Neuro-Inflammation Case Study
These analyses suggest that this individual’s depression may be a manifestation of cytokine-induced interference with the conversion of tryptophan to melatonin and serotonin in conjunction with increased glutamate receptor activation.
Recent studies have focused on the role of immune dysfunction in depression, and analogies to “cytokine-induced sickness behavior” have been established. Sickness behavior is a coordinated set of adaptive behavioral changes that develop in affected individuals during the course of an infection. Disease symptoms include lethargy, depression, failure to concentrate, anorexia, sleep disturbances, reduction in personal hygiene or social withdrawal, and are mediated by proinflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα).
Besides the well-known deficiency in serotonergic neurotransmission as a correlate of major depression (MD), recent evidence points to a pivotal role in increased glutamate receptor activation as well.
An immune activation including increased production of proinflammatory cytokines has repeatedly been described in major depression. Proinflammatory cytokines such as interleukin-2, interferon-γ, or tumor necrosis factor-α activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. Enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. Increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor.
In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes – counteracting this metabolism due to the lack of an enzyme of this metabolism – have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in the re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counter-regulation of IDO activity in microglia and altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction, and antagonizing neurotoxic effects of quinolinic acid.
This 39-year-old male presented for the treatment of treatment-resistant unipolar major depression without psychotic symptoms. Additional comorbid symptoms include:
- Skin – plaque psoriasis and acne
- Pain – Inflammatory joint pain, knee swelling, and back pain
- Mood – anhedonia, anxiety, unipolar depression
- Digestive Issues
- Loss of interest in daily activities
- Lack of energy
- Inability to focus (attention-deficit disorder)
- Irregular sleeping patterns
- Loss of appetite
- Low or decreased self-worth and self-esteem
- Suicidal thoughts
- Mild autistic symptoms
Onset & History:
- Age 8 – 39: Depression, anxiety
- Age 15 – 35: acne on face and back
- Age 15 – 35: Severe social anxiety
- Age 29 – 39: plaque psoriasis
- Age 15 – 35: back pain
- Age 39 – 39: guttate psoriasis
- Age 29 – 39: episodic arthritis
Quick Inventory of Depressive Symptomatology (QIDS)
Patient scored 21 points on QIDS inventory suggesting a state of severe depression.
Selective Serotonin Reuptake Inhibitors (SSRIs)
- 40 mg/day Citalopram (Celexa) for 6 months – No response, no remission
- 20 mg/day Escitalopram (Lexapro) for 3 months – No response, no remission
- 60 mg/day Fluoxetine (Prozac) for 6 months – No response, no remission
- 50 mg/day Paroxetine (Paxil) for 3 months – No response, no remission
- 100 mg/day Sertraline (Zoloft) for 9 months – No response, no remission
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
- 60 mg/day Cymbalta (duloxetine) – No response, no remission
- 150 mg/day Effexor (venlafaxine) – No response, no remission
Tricyclic Antidepressants (TCAs)
- 100 mg/day Anafranil – No response, no remission
Monoamine Oxidase Inhibitors (MAOIs)
- 10 mg/day Eldepryl (Selegiline Hcl) – Moderate response, no remission
- 30 mg/day Remeron (mirtazapine): Moderate response, no remission
- 300mg/day Wellbutrin (bupropion): Moderate response, no remission, increased energy
Analysis of regular self-reported pain and mood measurements by the patient reveals a strong correlation between inflammatory pain and severity of depressive symptoms. This is consistent with the hypothesis that elevated inflammatory cytokine levels may be initiating the shunt of tryptophan away from intracranial serotonin production as depicted in Figure 1. Tryptophan shunt away from serotonin/melatonin production to neurotoxic quinolinic acid.
Sleep quality was calculated based on the amount of movement during sleep as measured by a Fitbit accelerometer. Melatonin is the main hormone involved in the control of the sleep-wake cycle. Cytokine-induced depletion of serotonin and melatonin (Figure 1) is further supported by a strong correlation between the patient’s sleep quality and mood the preceding day.
The fact that the correlation between mood and sleep quality is highest without pairing the sleep quality measurements with mood outcome data lagged by a day suggests that the relationship is correlational rather than causal. This is illustrated in the following chart where the correlation at a 0-day lag is much higher than the correlation at a 1-day lag.
Acne, social anxiety, and inflammatory back pain were completely alleviated following the removal of gluten from the subject’s diet at age 35. Several attempts at the reintroduction of gluten result in the recurrence of acne, social anxiety, and inflammatory pain within 2 days and gradually subside over the following 2 weeks after the last gluten exposure.
It has been shown that gluten can trigger the release of the protein zonulin. Zonulin then loosens the tight junctions in the intestinal wall. This allows toxins to enter the bloodstream triggering an immune response. This leads to the elevation of the cytokines which interfere with the conversion of tryptophan to serotonin and melatonin.
Psoriasis is a systemic autoimmune inflammatory disease that shares some immunological aspects with other inflammatory-based diseases, such as Crohn’s disease.1 Bacterial DNA (bactDNA) fragments have been shown to induce a systemic immunological response in Crohn’s disease and other settings. The translocation of gut bacteria to the bloodstream is also associated with the increase in inflammatory mediators that can lead to inflammatory and neuro-inflammatory disease.
|Inflammatory Mediator (mean pg/mL)||BactDNA-Positive Psoriasis (n = 16)||BactDNA-Negative Psoriasis (n = 38)||P|
|Tumor necrosis factor||95.2||21.7||<.001|
Intake of the probiotic Bacillus coagulans (Probiotics Plus) is predictive of elevated overall mood. It has been shown in mouse models that Bacillus coagulans combined with a prebiotic can reduce intestinal permeability and associated inflammatory reactions.
Physical activity appears to provide lesser medium-term benefits.
Likely Prognosis or Disease Progression
N-methyl-D-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration. The current prevailing theory suggests that synaptic and extrasynaptic NMDAR (syn- and ex-NMDAR) impose counteracting effects on cell fate, and neuronal cell death is mainly mediated by the activation of ex-NMDAR.
N-methyl-D-aspartate receptors (NMDARs) mediate excitatory neural transmission. In addition to their physiological functions, mounting evidence has suggested their involvement in excitotoxicity. Cell death triggered by seizure or ischemic stroke is attributed to NMDAR overactivation.1, 2 Abnormal NMDAR activity is also associated with neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease.3 Thus, it is concluded that, while appropriate NMDAR activation is essential for neuronal survival and physiological functions, excessive activation contributes to pathological changes including cell death.4
The most plausible mechanism of action is related to inflammatory cytokine-induced NMDA ecotoxicity. Inflammation has been widely observed to significantly increase with aging. This suggests that the severity of the patient’s depression and suicidal ideation may only increase without intervention such as the NMDA-receptor antagonist Spravato to address the potential mechanism of action.