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Brain Bioenergetics and Response to Triiodothyronine Augmentation in Major Depressive Disorder

      Background

      Low cerebral bioenergetic metabolism has been reported in subjects with major depressive disorder (MDD). Thyroid hormones have been shown to increase brain bioenergetic metabolism. We assessed whether changes in brain bioenergetics measured with phosphorus magnetic resonance spectroscopy (31P MRS) correlate with treatment outcome during augmentation treatment with triiodothyronine (T3) in MDD.

      Methods

      Nineteen subjects meeting DSM-IV criteria for MDD who had previously failed to respond to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs received open label and prospective augmentation treatment with T3 for 4 weeks. We obtained 31P MRS spectra before and after treatment from all MDD subjects and baseline 31P MRS from nine normal control subjects matched for age and gender.

      Results

      At baseline, depressed subjects had lower intracellular Mg2+ compared with control subjects. Seven MDD subjects (38.9%) were treatment responders (≥ 50% improvement). Total nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP), increased significantly in MDD subjects responding to T3 augmentation compared with treatment nonresponders. Phosphocreatine, which has a buffer role for ATP, decreased in treatment responders compared with nonresponders.

      Conclusions

      The antidepressant effect of thyroid hormone (T3) augmentation of SSRIs is correlated with significant changes in the brain bioenergetic metabolism. This seems to be a re-normalization of brain bioenergetics in treatment responders. Further studies will determine whether these findings can be generalized to other antidepressant treatments.

      Key Words

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      References

        • Mayberg H.S.
        • Liotti M.
        • Brannan S.K.
        • McGinnis S.
        • Mahurin R.K.
        • Jerabek P.A.
        • et al.
        Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness.
        Am J Psychiatry. 1999; 156: 675-682
        • Drevets W.C.
        • Price J.L.
        • Simpson Jr, J.R.
        • Todd R.D.
        • Reich T.
        • Vannier M.
        • Raichle M.E.
        Subgenual prefrontal cortex abnormalities in mood disorders.
        Nature. 1997; 386: 824-827
        • Mayberg H.S.
        • Brannan S.K.
        • Tekell J.L.
        • Silva J.A.
        • Mahurin R.K.
        • McGinnis S.
        • Jerabek P.A.
        Regional metabolic effects of fluoxetine in major depression: Serial changes and relationship to clinical response.
        Biol Psychiatry. 2000; 48: 830-843
        • Drevets W.C.
        • Bogers W.
        • Raichle M.E.
        Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.
        Eur Neuropsychopharmacol. 2002; 12: 527-544
        • Steingard R.J.
        • Yurgelun-Todd D.A.
        • Hennen J.
        • Moore J.C.
        • Moore C.M.
        • Vakili K.
        • Young A.D.
        • Katic A.
        • Beardslee W.R.
        • Renshaw P.F.
        Increased orbitofrontal cortex levels of cytosolic choline in depressed adolescents.
        Biol Psychiatry. 2000; 48: 1053-1061
        • Stork C.
        • Renshaw P.F.
        Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research.
        Mol Psychiatry. 2005; 10: 900-919
        • Iosifescu D.V.
        • Renshaw P.F.
        31P-magnetic resonance spectroscopy and thyroid hormones in major depressive disorder: Toward a bioenergetic mechanism in depression?.
        Harv Rev Psychiatry. 2003; 11: 51-63
        • Moore C.M.
        • Christensen J.D.
        • Lafer B.
        • Fava M.
        • Renshaw P.F.
        Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: A phosphorous-31 magnetic resonance spectroscopy study.
        Am J Psychiatry. 1997; 154: 116-118
        • Volz H.P.
        • Rzanny R.
        • Riehemann S.
        • May S.
        • Hegewald H.
        • Preussler B.
        • et al.
        31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients.
        Eur Arch Psychiatry Clin Neurosci. 1998; 248: 289-295
        • Renshaw P.F.
        • Parow A.M.
        • Hirashima F.
        • Ke Y.
        • Moore C.M.
        • Frederick Bd B.
        • et al.
        Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression.
        Am J Psychiatry. 2001; 158: 2048-2055
        • Pettegrew J.W.
        • Levine J.
        • Gershon S.
        • Stanley J.A.
        • Servan-Schreiber D.
        • Panchalingam K.
        • McClure R.J.
        31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: Preliminary results.
        Bipolar Disord. 2002; 4: 61-66
        • Joffe R.T.
        • Singer W.
        A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants.
        Psychiatry Res. 1990; 32: 241-251
        • Aronson R.
        • Offman H.J.
        • Joffe R.T.
        • Naylor C.D.
        Triiodothyronine augmentation in the treatment of refractory depression.
        Arch Gen Psychiatry. 1996; 53: 842-848
        • Bauer M.
        • Hellweg R.
        • Graf K.J.
        • Baumgartner A.
        Treatment of refractory depression with high-dose thyroxine.
        Neuropsychopharmacology. 1998; 18: 444-455
        • Agid O.
        • Lerer B.
        Algorithm-based treatment of major depression in an outpatient clinic: Clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation.
        Int J Neuropsychopharmacol. 2003; 6: 41-49
        • Iosifescu D.V.
        • Nierenberg A.A.
        • Mischoulon D.
        • Perlis R.H.
        • Papakostas G.I.
        • Ryan J.L.
        • et al.
        An open study of triiodothyronine (T3) augmentation of SSRIs in treatment-resistant major depressive disorder.
        J Clin Psych. 2005; 66: 1038-1042
        • Abraham G.
        • Milev R.
        • Stuart Lawson J.
        T3 augmentation of SSRI resistant depression.
        J Affect Disord. 2006; 91: 211-215
        • Hagspiel K.D.
        • von Weymarn C.
        • McKinnon G.
        • Haldemann R.
        • Marincek B.
        • von Schulthess G.K.
        Effect of hypothyroidism on phosphorus metabolism in muscle and liver: In vivo P-31 MR spectroscopy study.
        J Magn Reson Imaging. 1992; 2: 527-532
        • Smith C.D.
        • Ain K.B.
        Brain metabolism in hypothyroidism studied with 31P magnetic-resonance spectroscopy.
        Lancet. 1995; 345: 619-620
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Williams J.B.W.
        Structured Clinical Interview for DSM-IV Axis I Disorders—Patient edition (SCID-I/P).
        Biometrics Research Department, New York State Psychiatric Institute, New York1996
        • Hamilton M.
        Development of a rating scale for primary depressive illness.
        Br J Soc Clin Psychol. 1967; 6: 278-296
        • Jensen J.E.
        • Drost D.J.
        • Menon R.S.
        • Williamson P.C.
        In vivo brain (31)P-MRS: Measuring the phospholipid resonances at 4 Tesla from small voxels.
        NMR in Biomed. 2002; 15: 338-347
        • Petroff O.A.C.
        • Prichard J.W.
        • Behar K.L.
        • Alger J.R.
        • den Hollander J.A.
        • Shulman R.G.
        Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy.
        Neurology. 1985; 35: 781-788
        • Iotti S.
        • Frassineti C.
        • Alderighi L.
        • Sabatini A.
        • Vacca A.
        • Barbiroli B.
        In vivo assessment of free magnesium concentration in human brain by 31P MRS.
        NMR in Biomed. 1996; 9: 24-32
        • Pissarek M.
        • Garcia de Arriba S.
        • Schafer M.
        • Sieler D.
        • Nieber K.
        • Illes P.
        Changes by short-term hypoxia in the membrane properties of pyramidal cells and the levels of purine and pyrimidine nucleotides in slices of rat neocortex; effects of agonists and antagonists of ATP-dependent potassium channels.
        Naunyn Schmiederbergs Arch Pharmacol. 1998; 358: 359-430
        • Pettegrew J.W.
        • Keshavan M.S.
        • Panchalingam K.
        • Strychor S.
        • Kaplan D.B.
        • Tretta M.G.
        • Allen M.
        Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics.
        Arch Gen Psychiatry. 1991; 48: 563-568
        • Bessman S.P.
        The creatine phosphate energy shuttle—the molecular asymmetry of a “pool”.
        Anal Biochem. 1987; 161: 519-523
        • Lyoo I.K.
        • Kong S.W.
        • Sung S.M.
        • Hirashima F.
        • Parow A.
        • Hennen J.
        • et al.
        Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate.
        Psychiatry Res. 2003; 123: 87-100
        • Silveri M.M.
        • Parow A.M.
        • Villafuerte R.A.
        • Damico K.E.
        • Goren J.
        • Stoll A.L.
        • et al.
        S-adenosyl-L-methionine: Effects on brain bioenergetic status and transverse relaxation time in healthy subjects.
        Biol Psychiatry. 2003; 54: 833-839
        • Iotti S.
        • Frassineti C.
        • Sabatini A.
        • Vacca A.
        • Barbiroli B.
        Quantitative mathematical expressions for accurate in vivo assessment of cytosolic [ADP] and ΔG of ATP hydrolysis in the human brain and skeletal muscle.
        Biochim Biophys Acta. 2005; 1708: 164-177
        • Alpert J.E.
        • Papakostas G.
        • Mischoulon D.
        • Worthington 3rd, J.J.
        • Petersen T.
        • Mahal Y.
        • et al.
        S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: An open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine.
        J Clin Psychopharmacol. 2004; 24: 661-664
        • Esposito K.
        • Goodnick P.
        Predictors of response in depression.
        Psychiatr Clin North Am. 2003; 26: 353-365
        • Lawson J.W.
        • Veech R.L.
        Effects of pH and free Mg2+ on the Keq of the creatine kinase reaction and other phosphate hydrolyses and phosphate transfer reactions.
        J Biol Chem. 1979; 254: 6528-6537
        • Levine J.
        • Stein D.
        • Rapoport A.
        • Kurtzman L.
        High serum and cerebrospinal fluid Ca/Mg ratio in recently hospitalized acutely depressed patients.
        Neuropsychobiology. 1999; 39: 63-70
        • Imada Y.
        • Yoshioka S.
        • Ueda T.
        • Katayama S.
        • Kuno Y.
        • Kawahara R.
        Relationships between serum magnesium levels and clinical background factors in patients with mood disorders.
        Psychiatry Clin Neurosci. 2002; 56: 509-514
        • Young L.T.
        • Robb J.C.
        • Levitt A.J.
        • Cooke R.G.
        • Joffe R.T.
        Serum Mg2+ and Ca2+/Mg2+ ratio in major depressive disorder.
        Neuropsychobiology. 1996; 34: 26-28
        • Carman J.S.
        • Post R.M.
        • Teplitz T.A.
        • Goodwin F.K.
        Letter: Divalent cations in predicting antidepressant response to lithium.
        Lancet. 1974; 2: 1454
        • Linder J.
        • Fyro B.
        • Pettersson U.
        • Werner S.
        Acute antidepressant effect of lithium is associated with fluctuation of calcium and magnesium in plasma.
        Acta Psychiatr Scand. 1989; 80: 27-36
        • Barbiroli B.
        • Iotti S.
        • Cortelli P.
        • Martinelli P.
        • Lodi R.
        • Carelli V.
        • Montagna P.
        Low brain intracellular free magnesium in mitochondrial cytopathies.
        J Cereb Blood Flow Metab. 1999; 19: 528-532
        • Lodi R.
        • Iotti S.
        • Cortelli P.
        • Pierangeli G.
        • Cevoli S.
        • Clementi V.
        Deficient energy metabolism is associated with low free magnesium in the brains of patients with migraine and cluster headache.
        Brain Res Bull. 2001; 54: 437-441
        • Thase M.E.
        • Kupfer D.J.
        • Jarrett D.B.
        Treatment of imipramine-resistant recurrent depression, I: An open clinical trial of adjunctive l-triiodothyronine.
        J Clin Psychiatry. 1989; 50: 385-388
        • Joffe R.T.
        • Singer W.
        • Levitt A.J.
        • MacDonald C.
        A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression.
        Arch Gen Psychiatry. 1993; 50: 387-393
        • Christensen J.D.
        • Kaufman M.J.
        • Levin J.M.
        • Mendelson J.H.
        • Holman B.L.
        • Cohen B.M.
        • Renshaw P.F.
        Abnormal cerebral metabolism in polydrug abusers during early withdrawal: A 31P MR spectroscopy study.
        Magn Reson Med. 1996; 35: 658-663
        • Burt C.T.
        • Glonek T.
        • Barany M.
        Analysis of phosphate metabolites, the intracellular pH, and the state of adenosine triphosphate in intact muscle by phosphorus nuclear magnetic resonance.
        J Biol Chem. 1976; 251: 2584-2591
        • Kemp G.J.
        • Meyerspeer M.
        • Moser E.
        Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by (31)P MRS: A quantitative review.
        NMR Biomed. 2007; 20: 555-565