Does the “Silver Bullet” Lose its Shine Over the Time? Assessment of Loss of Lithium Response in a Preliminary Sample of Bipolar Disorder Outpatients

M. Fornaro1, *, B. Stubbs2, 3, D. De Berardis4, F. Iasevoli5, M. Solmi6, 7, N. Veronese7, 8, A. Carano9, G. Perna10, 11, 12, A. De Bartolomeis5
1 New York State Psychiatric Institute (NYPSI); Columbia University, NYC, NY, USA
2 Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
3 Health Service and Population Research Department, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK
4 National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, "G. Mazzini" Hospital, ASL 4 Teramo, Italy
5 Outpatient Unit on Treatment Resistant Psychosis, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy
6 Department of Neurosciences, University of Padova, Padova, Italy
7 I.R.E.M. (Institute for clinical Research and Education in Medicine), Padova, Italy
8 Geriatrics Section, Department of Medicine (DIMED), University of Padova, Padova, Italy
9 Hospital "C. G. Mazzoni", Ascoli Piceno, Italy
10 Department of Clinical Neurosciences, Hermanas Hospitalarias, FoRiPsi, Villa San Benedetto Menni, Albese con Cassano, 22032 Como, Italy
11 Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands
12 Department of Psychiatry and Behavioral Sciences, Leonard Miller School of Medicine, Miami University, Miami, FL 33136, USA

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© Fornaro et al.; Licensee Bentham Open

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the New York State Psychiatric Institute (NYPSI), 1051 Riverside, NYC, ZIP 10032; USA; Tel: (001) 646-705-2586; E-mail:



Though often perceived as a “silver bullet” treatment for bipolar disorder (BD), lithium has seldom reported to lose its efficacy over the time.


The aim of the present study was to assess cases of refractoriness toward restarted lithium in BD patients who failed to preserve maintenance.


Treatment trajectories associated with re-instituted lithium following loss of achieved lithium-based maintenance in BD were retrospectively reviewed for 37 BD-I patients (median age 52 years; F:M=17:20 or 46% of the total) over an 8.1-month period on average.


In our sample only 4 cases (roughly 11% of the total, of whom F:M=2:2) developed refractoriness towards lithium after its discontinuation. Thirty-three controls (F:M=15:18) maintained lithium response at the time of re-institution. No statistically significant difference between cases and controls was observed with respect to a number of demographic and clinical features but for time spent before first trial ever with lithium in life (8.5 vs. 3 years; U=24.5, Z=-2.048, p=.041) and length of lithium discontinuation until new therapeutic attempt (5.5 vs. 2 years; U=8, Z=-2.927, p=.003) between cases vs. controls respectively. Tapering off of lithium was significantly faster among cases vs. controls (1 vs. 7 days; U=22, Z=-2.187), though both subgroups had worrisome high rates of poor adherence overall.


Although intrinsic limitations of the present preliminary assessment hamper the validity and generalizability of overall results, stating the clinical relevance of the topic further prospective research is warranted. The eventual occurrence of lithium refractoriness may indeed be associated with peculiar course trajectories and therapeutic outcomes ultimately urging the prescribing clinicians to put efforts in preserving maintenance of BD in the absence of any conclusive research insight on the matter.

Keywords: Discontinuation, Maintenance, Refractoriness, Tolerance.