Table 1 Summary of included studies studying the effects of lithium on BDP

11

Increased right amygdala volume in lithium-treated patients with bipolar I disorder

Usher et al.

Cross-

sectional Study

15 BDP with lithium

24 BDP without lithium

41 HC

MRI

Focus:

This study focused on determining if lithium influenced the volume of the amygdala.

Limitations:

(i) Small sample size

(ii) Cross-sectional study design

In comparison with HC, BDP on lithium showed a larger right absolute (+ 17.9%, P = .015, d = 0.831) and relative (+ 18%, P = .017, d = 0.8) amygdala volume.

12

Increased hippocampal, thalamus and amygdala volume in long-term lithium-treated bipolar I disorder patients compared with unmedicated patients and healthy subjects

López- Jaramillo et al.

Cross-

sectional Study

16 BDP with lithium

16 BDP without lithium

20 HC

MRI

Focus:

This study focused on volume changes in cortico-limbic structures (including the amygdala) using multivariable analysis. All BDP had a relatively long duration of illness (mean = 17 yrs), and the BDP on lithium were long-term lithium users (mean = 0.8 yrs).

Limitations:

(i) Small sample size

(ii) Unable to determine a cause‒effect relationship between lithium treatment and brain volume increase

(iii) Neuroprotection and neurotropism may also have been the cause for changes

In comparison with BDP without lithium, BDP on lithium showed a larger right (+ 10.2332%, P = .04, d = 0.557) and left (+ 32.4281%, P = .002, d = 1.328) amygdala volume.

13

Association between duration of lithium exposure and hippocampus/amygdala volumes in type I bipolar disorder

Sani et al.

Cross-

sectional Study

30 BDP with lithium (15 long exposure, 15 short exposure)

15 BDP without lithium

15 HC

MRI

Focus:

This study focused on volume changes in limbic and subcortical GMV. BDP using lithium were included in the study, but this study uniquely included duration of treatment as an important variable regarding changes in volume. The BDP using lithium group was divided into a short exposure (SE; exposed to lithium for < 24 months) and long exposure (LE; exposed to lithium for > 24 months) to assess if the length of treatment resulted in different changes in volume.

Limitations:

(i) Retrospective, cross-sectional design

(ii) Other medications used along with lithium (anticonvulsants, antipsychotics) which may have normalizing effects on the brain structure of BDP

In comparison with BDP without lithium, BDP on lithium with SE showed a larger right (+ 16.1386%, P = .002, d = 1.182) and left (+ 20.352%, P = .002, d = 1.482) amygdala volume, and BDP on lithium with LE showed a larger right (+ 11.7822%, P = .021, d = 1.196) and left (+ 20.352%, P = .018, d = 1.186) amygdala volume.

14

Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium

Foland et al.

Cross-

sectional Study

12 BDP with lithium

37 BDP without lithium

N/A HC

MRI and TBM

Focus:

This study tested if lithium treatment led to an increase in amygdalar volumes in BDP using lithium in comparison to euthymic BDP who were lithium-free but taking other medications. Foland et al. employed tensor-based morphometry (TBM) in addition to MRI to analyze the effect of lithium treatment of the amygdala. As part of the TBM technique, the study used MRI to create a template scan based on the average of 27 T-1 weighted MRI acquisitions, compared the MRI scans of each individual to this template scan, and noted the warping.

Limitations:

(i) Small sample size

(ii) Higher proportion of males in BD group

(iii) Younger lithium-free group compared to lithium-treated group

(iv) Other medications used along with lithium

(v) Unknown if lithium-free group had taken lithium in the past

(vi) No HC group

In comparison with BDP without lithium, BDP on lithium showed larger right (+ 1.53846%, P = 1.63, d = 1.9), left (+ 3.82775%, P = .035, d = 3.138), and bilateral (+ 2.9703%, P = .023, d = 3.795) amygdala volumes.

15

The effects of lithium and anticonvulsants on brain structure in bipolar disorder

Germaná et al.

Cross-

sectional Study

28 BDP with lithium

28 BDP without lithium

18 BDP on antipsychotics

N/A HC

MRI and VBM

Focus:

This study focused on the effect of not only lithium but also other anticonvulsants and antipsychotics on the brain structure of BDP. BDP using lithium were not compared to a control group as there were no HC or BDP not using medication. Voxel-based morphometry (VBM) was used to analyze 74 MRI scans to identify changes in GMV as a result of lithium treatment.

Limitations:

(i) Unable to determine if changes in volume were from a neurotropic/neuroprotective effect or osmotic effect

(ii) No HC group or unmedicated BDP group

(iii) No random assignment, possibility of bias

In comparison with BDP without lithium, BDP on lithium showed a larger left hippocampus/amygdala complex (P < .001).

16

In Vivo Amygdala Nuclei Volumes in Schizophrenia and Bipolar Disorders (supplementary material)

C. Barth et al.

Cross-

sectional Study

54 BDP on lithium

247 BDP without lithium

N/A HC

MRI

Focus:

This study focused on amygdalar volume changes in people with both schizophrenia and BD. While this study did not focus on the effect of lithium, supplementary material was provided that covered the effect of lithium on the amygdalae of BDP.

Limitations:

(i) Cross-sectional design study

(ii) MRI has limited ability in imaging technology so volumes of smaller regions within the amygdala should be treated with caution

No association was found between psychotropic drugs or mood stabilizers (lithium) and volume in schizophrenia and bipolar patients.

17

Lithium treatment and hippocampal subfields and amygdala volumes in bipolar disorder

Hartberg et al.

Cross-

sectional Study

34 BDP with lithium

147 BDP without lithium

300 HC

MRI

Focus:

This study focused on comparing amygdalar, and hippocampal, volumes between BDP using lithium, BDP not using lithium, and HC, and on the statistical effects of the illness’ course.

Limitations:

(i) No randomization in treatment groups, may have selection bias

(ii) Small BDP on lithium group compared to HC and nonlithium BDP

(iii) No system to check for previous compliance with lithium treatment

(iv) Use of neuroleptic medications other than lithium (however, was corrected for)

(v) Drug or alcohol use may have affected results

(vi) Results may have been a result of statistical power issues

In comparison with BDP without lithium, BDP on lithium showed a larger right (+ 3.4891%, d = 2.236) and left (+ 1.98718%, d = 1.2) amygdala volumes. However, these values were not significant.

18

Volume and shape analysis of subcortical brain structures and ventricles in euthymic bipolar I disorder

Quigley et al.

Cross-

sectional Study

46 BDP with lithium

14 BDP without lithium

60 HC

MRI

Focus:

This study aimed to establish trait-related subcortical structural and volumetric changes or abnormalities, by comparing euthymic BDP using lithium to HC. Such a large cohort size was purposefully used to attempt to combat the heterogeneity of previous studies.

Limitations:

(i) Varied individual clinical histories of BDP

(ii) Other medications used along with lithium

(iii) Unable to determine causation effect of lithium due to not being a longitudinal study

(iv) Only euthymic BDP in study; inclusion of manic or depressed may have an effect

In comparison with HC, BDP on lithium showed a larger right (+ 3.34262%, P = .397, d = 0.174) and left (+ 3.46608%, P = .419, d = 0.171) amygdalar volume.

19

A 7 Tesla Amygdalar- Hippocampal Shape Analysis of Lithium Response in Bipolar Disorder

Athey et al.

Cross-

sectional Study

14 BDP on lithium

21 HC

MRI

Focus:

This study aimed to investigate structural surface anatomy–volume and shape metrics–in the amygdala and hippocampus as a result of treatment for BDP. Participants in this study went through a 16-week stabilization phase and a 4-week observation phase. Afterwards, those who were considered mildly ill according to the Clinical Global Impression Severity Test advanced to a maintenance phase that lasted between 4 weeks to 24 months. Every 2 months participants were assessed and those who relapsed or had failed to remit during the stabilization/observation phase were deemed nonresponders, referencing their lithium response. Scans using 7 Tesla structural MRI were taken of the BDP using lithium and compared to those of nonresponders and HC.

Limitations:

(i) Small sample size

(ii) No males in nonresponder group, may impact generalization-ability of results

(iii) Confounding variables such as duration of treatment, depressive predominant polarity, or stressful life events may have affected results

(iv) Used a manual segmentation process

(v) Changes within structures would not have been detected because subregions were split on the surface

There were no significant differences in volumes of amygdalae or hippocampi between the lithium responders, nonresponders, and HC groups.