IFN - Serotonin link

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Psychosom Med. 2005 Sep-Oct;67(5):773-7.

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Irritability rather than depression during interferon treatment is

linked to increased tryptophan catabolism.

Russo S, Kema IP, Haagsma EB, Boon JC, Willemse PH, den Boer JA, de

Vries EG, Korf J.

Department of Biological Psychiatry, University Hospital Groningen,

Groningen, The Netherlands. s.r.russo@...

OBJECTIVE: Treatment with recombinant interferon is associated with high

rates of psychiatric comorbidity. We investigated the relation between

catabolism of the essential amino acid tryptophan, being rate-limiting of

peripheral and cerebral serotonin formation, and psychiatric symptoms in

patients undergoing combination treatment with interferon-alpha and

ribavirin. PATIENTS AND METHODS: Eighteen patients with viral hepatitis C

who received interferon were included. A psychiatrist screened patients

before and while on interferon-alpha treatment for 2 months, using a

structured diagnostic interview. Fasting plasma tryptophan and platelet

serotonin levels were measured at each visit. RESULTS: At baseline no

evident psychopathology was observed. After 2 months of interferon

treatment, 10 patients experienced increased irritability. No other

structural psychopathology was observed. Decreased plasma tryptophan level

correlated with the presence of irritability (p = .047). Platelet serotonin

levels were found to be decreased during treatment (p = .002). CONCLUSIONS:

Aggressive impulse dysregulation is highly prevalent in patients receiving

interferon treatment. This is associated with decreased plasma tryptophan

levels which may lead to attenuated peripheral and central serotonergic

neurotransmission.

PMID: 16204437 [PubMed - in process]

Antidepressants suppress production of the Th(1) cytokine interferon-gamma,

independent of monoamine transporter blockade.

Diamond M, JP, Connor TJ.

Department of Pharmacology, National University of Ireland, Galway, Ireland.

In this study, antidepressants with selectivity for the noradrenaline

transporter (reboxetine and desipramine), or the serotonin transporter

(fluoxetine and clomipramine) were examined in terms of their ability to

promote an anti-inflammatory cytokine phenotype in human blood. In addition,

we examined the ability of trimipramine; a tricyclic antidepressant that is

devoid of monoamine reuptake inhibitory properties on cytokine production.

Lipopolysaccharide (LPS) was used to stimulate monocyte-derived

pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10)

cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell

(Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants

suppressed IFN-gamma production in the 10-50 muM concentration range,

irrespective of their preference for serotonin or noradrenaline

transporters. This suppression of IFN-gamma production was paralleled by

reduced T-cell proliferation, therefore we suggest that the ability of

antidepressants to suppress IFN-gamma production may be related to their

anti-proliferative properties. The fact that trimipramine also suppressed

IFN-gamma production and T-cell proliferation indicates that these

immunomodulatory actions of antidepressants are most likely unrelated to

inhibition of monoamine reuptake. Interestingly, exposure to a lower

concentration (1 muM) of the antidepressants tended to increase

T-cell-derived IL-10 production, with significant effects elicited by the

noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to

the robust actions of antidepressants on T-cell derived cytokine production,

they failed to induce any consistent change in LPS-induced monocyte cytokine

production. Overall, our results indicate that IFN-gamma producing T-cells

(Th(1) cells) are the major target for the immunomodulatory actions of

antidepressants, and provide evidence questioning the relationship between

the monoaminergic reuptake properties of antidepressants and their

immunomodulatory effects. The potential clinical significance of the

anti-inflammatory actions of antidepressants is discussed.

PMID: 16388933 [PubMed - as supplied by publisher]

Encephale. 2005 May-Jun;31(3):349-57.

Hepatitis C, interferon a and depression: main physiopathologic hypothesis

Vignau J, Karila L, Costisella O, Canva V.

Service d'Addictologie, CHRU de Lille.

Imputability of thymic disorders caused by IFNalpha during the chronic

Hepatitis C treatment -- hepatitis C and depression -- the infection by the

hepatitis C virus (HCV) is a major public health concern since it affects

1.2% in the French population. Eighty percent of those contaminated by HCV

keep bearing the virus chronically although they remain asymptomatic during

many years. HCV infection is associated with psychiatric symptoms like

depression. Together with other factors (eg the severity of hepatic

condition), depression may induce significant impairment in quality of life.

Conversely, some psychiatric conditions may increase the risk of HCV

infection. In drug-addicted subjects using intravenous route, HCV

contamination rate ranges from 74 to 100%. Compared with general population,

a higher HCV contamination rate has also been noticed in some other

subgroups of subjects (patients with alcohol abuse or dependence, with

alcohol-induced hepatic disease and psychiatric inpatients). However, no

valid explanation to this phenomenon has been established. Interferon alpha

and depression - Interferons are a variety of cytokines naturally produced

by human tissues and have also been synthesized for therapeutic purposes

(treatment of a variety of cancers and viral infections). Many

psychobehavioural symptoms are observed under IFNalpha treatment. Among

them, mood disorders are known to occur early after entry into treatment and

to be within the reach of preventive measures. The reported frequency of

depression during IFNalpha treatment ranges from 0 to 37%. This variation

reflects either methodological biases (eg differences in psychiatric

assessment) or the heterogeneity of the population of patients accepted in

therapeutic protocols. Note that the adjunction of ribavirine to IFNalpha in

therapeutic protocols has not brought any changes in the depression

frequency. The causal relationship between IFNalpha administration and the

occurrence of mood disorders has been tackled by various recent research

works focusing on the importance of the immune system in the pathophysiology

of depression. Miscellaneous pathophysiological hypotheses -- nature of the

psychobehavioural symptomatology -- in addition to depressive symptoms,

IFNalpha treatment also induces various cognitive impairments and

disruptions in EEG patterns. These symptoms are consistent with a mild

subcortical dementia. Data resulting from pharmacological trials in humans

and in animals are controversial (eg IFNalpha-induced symptoms being

alleviated by both immune and antidepressant therapies). However, the debate

about the nature of the psychobehavioural disorders observed under IFNalpha

treatment might be no longer relevant in the light of recent theories which

regard depression as a maladaptive response to a particular form of stress,

namely a deep and diffuse feeling of sickness ( " malaise " ). These theoretical

views ascribe the production of depressive symptoms to a disruption in the

immune function, mediated by the variety of cytokines. The therapeutic

effects of anti-depressive drugs are thus attributed to their analgesic

properties, reducing the " malaise " feeling underlying depressive symptoms.

Necessity of a second messanger -- accordingly to current pathophysiological

theories, depression results from disorders of various CNS functions, mainly

limbic, monaminergic and neuroendocrinal systems. Though, exogenous IFNalpha

does not cross the blood-brain barrier when unscathed and an intermediary

mechanism is necessary. First to be addressed is the cytokines system itself

since it is composed of numerous different molecules interacting in an

infinite number of possible combinations. Some of these cytokines (eg some

interleukins) both are activated by IFNalpha and can reach CNS; they are

good candidates for the role of second messenger mediating the induction of

psychobehavioural disorders. Second, keeping in mind that serotonin is a

monoaminergic neurotransmitter classically involved in depression

pathophysiology, other works have demonstrated that IFNalpha modulates the

peripheral activity of indolamine-dioxygenase -- a regulating enzyme of

serotonin metabolism -- possibly through lymphocyte T CD4 activation. Third,

other authors have postulated an immune-induced vagal mechanism to explain

depression caused by IFNalpha. Action of IFNalpha on the neuroendocrine and

on neuromodulating functions: monoaminergic hypothesis -- cytokines could

have an influence on the mood through their modulating role on the

serotoninergic system. IFNalpha treatment is reported to produce: 1) a

decrease in tryptophan availability for serotonin synthesis, 2) a decrease

in the 5-HIAA level in the LCR, and 3) a modification of the central

serotoninergic receptors. Moreover, selective inhibitors of serotonin

transporters are effective to treat or prevent depression caused by

IFNalpha. Many studies support the serotonin-transporter hypothesis: in

vitro, both IFNalpha and interleukine 4 (IL-4) increases the expression of

serotonin transporter gene, IFNalpha increases in the production of IL-4 by

mononucleus cells (not found in vivo). Serotoninergic system can also be

altered by a peripheral action of IFNalpha on trytophan catabolism by

activating a concurrent pathway (known as " kynurenine pathway " ) to serotonin

synthesis. Finally, serotonin-mediated vulnerability to the

psychobehavioural effects of IFNalpha could be underlain by a polymorphism

of serotonin transporter gene. Concerning the other monoaminergic systems,

IFNalpha seems to have an amphetamine-like effect at its first

administration, followed by a decrease in dopaminergic tone with chronic

administration. Dopaminergic depletion, subsequent to psychostimulant abuse

for instance, results in severe depressive syndromes. Interactions between

IFNalpha and noradrenergic system have also been reported. Neuroendocrinian

hypothesis -- when administered through central or peripheral way, IFNalpha

simulates/inhibits the corticotrope axis and alters endorphin system as

shown by the induction of analgesia, catatonia and behavioural slowdown that

can be suppressed by opioid antagonists. IFNalpha neurotoxic effects are

successfully treated by naltrexone. Lastly, IFNalpha is known to cause

disorders in thyroid function that are likely to contribute to the

production or aggravation of mood disorders. CONCLUSION: A better

understanding of pathophysiologic mechanisms underlying psychiatric

side-effects of IFNalpha is essential to extend access to treatment to some

categories of patients that remain excluded from the protocols. A better

management of those psychiatric side effects should help the clinician not

to draw aside patients at risk, ie patients with depression, drug and

alcohol addiction. Treating them in a pragmatic and careful way is a major

issue, since this population represents a high percentage of the potential

candidates for interferon therapy.

Publication Types:

* Review

PMID: 16142050 [PubMed - indexed for MEDLINE]

Clin Chim Acta. 2005 Aug 31;

Monitoring tryptophan metabolism in chronic immune activation.

Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D.

Division of Biological Chemistry, Biocentre, Innsbruck Medical

University, Fritz Pregl Strasse 3 A-6020 Innsbruck, Austria; Ludwig

Boltzmann Institute of AIDS Research, Innsbruck, Austria.

The essential amino acid tryptophan is a constituent of proteins and is

also a substrate for two important biosynthetic pathways: the generation of

neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan

5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide

adenine dinucleotides. The latter pathway is initiated by the enzymes

tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine

2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is

expressed in a variety of cells including monocyte-derived macrophages and

dendritic cells and is preferentially induced by Th1-type cytokine

interferon-gamma. Tryptophan depletion via IDO is part of the cytostatic and

antiproliferative activity mediated by interferon-gamma in cells. In vivo

tryptophan concentration can be measured by HPLC by monitoring its natural

fluorescence (285 nm excitation and 365 nm emission wavelength). IDO

activity is characterized best by the kynurenine to tryptophan ratio which

correlates with concentrations of immune activation markers such as

neopterin. Low serum/plasma tryptophan concentration is observed in

infectious, autoimmune, and malignant diseases and disorders that involve

cellular (Th1-type) immune activation as well as during pregnancy due to

accelerated tryptophan conversion. Thus, in states of persistent immune

activation, low tryptophan concentration may contribute to immunodeficiency.

Decreased serum tryptophan can also effect serotonin biosynthesis and thus

contribute to impaired quality of life and depressive mood. As such,

monitoring tryptophan metabolism in chronic immunopathology provides a

better understanding of the association between immune activation and IDO

and its role in the development of immunodeficiency, anemia and mood

disorders.

PMID: 16139256 [PubMed - as supplied by publisher]

Med Hypotheses. 2005;65(1):138-44.

5-Hydroxytryptophan plus SSRIs for interferon-induced depression:

synergistic mechanisms for normalizing synaptic serotonin.

EH, Blackwell AD.

Mental Health Division, Mood Disorders Research Center, Portland VA

Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA.

.turner@...

Interferon-alpha (IFN) is widely used in the treatment of certain

cancers and viral infections, including hepatitis C (HCV). Unfortunately,

depression is a common side effect of IFN therapy, affecting approximately a

third of HCV patients receiving IFN therapy. Studies have shown that

selective serotonin reuptake inhibitors (SSRIs) can effectively treat

IFN-induced depression in only 63-75% of cases. For the remaining

percentage, depression often necessitates dose reduction of or

discontinuation from IFN therapy. Emerging evidence indicates that IFN may

cause depression by affecting brain serotonin. IFN has been shown to

increase serotonin reuptake and to decrease serotonin synthesis. We

hypothesize that SSRIs are not fully effective because they affect only

serotonin reuptake, not serotonin synthesis, and that effective treatment

must address both uptake and synthesis. 5-Hydroxytryptophan (5-HTP)

effectively increases central nervous system synthesis of serotonin. It is

the immediate precursor of serotonin and is widely available as a dietary

supplement, which is well absorbed after an oral dose. Several double-blind

studies have shown 5-HTP to be effective in the treatment of nondrug-induced

depression. We hypothesize that patients who become depressed on IFN will

respond to the synergistic combination of SSRIs plus 5-HTP.

PMID: 15893130 [PubMed - indexed for MEDLINE]

Dig Liver Dis. 2005 Feb;37(2):102-7.

Interferon-induced depression: prevalence and management.

Scalori A, Pozzi M, Bellia V, Apale P, Santamaria G, Bordoni T, Redaelli

A, Avolio A, Parravicini P, Pioltelli P, Roffi L.

Department of Medicine, University of Milano-Bicocca, S. Gerardo

Hospital, Monza, Italy.

BACKGROUND: Interferon-induced depression ranges from 0 to 50%.

Interferon schedule and a history of psychiatric illnesses are not enough to

predict who will develop symptoms and who will not. AIMS: To assess the

prevalence of depression during interferon therapy; to test whether

Minnesota Multiphasic Personality Inventory is useful in clinical practice

for the early identification of patients at risk of depression; whether and

how the depression can be cured. PATIENTS: One hundred and eighty-five

patients treated with interferon and ribavirin for chronic hepatitis C.

METHODS: Before therapy, all patients underwent a Minnesota Multiphasic

Personality Inventory and a clinical examination, specifically for the

identification of depressive symptoms. RESULTS: Thirty-one patients

developed a psychiatric disorder, 11 of them requiring treatment with

anti-depressant drugs. Among the 18 patients with Minnesota Multiphasic

Personality Inventory positive tests, 16 developed a psychiatric disorder, 8

of them a severe disorder (sensitivity of 0.58; 0.73 for severe disorders).

Among the 154 who did not develop psychiatric side effects, 152 had a

negative Minnesota Multiphasic Personality Inventory (specificity: 0.99).

Severe psychiatric disorders were successfully treated with anti-depressant

drugs. CONCLUSIONS: Psychiatric side effects are easy to see during

interferon therapy. A psychiatric evaluation should be considered on all

patients before treatment. If depression develops, it should be treated

aggressively, and selective serotonin re-uptake inhibitors are the

anti-depressants of choice.

PMID: 15733522 [PubMed - indexed for MEDLINE]