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Treatment-emergent mania with psychosis in bipolar depression with left intermittent theta-burst rTMS

Open AccessPublished:February 19, 2020DOI:https://doi.org/10.1016/j.brs.2020.02.018
      Dear Editor,
      We wish to report a case of treatment-emergent mania (TEM) with psychosis as a result of treatment with intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC) in a female patient in their mid-thirties with an established diagnosis of bipolar affective disorder type 1 experiencing a major depressive episode.

      Background

      This patient was referred to our clinic for suitability assessment for repetitive transcranial magnetic stimulation (rTMS) for a 5-month long major depressive episode, severe, without psychotic features, after having failed adequate trials of quetiapine and aripiprazole. Her QIDS-SR was 18/27 and there was no indication of a current mixed or manic episode. The only comorbid psychiatric diagnosis was an opioid use disorder in early sustained remission. There was a history of migraines treated with topiramate, but no other medical comorbidities. She had a history of recurrent episodes of mania with psychotic features resulting in hospitalization – in the preceding 3 years she had been admitted 3 times due to severe mania with psychosis that resulted in admissions lasting one to four months. During the preceding 3 years, while she experienced several depressive episodes, these were managed as an outpatient and none required inpatient admission. The most recent manic episode and hospitalization was 6 months prior to starting treatment. Medications at the time of iTBS treatment were aripiprazole 4mg, quetiapine 350mg and topiramate 250mg. Though this patient was not receiving treatment with a classic mood stabilizer (e.g. lithium or an anticonvulsant), she was on an adequate dose of the atypical antipsychotic quetiapine, which is a first-line recommendation for both acute bipolar depression and prevention of mania [
      • Yatham L.N.
      • Kennedy S.H.
      • Parikh S.V.
      • Schaffer A.
      • Bond D.J.
      • Frey B.N.
      • et al.
      Canadian network for mood and anxiety treatments (CANMAT) and international society for bipolar disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.
      ]. Topiramate, an anticonvulsant that is not recommended as a mood stabilizer [
      • Yatham L.N.
      • Kennedy S.H.
      • Parikh S.V.
      • Schaffer A.
      • Bond D.J.
      • Frey B.N.
      • et al.
      Canadian network for mood and anxiety treatments (CANMAT) and international society for bipolar disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.
      ], was being used for the treatment of migraines and therefore could not be discontinued.

      iTBS treatment course

      iTBS treatment was delivered with a MagPro X100 equipped with a B65 fluid-cooled coil (MagVentre, Farum, Denmark) to the left DLPFC at 120% resting motor threshold according to standard protocols for unipolar depression [
      • Kaster T.S.
      • Downar J.
      • Vila-Rodriguez F.
      • Thorpe K.E.
      • Feffer K.
      • Noda Y.
      • et al.
      Trajectories of response to dorsolateral prefrontal rTMS in major depression: a THREE-D study.
      ,
      • Blumberger D.M.
      • Vila-Rodriguez F.
      • Thorpe K.E.
      • Feffer K.
      • Noda Y.
      • Giacobbe P.
      • et al.
      Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
      ]. Coil positioning was achieved using the BeamF3 method [
      • Mir-Moghtadaei A.
      • Caballero R.
      • Fried P.
      • Fox M.D.
      • Lee K.
      • Giacobbe P.
      • et al.
      Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
      ]. The stimulation pattern was triplet 50 Hz bursts repeated at 5 Hz with 2 s on and 8 s off for a total of 600 pulses per session and total duration of 3 minutes, 9 seconds [
      • Blumberger D.M.
      • Vila-Rodriguez F.
      • Thorpe K.E.
      • Feffer K.
      • Noda Y.
      • Giacobbe P.
      • et al.
      Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
      ]. Treatment was delivered once daily, five days per week.
      The initial portion of this patient’s iTBS treatment was uneventful – after four treatments her QIDS-SR was 16/27. However, after nine treatments, there was a change in her clinical presentation. She began to complain of severe insomnia and the clinicians involved in her care noted increasing restlessness, talkativeness, and a lack of fatigue despite self-reported insomnia. After 10 treatments the QIDS-SR reduced markedly to 7/27; however, her restlessness continued to increase, her mood had become elevated, and there was increased energy and goal-directed activities At this point, she was assessed by the attending psychiatrist who did not have acute safety concerns but recommended close, daily follow-up to determine if this presentation would be self-limiting. The patient attended for treatment sessions 11 and 12, but was unwilling to meet with the attending psychiatrist. Subsequently, on the day of her planned 13th treatment, the patient was displaying signs of severe mania with psychotic features that included grandiose delusions (e.g. special powers and invincibility) and delusional parasitosis.
      Due to the severity of symptoms, the iTBS treatments were discontinued and she was admitted involuntarily to a psychiatric hospital with a diagnosis of mania with psychotic features. During this admission she was treated with an increased dose of quetiapine (550mg) and the addition of divalproex sodium at 750mg, which resulted in therapeutic levels. During the course of her 3-month admission with the above treatment, her symptoms of mania and psychosis fully resolved and she was discharged in a euthymic state.

      Summary

      To our knowledge, this is the first case report of TEM with psychosis precipitated by iTBS applied to the left DLPFC in bipolar depression that has been reported in the literature. With the recent approval of iTBS for major depressive disorder by the FDA in 2018 [
      • MagVenture
      Another FDA clearance for MagVenture: 3 minute depression treatment n.d.
      ], it is likely that increasing numbers of patients with depression – including off-label use in patients with bipolar depression – will receive iTBS in the coming years. This case report highlights the potential risk for iTBS to precipitate mania in patients with an established bipolar disorder diagnosis, even when receiving treatment with mood stabilizing agents [
      • Yatham L.N.
      • Kennedy S.H.
      • Parikh S.V.
      • Schaffer A.
      • Bond D.J.
      • Frey B.N.
      • et al.
      Canadian network for mood and anxiety treatments (CANMAT) and international society for bipolar disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.
      ].
      Though some studies have suggested that active rTMS is not associated with TEM [
      • McGirr A.
      • Karmani S.
      • Arsappa R.
      • Berlim M.T.
      • Thirthalli J.
      • Muralidharan K.
      • et al.
      Clinical efficacy and safety of repetitive transcranial magnetic stimulation in acute bipolar depression.
      ,
      • Xia G.
      • Gajwani P.
      • Muzina D.J.
      • Kemp D.E.
      • Gao K.
      • Ganocy S.J.
      • et al.
      Treatment-emergent mania in unipolar and bipolar depression: focus on repetitive transcranial magnetic stimulation.
      ], this conclusion is drawn from studies hampered by small sample sizes, publication bias, and heterogeneous samples (e.g. combination of bipolar and unipolar participants). We do not believe that the failure to find an increased risk of TEM is evidence for the safety of rTMS in bipolar disorder, or as the traditional aphorism goes “absence of evidence is not evidence of absence”. Instead, we hypothesize that there exists a biological basis for the potential risk of iTBS, and excitatory rTMS more broadly, to precipitate mania.
      The pathophysiology of depression (both bipolar and unipolar) may involve abnormalities in large-scale neuronal networks such as the default mode network and central executive network [
      • Liston C.
      • Chen A.C.
      • Zebley B.D.
      • Drysdale A.T.
      • Gordon R.
      • Leuchter B.
      • et al.
      Default mode network mechanisms of transcranial magnetic stimulation in depression.
      ]. Excitatory rTMS, such as high-frequency rTMS or iTBS [
      • Huang Y.-Z.
      • Edwards M.J.
      • Rounis E.
      • Bhatia K.P.
      • Rothwell J.C.
      Theta burst stimulation of the human motor cortex.
      ], when applied to the left DLPFC has been suggested to normalize these network abnormalities in depression [
      • Liston C.
      • Chen A.C.
      • Zebley B.D.
      • Drysdale A.T.
      • Gordon R.
      • Leuchter B.
      • et al.
      Default mode network mechanisms of transcranial magnetic stimulation in depression.
      ]. Furthermore, bipolar disorder has been suggested to have trait-related abnormally elevated activity in the left prefrontal and orbitofrontal cortex, which may be the neurophysiological basis for heightened reward sensitivity that predisposes to hypomania/mania [
      • Phillips M.L.
      • Swartz H.A.
      A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research.
      ]. If these biological mechanisms accurately reflect the pathophysiology of bipolar depression, we hypothesize that in a susceptible individual, the excitatory effect of iTBS may precipitate mania through unintended upregulation of neuronal networks.
      Our speculative hypothesis, if correct, has important implications for the direction of rTMS research in bipolar disorder. If correct, it suggests that rTMS protocols developed in unipolar depression cannot be directly translated into bipolar depression due to differences in underlying neurobiology. One such approach would be to focus research efforts on right-sided stimulation treatment protocols. Indeed, preliminary evidence suggests that protocols targeting the right DLPFC may have superior efficacy compared to those targeting the left DLPFC in bipolar depression [
      • McGirr A.
      • Karmani S.
      • Arsappa R.
      • Berlim M.T.
      • Thirthalli J.
      • Muralidharan K.
      • et al.
      Clinical efficacy and safety of repetitive transcranial magnetic stimulation in acute bipolar depression.
      ].
      Taken together, and based on our experiences in the present case report, we urge clinicians to exercise caution if they are providing left sided iTBS to patients with established bipolar affective disorder given the risk of precipitating mania and conduct an informed consent discussion with the patient regarding treatment risks, benefits, and alternatives. Given the current limited state of evidence supporting rTMS for bipolar depression, large-scale, definitive clinical trials testing the safety and efficacy of biologically validated treatment targets are urgently required.

      Acknowledgements

      This work was funded by the Temerty Family Foundation through the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health.

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