Impact of lithium alone and in combination with antidepressants on cytokine production in vitro.

Lithium is an important psychopharmacological agent for the treatment of unipolar as well as bipolar affective disorders. Lithium has a number of side effects such as hypothyroidism and aggravation of psoriasis. On the other hand, lithium has pro-inflammatory effects, which appear beneficial in some disorders associated with immunological deficits, such as human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE). Therefore, immunological characteristics of lithium may be an important consideration in individualized therapeutic decisions. We measured the levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-22, IL-17 and tumour necrosis factor (TNF)-α in the stimulated blood of thirty healthy subjects supplemented with lithium alone, the antidepressants citalopram, escitalopram or mirtazapine alone, the combination of each antidepressant with lithium, and a no drug control. These drugs were tested under three blood stimulant conditions: murine anti-human CD3 monoclonal antibody OKT3 and the 5C3 monoclonal antibody (OKT3/5C3), phytohemagglutinin (PHA), and unstimulated blood. Lithium, alone and in combination with any of the tested antidepressants, led to a consistent increase of IL-1ß, IL-6 and TNF-α levels in the unstimulated as well as the stimulated blood. In the OKT3/5C3- and PHA-stimulated blood, IL-17 production was significantly enhanced by lithium. Lithium additionally increased IL-2 concentrations significantly in PHA-stimulated blood. The data support the view that lithium has pro-inflammatory properties. These immunological characteristics may contribute to side effects of lithium, but may also explain its beneficial effects in patients suffering from HIV infection or SLE.

Modulation of cytokine production by drugs with antiepileptic or mood stabilizer properties in anti-CD3- and anti-Cd40-stimulated blood in vitro.

Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA) report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), VPA, oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), and lithium on the production of the following cytokines in vitro: interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-α. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1ß, IL-2, IL-4, IL-6, IL-17, and TNF-α production, which substantiates and adds knowledge to current hypotheses on VPA's anti-inflammatory properties.

Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro.

Changes within the immune system have been reported to contribute to the pathophysiology of bipolar disorder and epilepsy. Interestingly, overlapping results regarding the cytokine system have been found for both diseases, namely alterations of interleukins IL-1ß, IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α). However, the effect of mood stabilizers and antiepileptic drugs (AEDs) on these cytokines has not been systematically evaluated, and their effect on IL-17 and IL-22, other immunologically important cytokines, has not been reported. Therefore, we systematically measured levels of IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in stimulated blood of 14 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was supplemented with the mood stabilizers or antiepileptic drugs primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), valproic acid (VPA), oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), lithium, or no drug. IL-1ß production was significantly decreased by PRM, CBZ, LEV, LTG, OXC, PB and lithium. IL-2 significantly decreased by PRM, CBZ, LEV, LTG, VPA, OXC, TPM and PB. IL-22 significantly increased by PRM, CBZ, LEV, OXC, TPM and lithium and decreased by VPA. TNF-α production significantly decreased under all applied drugs. The mechanism of action and side effects of mood stabilizers and AEDs may involve modulation of IL-1ß, IL-2, IL-22 and TNF-α signaling pathways. IL-22 may be a research target for specific therapeutic effects of mood stabilizers and AEDs. These drugs might influence cytokine production by modulating ion channels and γ-aminobutyric acid (GABA) receptors of immune cells.

Impact of antidepressants on cytokine production of depressed patients in vitro.

The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1ß, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1ß, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1ß, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1ß, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

Impact of clozapine, N-desmethylclozapine and chlorpromazine on thromboxane production in vitro.

Thromboxane A2 (TxA2) and the activation of its receptor have been shown to modulate vasoconstriction and platelet aggregation as well as dopaminergic and serotonergic signalling. Dopaminergic and serotonergic systems play a crucial role in the pathophysiology of schizophrenia and these systems are the main targets of antipsychotics (APs). As the first antipsychotic (AP) chlorpromazine (CPZ) has already been shown to reduce TxA2, we hypothesized that the AP clozapine and its metabolite N-desmethylclozapine (NDMC) might also influence TxA2 production. We measured levels of thromboxane B2 (TxB2), the metabolite of the very unstable molecule TxA2, in unstimulated and stimulated blood samples of 10 healthy female subjects in a whole blood assay using toxic shock syndrome toxin-1 (TSST-1) and monoclonal antibody against surface antigen CD3 combined with protein CD40 (OKT3/CD40) as stimulants. Blood was supplemented with the APs CPZ, clozapine or NDMC in one of four different concentrations. Additionally, thromboxane levels were measured in blood without the addition of APs under different stimulation conditions. Under TSST-1 as well as OKT3/CD40 stimulation, mean TxB2 concentrations were significantly (p < 0.05) decreased by clozapine over all applied concentrations. NDMC led to a decrease in TxB2 levels under unstimulated conditions as well as under TSST-1 stimulation. CPZ reduced TxB2 production at low concentrations under unstimulated and TSST-1- stimulated conditions. Clozapine, NDMC and CPZ possibly act on neurotransmitter systems via modulation of TxA2 or TxB2 production. Additionally, known side effects of APs such as orthostatic hypotension may be a result of changes in the concentrations of TxA2 or TxB2.

Impact of antipsychotics on cytokine production in-vitro.

OBJECTIVE: A growing body of data from genetic, immunological and clinical studies indicates an involvement of the immune system in the pathophysiology of schizophrenia and suggests that the modulation of the cytokine system by antipsychotics may be one cause for the improvement of psychotic symptoms. However, the influence of the typical antipsychotics chlorpromazine and haloperidol, and the effect of typical and atypical antipsychotics on the TSST-1-stimulated blood cell secretion of cytokines, and specifically the interleukin (IL)-17 production have not been studied so far, although IL-17 is a leading pro-inflammatory cytokine. METHOD: We measured levels of IL-1ß, IL-2, IL-4, IL-6, IL-17 and tumor necrosis factor-α (TNF-α) in stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was either supplemented with antipsychotics (chlorpromazine, haloperidol, clozapine, N-desmethylclozapine and quetiapine with four different concentrations each) or not. RESULTS: Under TSST-1 stimulation, antipsychotics as a group had no influence on IL-1ß or IL-6 concentrations but increased IL-4 levels. The most consistent findings were seen regarding IL-17. Mean IL-17 concentrations differed significantly between blood with and without antipsychotic supplements and were increased over all antipsychotics and almost all of the applied antipsychotic concentrations. TNF-α levels were increased by chlorpromazine; N-desmethylclozapine and quetiapine reduced IL-2 production. CONCLUSIONS: Antipsychotics might, among other mechanisms, act as such by increasing the production of IL-17.