Antimanic Differences

Lithium decreases available cAMP, causing resistance to hormones reliant on cAMP signaling, including angiotensin, AVP/ADH, and aldosterone, all part of the Renin-Angiotensin-Aldosterone (RAAS) pathway: PMID 23408166.

I recently attended a case of bipolar mania with non-surgical adrenal hyperplasia resulting in comorbid severe hypertension. Lithium nightly to cause RAAS resistance (anti-RAAS agents including ACE inhibitors should be given at night: PMID 23077971) and low-dose anti-cortisol adequately managed hypertension and most bipolar symptoms.

Lithium-induced resistance to angiotensin, AVP/ADH, and aldosterone can cause decreased urine concentrating capacity/ polyuria sometimes progressing to nephrogenic diabetes insipidus (NDI). NDI can be treated with exogenous stabilized AVP/ADH desmopressin: PMID 2123565, similar to treating insulin-resistant diabetes with insulin.

Lithium-induced polyuria is traditionally treated with amiloride: PMID 3538913; triamterene may also be effective: PMID 32772236, even in cases of severe nephrogenic diabetes insipidus.

Both amiloride and triamterene share 2,6 di-amino purine structures with AMP/adenosine deaminase inhibitors regadenoson and dipyridamole. Lamotrigine also shares the 2,6 di-amino purine structure and was incidentally reported to treat non-nephrogenic diabetes insipidus: PMID 10968444, case 1.

Inhibiting adenosine metabolism increases adenosine-derivatives including cAMP, increasing responsiveness to angiotensin, AVP/ADH, and aldosterone.

Lithium-induced diabetes insipidus causes excessively high sodium levels: the opposite problem, excessively low sodium levels, is commonly caused by anti-manic carbamazepine and oxcarbazepine: PMID 8112243, and less commonly by lamotrigine: PMID 31832263 and valproate: PMID 9485070.

While lithium induces AVP/ADH resistance via cAMP: PMID 23408166, carbamazepine and oxcarbazepine cause excessive AVP/ADH sensitivity: PMID 8112243.

Clinical observations are consistent with a single purinergic side-effect mechanism (cAMP-dependent responsiveness to AVP/ADH) and proposed unifying purinergic anti-manic mechanisms of action: increasing adenosine-derivatives.

While cAMP would suggest that lithium is anti-RAAS while other antimanic agents may be pro-RAAS, carbamazepine (and likely oxcarbazepine) have an additional mechanism of action that inhibits angiotensin converting enzyme ACE: PMID 22832858, interrupting the RAAS signal.

One of the major differences between antimanic agents is the effect upon RAAS hormones. Disparate response to antimanic agents may represent different underlying RAAS pathology/response.

Severe hypertension seems clinically associated with treatment-resistant symptoms. Worsening hypertension often predicts non-response/ clinical worsening. Blood pressure (BP) normalization predicts treatment response.

Serial BP can provide early (next-day) feedback about the likely treatment response. Compare BP values using MAP weighted average: SBP + DBP + DBP, divided by 3.

Carbamazepine and oxcarbazepine cause frequent dose-dependent increased risk of hyponatremia, concerning in psychotic mania since hyponatremia-induced confusion can be mistaken as fluctuating psychosis.

In my clinical experience, hyponatremia can be reliably prevented simply by prescribing a dose-dependent NaCl supplement.