Psychotherapy and Neuroscience

Inflammatory Proteins in Psychiatric Populations

Immunological alterations are also associated with post-trauma adaptations. Adult survivors of childhood sexual abuse exhibit increased CD45RO/CD45RA ratios that reflect increased levels of lymphocyte immune activation in vivo (Wilson et al., 1999). After having lived 4-7 months in a Bosnian prison camp, survivors during the two months post- incarceration period presented immunological alterations of increased serum TNF concentrations and decreased IFN and natural killer (NK) cell cytotoxic activity (Dekaris et al., 1993). At two month follow-up those who had worked at the crash site of 1994 USAir Flight 427 (Delahanty et al., 1997), but neither saw nor handled body parts, tended to report greater health problems when compared to other workers who had handled body parts at the site or in the morgue. Apparently those who had less systematic exposure to bodies reported the highest levels of intrusive thoughts and increases in NK activity and systolic blood pressure readings that persisted four months beyond the initial testing. Workers with no apparent exposure to human remains faired more poorly with poorer health and higher levels of intrusive thoughts at 6-month follow-up.

The neuroimmune effects of trauma’s impact can be experienced as long as twenty years later. Vietnam combat veterans having PTSD symptoms of anxiety, depression, numbing, intrusive memories, etc., have higher adjusted mean white blood cell, total lymphocyte, T-cell, and CD4 cell counts (Boscarino & Chang, 1999) and greater incidence of circulatory, digestive, musculoskeletal, CNS, respiratory, and infectious diseases than veterans not exposed to battle (Boscarino, 1997). Israeli combat veterans also symptomatic for PTSD present increased plasma IL-1β levels that are also positively correlated with the duration of symptoms (Spivak et al., 1997). Cerebrospinal fluid concentrations for IL-6 and norepinephrine (Baker et al., 2001) and serum IL-6 levels are higher in PTSD patients without depression (Maes et al. 1999a) when compared with healthy volunteers. Serum levels for the IL-6 receptor (IL-6R) tend to be higher in PTSD patients with comorbid depression (Maes et al., 1999a) when compared with PTSD without depression and healthy volunteers. Patients with somatization disorder present significantly higher serum concentrations of the interleukin-one receptor antagonist (IL-1RA) and the IL-6R (Rief et al., 2001).

Depressed symptoms, as rated by the Beck Depression Inventory, are positively associated with proinflammatory increases in serum tumor necrosis factor-alpha (TNF-α) (Mikova et al., 2001; Tughi et al., 2003), plasma interleukin-6 (IL-6) (Maes et al., 1995; Appels et al., 2000; Kiecolt-Glaser & Glaser, 2002), and IL-1β (Schlatter et al., 2001; Suarez et al., 2003). Although serum IL-1β levels are found to be no different from healthy controls in another study; natural killer cell (NK) increases are positively associated with negative affect (Miller et al., 1999). The state of depression is also strongly associated with higher serum concentrations of the IL-1RA (Song et al.,1998) and decreases in plasma IL-6R (Rief et al., 2001). Increases in plasma IL-6 and IL-1RA are not only significantly associated with depression, but also sleep disorders (Song et al., 1998). Circulating IL-6 levels and expression may be associated with the sense of fatigue (Swain, 2000) that is associated with chronic anxiety, depression, and sleep disorders. Serum TNF-α, IL-1β, and IL-6 levels that are above normal values are also associated with coronary heart disease (Appels et al., 2000).

Plasma TNF-α increases are positively correlated with depression duration (Schlatter et al., 2001; Suarez et al., 2003) and age (Penninx et al., 2003) and can be effectively regulated by electroconvulsive therapy (ECT) (Hestad et al., 2003). Antidepressant therapies, such as clomipramine, sertraline, trazodone (Maes et al., 1999b), and fluoxetine (Kubera et al., 2001) produce plasma decreases in interferon-gamma (IFN-γ) levels by increasing IL-10 levels and is evidenced in suppression of the IFN-γ/IL-10 ratio. IFN-γ seems to have a role in raising resting energy expenditure. It has been implicated in increasing body temperature. It underlies increases in IL-6, ACTH, and cortisol levels and regulates insulin-like growth factor I (IGF) levels (de Metz et al., 1999). Antidepressants have little or no effect on serum IL-8, IL-6, IL-RA, CC16 (Mikova et al., 2001) or SCD8 levels. Although depressed subjects’ serum TNF-a levels tend to be higher than normal control subjects before therapy, tricylic antidepressant therapies with clomipramine, mianserine, and amitriptyline as well as paroxetine present even greater increases in serum TNF-a (Mikova et al., 2001). Certain antipsychotic drugs, like clozapine, lithium, and olanzapine, that block the D2 receptor post-synaptically, produce circulating increases in TNF-α along with concurrent increases in its receptor’s expression, that underlie drug-induced increases in glucose levels and weight gain and, in the predisposed individual, insulin resistant diabetes (Pollmacher et al., 2000). Clozapine and olanzapine have been associated with metabolic abnormalities of hyperinsulinemia, hyperlipidemia, hyperleptinemia, and insulin resistance (Melkersson & Dahl, 2003).

TNF-α stimulation also increases plasma leptin levels (Zumbach et al., 1997; Finch & Johnson, 2002) due to the posttranslational stimulation of leptin secretion (Kirshgessner et al., 1997). Both mean serum leptin (Considine et al., 1996) and TNF-α concentrations (Katsuki et al., 1998) are higher in obese patients than normal weight subjects. In fact there is a significant positive relationship between increases in adipose (fat tissue) TNF-α and IL-6 expression and increases in the body mass index (Yudkin et al., 1999; Bullo et al., 2002). Increases in the TNF receptor two (TNFR-2) expression are associated with obesity, insulin resistance, endothelial dysfunction, high C-reactive protein concentrations and IL-6 in obese subjects (Yukdin et al., 1999; Wiecek et al., 2002; Warne et al., 2003). TNF-α and leptin-mediated insulin resistance causes the serine phosphorylation of the insulin receptor substrate-1 (IRS-1). This inhibits insulin-dependent tyrosine phosphorylation and kinase of IRS-1causing a suppression of insulin expression (Cohen et al., 1996; Kroder et al., 1996; Qi & Pekala, 2000; Finch & Johnson, 2002).

Miller and colleagues (2003) support the development of a model, which views depressive symptoms as promoting weight accumulation. They note that depression induced weight gain activates inflammatory responses through two pathways, one which expands the release of IL-6 (and TNF-α) in adipose tissue and (TNF-α stimulated) leptin-induced upregulation of IL-6 release by white blood cells.

The Miller model overlooks that both proinflammatory cytokines, TNF-α and IL-6, are initially stress-responsive. They are activated in response to psychological stress in healthy adults and then decrease as stress is reduced. This has been referenced in the neuroimmune responses in healthy controls. Repeated and chronic stressors over time may increase serum-circulating levels of cytokines in a variety of body tissues and secretions that are cumulative and persistent over time. This is how chronic stress activation may then further adipose TNF-α and leptin expression. Obesity-and insulin resistant diabetic-related symptoms may later develop in response to the intensity of this expression.

Interferon-alpha (IFN-α) immunotherapy is associated with depressive symptoms of slowness, severe fatigue, hypersomnia, lethargy, depressed mood, irritability, short temper, emotional lability, social withdrawal, and lack of concentration (Bonaccorso et al., 2000). IFN-α therapy not only suppresses HPA activity but also leads to the future development of depressive and fatigue symptoms in predisposed individuals (Malik et al., 2001). Patients with malignant melanoma receiving IFN-α immunotherapy and susceptible (though not necessarily symptomatic at the start of testing) for developing later depressive symptoms and who later develop IFN-α clinical depression, present significantly greater initial levels of ACTH and cortisol. Initial increases in HPA activity in response to IFN-α therapy are predictive for the later development of depressive symptoms. In contrast patients who do not develop depressive symptoms after receiving initial injection of IFN-α also exhibit significantly lower serum ACTH and cortisol (Capuron et al., 2003) and higher serum L-tryptophan (L-TRP) levels (Van Gool et al., 2003). L-TRP is an essential amino acid and precursor of serotonin. Reductions in its availability downregulates serotonin availability in postsynaptic 5-HT1A neurons and increases the number, affinity and responsivity of serotonin in postsynaptic 5-HT2A/C neurons (Bonaccorso et al., 2000). Patients who develop IFN-α induced depressive symptoms also show strongly significant decreases in L-TRP (Van Gool et al., 2003). Pretreatment with the antidepressant paroxetine can protect the potentially depressed asymptomatic patient from developing later IFN-α-induced suppression of tryptophan (Capuron et al., 2003) and later manifested depressive symptoms (Musselman et al., 2001). Antidepressants can reverse IFN-α induced anhedonia and depression (Sammut et al., 2002). Previously remitted depressive symptoms in response to paroxetine therapy can return after the onset of IFN-α immunotherapy (McAllister-Williams & Young, 2000) in response to IFN-α’s ability to alter serotonin activity. IFN-α’s effects are mediated by IL-6-induced release of CRH (Navarra et al., 1990; Harbuz et al., 1995; Cassiday & O’Keane, 2000) as a CRH receptor 1 antagonist (CRH-R1) can significantly reverse IFN-α-induced immobility in laboratory animals (Yamano et al., 2000). Injection of IFN-α can reduce 5-HT levels in the frontal cortex, striatum, hypothalamus and midbrain. IFN-α reduces mean concentrations of norephinephrine in the frontal cortex and produces significant increases in the striatum, hypothalamus, and medulla. IFN-α induced dopamine release is significantly reduced in the striatum (Kamata et al., 2000).

In summary traumatic and chronic stress seems to have an impact on the immune system in different ways. Increases in IL-1β and IL-6 are noted in response to sustained and chronic traumatic stress and in the state of PTSD. PTSD with and without comorbid depression increases the expression of serum IL-6R and IL-6 levels, respectively. Major depression appears to present increases in serum IL-6, IL1-β, TNF-α and the IL1-RA (IL-1 receptor antagonist) along with decreases in IL-6R expression. IL-6 alters resting energy expenditure by mediating increases in body temperature (in concert with IFN-γ-de Metz et al., 1999), plasma concentrations of anti-inflammatory norepinephrine and cortisol, glucagon, glucose and fatty acids in concert with TNF-α (Stouthard et al., 1995). Increasing chronicity of the depressed state is associated with increased circulating levels of TNF-α, which is later associated with increased leptin levels in predisposed individuals. Increases in both TNF-α and leptin levels are associated with the risk for obesity and insulin resistant diabetes. Heightened TNF-α levels are also associated with the later development of coronary heart disease. IFN-α seems to have a contributory role in depressed behavior. This is based on the nature of IFN-α neurotherapy’s side effects in producing depressive symptoms in asymptomatic but later vulnerable patients, its impact on triptophan synthesis, and antidepressant responsivity for symptom regulation. IFN-α appears to play a critical role in mediating the later development of depressive symptoms that are manifested in the syndrome.


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