient can employ mindfulness techniques such as meditation and relaxation. In a 2012 study that focused on Mindfulness-Based Cognitive Therapy, they found that two-thirds of their patients experienced a decrease in OCD symptoms over the course of 8 weeks.
Unlike ERP, MBCT does not involve exposing patients to their fear intentionally. Still, when the stressful event arises, the patient is encouraged to take time and examine their thoughts and feelings during the unpleasant time. MBCT targets less the thoughts themselves, but more the attitude towards the obsession.
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