Table 3. Differential biological mechanisms within bipolar disorders.
| Authors | Objective | Design/sample | Subjects | Procedure | Depressive subtypes | Reported Severity of symptoms | Results |
|---|---|---|---|---|---|---|---|
| Rapaport et al.109 | Examine immune function in euthymic BD patients | Cross-sectional/clinical | 16 euthymic patients with BD-I, 10 BD-II, 34 controls | SCID diagnosed BD | BD-I, BD-II | No | Relative to controls BD patients had similar lymphocyte populations, sIL-2R and IL-2 levels. |
| Cassidy et al.120 | Investigate the utility of the DST in patients with manic or mixed episodes of BD | Cross-sectional/clinical | 46 inpatients with BD (37 manic, 7 mixed) | Diagnosis of BD with mixed/manic episode on admission. DST administered around day 5 of admission. Mania severity assessed with in-house scale | BD (manic/mixed) | Yes | A mixed episode was significantly associated with dexamethasone non-suppression as compared with a manic episode. Cortisol levels were significantly higher at all time points for patients with a mixed episode compared to manic patients. The relationship between mania severity score and cortisol level was non-significant. |
| Rapaport et al.107 | Examine immune function in rapid cycling BD patients before and after lithium treatment | Prospective/clinical | 17 rapid cycling bipolar patients (3 BD-I, 14 BD-II), 18 controls | SCID diagnosed BD. Cytokine assays at initiation of lithium, and at 4 weeks | BD-I, BD-II | No | Relative to controls, unmedicated symptomatic BD patients had higher levels of sIL-2R and sIL-6R. These levels normalized with lithium treatment. |
| Tsai et al.108 | Examine induces of cell mediated immunity in Bipolar mania | Prospective/clinical | 23 inpatients with BD in acute mania, 23 controls | SCID diagnosed BD. Cytokine assays when ⩾26 on YMRS (Manic) and ⩽12 on YMRS (remission) | BD-I (manic/remitted) | Yes | Relative to controls, manic BD patients had higher levels of sIL-2R. These levels decreased in remission. Mitogen induced lymphocyte proliferation was also increased in manic BD patients relative to BD patients in remission. |
| Su et al.96 | Examine ex-vivo mitogen stimulated IFN-γ and IL-10 production in patients with bipolar mania | Prospective/clinical | 20 inpatients with bipolar mania, 15 controls | SCID diagnosed BD. Cytokine assays when ⩾26 on YMRS (Manic) and ⩽12 on YMRS (remission) | BD-I (manic/remitted) | Yes | Relative to controls, BD-I patients demonstrated significantly lower IFN-γ production than controls in both manic and remitted states. No significant difference for IL-10 |
| Liu et al.97 | Examine lymphocyte and cytokine activity in bipolar patients in medicated and pre-medicated states | Prospective/clinical | 29 inpatients with bipolar mania, 20 controls | SCID diagnosed BD. Cytokine assays when ⩾26 on YMRS (Manic) and ⩽12 on YMRS (remission) | BD-I (manic/remitted) | Yes | Relative to controls, manic BD patients demonstrated increased plasma levels of IL-1ra, sCD4, sCD8 and decreased IFN-γ production. IL-1ra and sCD8 remained increased, and IFN-γ production remained decreased relative to controls when BD patients were in remission. No significant differences in IL-4 or IL-10. |
| Watson et al.124 | Assess basal salivary cortisol, and post DEX/CRH serum cortisol in bipolar patients | Cross-sectional/clinical | 53 outpatients with BD (27 remitted, 14 depressed, 12 subclinically depressed) 28 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression with HAM-D. DEX/CRH test performed | BD (manic/depressed/remitted) | Yes | Relative to controls, patients with BD demonstrated higher post DEX/CRH cortisol irrespective of remission or current symptoms. Basal salivary cortisol was not significantly different between BD patients and controls. Symptom severity was not associated with either measure of cortisol. |
| O'Brien et al.99 | Examine cytokine and cortisol levels in the plasma of manic of depressed patients with BD | Cross-sectional/clinical | 21 patients with BD, 42 controls | SCID diagnosed BD. Mania⩾26 on YMRS, Depression ⩾17 on HAM-D | BD-I (manic/depressed) | Yes | Relative to controls, both manic and depressed BD patients demonstrated increased plasma levels of IL-8, TNF-α. IL-6 was elevated in manic BD patients but not depressed BD patients. No difference in cortisol or IL-10 levels was observed between patients and controls. No correlation between symptom severity and cytokine levels was observed. |
| Deshauer et al.125 | Examine the normalization of salivary cortisol in remitted BD patients and offspring of BD patients | Cross-sectional/clinical | 15 remitted patients with BD (5 BD-I, 10 BD-II), 28 offspring of BD patients, 33 controls | SCID diagnosed BD. Remission ⩽1 score of > 13 on BDI-II in past 2 years. Salivary cortisol collected 6 times a day for 3 days, 3 consecutive weeks | BD-I, BD-II | No | Relative to controls, there was no significant difference in salivary cortisol levels in remitted BD patients or offspring of BD patients at any time point in the day. |
| Dickerson et al.114 | Examine the relationship between serum CRP levels and severity of BD symptoms | Cross-sectional/clinical | 122 outpatients with BD (91 BD-I, 30 BD-II), 165 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression with HAM-D | BD-I, BD-II | Yes | Serum CRP levels were significantly associated with YMRS score, but not HAM-D score. Serum CRP was also not significantly different between BD-I and BD-II. |
| Kim et al.98 | Examine the relationship between mitogen induced cytokine production and BD | Prospective/clinical | 37 manic inpatients with BD-I, 74 controls | SCID diagnosed BD | BD-I (response to treatment/no response) | No | Relative to controls, IL-6 and TNF-α production were higher in BD-I patients, and IL-4 production was lower. IFN-γ and IL-2 were not different from controls. IFN-γ/IL-4 ratio was higher in BD-I patients than controls. After 6 weeks of pharmacotherapy IL-6 levels decreased, however there were no significant changes in IL-2, IFN-γ, TNF-α, or IL-4. |
| Knijff et al.104 | Examine the ex-vivo IL-1β and IL-6 production of BD patients with/without lithium treatment | Cross-sectional/clinical | 80 patients with BD (61 BD-I, 19 BD-II), 59 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression assessed with CGI. Samples for lithium-free patients were treated with in-vitro lithium | BD-I, BD-II | Yes | Relative to controls, monocytes from non-lithium treated BD patients demonstrated increased IL-6 and decreased IL-1β production. Lithium treated BD patients did not demonstrate altered cytokine production. In-vitro exposure of monocytes did not replicate the effects of lithium treatment on cytokine production. No significant associations were found between manic, depressed, or euthymic states and cytokine production. |
| Brietzke et al.103 | Investigate serum chemokine levels in euthymic patients with bipolar disorder | Cross-sectional/clinical | 30 patients with BD-I, 30 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression assessed with HAM-D | BD-I (manic/depressed) | No | Relative to controls, euthymic patients with BD-I demonstrated an increase in CXCL10 and a reduction in CCL24 levels. No significant difference was demonstrated for CCL2, CCL3, CCL11, CXCL8, and CXCL9. |
| Brietzke et al.103 | Compare cytokine levels in depressed, manic and euthymic patients with bipolar disorder | Cross-sectional/clinical | 61 patients with BD-I, 25 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression assessed with HAM-D | BD-I (manic/depressed) | Yes | Relative to controls, IL-2, IL-4, and IL-6 were increased in the manic state, and IL-6 was increased in the depressed state. IL-4 was also increased in the euthymic state relative to controls. Manic symptoms (YMRS) demonstrated a positive correlation with both IL-6 and IL-2. Depressive symptoms (HAM-D) demonstrated a positive correlation with IL-6 only. |
| Hope et al.102 | Examine cytokine levels in patients with bipolar disorder and schizophrenia | Cross-sectional/clinical | 125 patients with BD (73 BD-I, 44 BD-II), 186 schizophrenia, 244 controls | SCID diagnosed BD and schizophrenia | BD-I, BD-II | No | Relative to controls, sTNF-RI and von-Willebrand factor were elevated in the serum of BD and schizophrenic patients. No significant difference was detected in sCD40L, IL-1ra, hsCRP, or IL-6. |
| Kauer-Sant'Anna et al.106 | Examine neurotrophin and cytokine levels in patients with BD-I in early and late stages of the disease | Cross-sectional/clinical | 60 patients with BD-I (30 early, 30 late), 60 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression assessed with HAM-D | BD-I (early/late stage) | Yes | Relative to controls, early stage BD-I demonstrated increased levels of TNF-α, IL-6 and IL-10. Late stage BD-I demonstrated increased levels of TNF-α and IL-6. Comparing early and late stage BD-I, TNF-α was significantly increased in the late stage, whereas IL-6 and IL-10 were significantly decreased. |
| Guloksuz et al.113 | Examine cytokine levels in euthymic bipolar patients | Cross-sectional/clinical | 31 euthymic BD patients (16 medication free) (26 BD-I, 5 BD-II), 16 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression assessed with HAM-D | BD-I, BD-II | No | Relative to controls, lithium treated euthymic patients demonstrated higher levels of TNF-α and IL-4. There were no significant differences between medication free euthymic BD patients and controls. There were no significant differences detected for IFN-γ, IL-10, IL-5, or IL-2. |
| Barbosa et al.101 | Examine levels of TNF-α and its soluble receptors in manic and euthymic BD patients | Cross-sectional/clinical | 53 patients with BD-I, 38 controls | MINI-Plus diagnosed BD. Mania assessed with YMRS. Depression assessed with HAM-D | BD-I (manic/remitted) | Yes | Relative to controls, BD patients demonstrated significantly higher sTNFR1 than controls. sTNFR1 was significantly higher in mania than euthymia. No significant differences were detected for TNF-α or sTNFR2. |
| Drexhage et al.111 | Examine indices of monocyte and T cell activation in patients with BD | Cross-sectional/clinical | 38 patients with BD, 22 controls | SCID diagnosed BD. Mania assessed with YMRS. Depression assessed with IDS | BD-I, BD-II | Yes | Relative to controls, younger (<40 YO) patients with BD demonstrated significantly higher levels of sCD25 and Treg cells. CCL2 and PTX3 were elevated in BD patients relative to controls. No significant differences were detected in TNF-α, IFN-γ, IL-1β, IL-3, IL-5, IL-6, IL-10, IL-17A, or IL-22. |
| Kapczinski et al.100 | Examine peripheral biomarkers in patients with BD and compare to patients with sepsis | Cross-sectional/clinical | 60 inpatients with BD, 80 controls, 15 sepsis | SCID diagnosed BD | BD (manic/remitted) | No | Relative to healthy controls, IL-10, TNF-α, neurotrophin 3, and several markers of oxidative stress were increased in patients with BD. There were no significant differences in IL-6 or brain derived neurotrophic factor. IL-10 was a marker of the depressed state, while IL-10 and TNF-α were markers of mania. Evidence of immune activation and oxidative stress were similar between patients with sepsis and BD. |
| Kunz et al.112 | Examine serum levels of IL-6, IL-10 andTNF-α inpatients with BD and schizophrenia | Cross-sectional/clinical | 20 euthymic patients with BD, 53 schizophrenia, 80 controls | SCID diagnosed BD and schizophrenia. Mania assessed with YMRS. Depression assessed with HAM-D | BD, schizophrenia | No | Relative to healthy controls, IL-10 levels were higher in patients with BD or schizophrenia. IL-6 was also increased in schizophrenia. No significant differences were determined for TNF-α. |
Abbreviations: BD, bipolar disorder; BDI, beck depression inventory; CGI, Clinical Global Impressions Scale; CRP, C-reactive protein; DST, dexamethasone test; HAM-D, The Hamilton Depression Scale; IDS, inventory of depressive symptoms; IL, interleukin; IFN-γ, interferon-γ MINI-Plus, mini-international neuopsychiatry interview; PT, prothrombin time; SCID, structured clinical interview for DSM; Sx, symptoms; TNF-α, tumor necrosis factor-alfa; YMRS, Young Mania Rating Scale.