Table 1.
Magnetic resonance spectroscopy studies of brain creatine metabolism in psychiatric disorders
| Reference | Subject comparison | ROI | Alteration in total creatine | Medication status and clarifying comments |
|---|---|---|---|---|
| (a) Schizophrenia | ||||
| Lutkenhoff et al. (2010) | 14 SCZ twin pairs (2 MZ, 12 DZ), 13 HC twin pairs (4 MZ, 9 DZ) | medial PFC GM, left PFC WM, left HPC | (1) HPC: SCZ > HC; (2) HPC: SCZ twin > unaffected co-twin | After exclusions, 12 co-twins, 9 probands, 21 HC analyzed. Psychotropic use unclear, but medication use by SCZ mentioned in discussion |
| Keshavan et al. (2009) | 40 HR-SCZ, 48 HC (adolescents) | WM, ACC, caudate, thalamus, POC | Caudate: HR-SCZ < HC | All subjects psychotropic medication naïve |
| Tayoshi et al. (2009) | 30 SCZ, 25 HC | ACC, left basal ganglia | (1) ACC: male SCZ < male HC; (2) Both regions: female SCZ = female HC; (3) left basal ganglia: males < females | Eleven patients received benzodiazepines and three patients received paroxetine |
| Yoo et al. (2009) | 22 HR-SCZ, 22 HC | ACC, DLPFC, thalamus | Left thalamus: HR-SCZ < HC | All participants were free of psychotropic drugs |
| Wood et al. (2008) | 34 SCZ (15 med- naïve), 19 HC | medial temporal lobes | medicated SCZ > HC = medication-naïve SCZ | Fifteen of the patients were antipsychotic-naïve |
| Ohrmann et al. (2007) | 15 first-episode SCZ, 20 chronic SCZ, 20 HC | DLPFC | chronic SCZ < first-episode SCZ < HC | First-episode SCZ patients were treatment naïve. All chronic SCZ patients were taking psychotropic medications |
| Jensen et al. (2004) | 15 SCZ, 15 HC | thalamus, cerebellum, HPC, ACC, PCC, PFC, POC | ACC: SCZ > HC | All but 5 were free of psychotropic medication |
| O’Neill et al. (2003) | 11 SCZ, 20 HC (children/adolescents) | ACC, frontal cortex, striatum, thalamus, parietal cortex, WM | ACC: SCZ > HC | Ongoing medication use in all but two treatment naïve patients |
| Sigmundsson et al. (2002) | 25 SCZ, 26 HC | DLPFC | SCZ = HC | All patients were receiving psychotropic medications at the time of the study |
| Klemm et al. (2001) | 14 HR-SCZ, 14 HC (children/adolescents) | frontal region | [PCr only] HR-SCZ < HC (trend, p = .05) | All subjects psychotropic medication naïve |
| Auer et al. (2001) | 32 SCZ, 17 HC | GM, WM, thalamus | (1) WM: SCZ < HC; (2) WM tCr correlated positively with BPRS scores | Ongoing psychotropic medications in all patients |
| Ende et al. (2000) | 13 SCZ, 15 HC | thalamus, basal ganglia, HPC | All regions: SCZ = HC | Ongoing psychotropic medications in all patients |
| Volz et al. (2000) | 11 SCZ, 11 HC | frontal lobes | [PCr only] SCZ < HC | All patients were medication free at time of study |
| Bluml et al. (1999) | 13 SCZ, 15 HC | parietal cortex | SCZ > HC | Ongoing medication in all but two patients |
| Fukuzako et al. (1999) | 17 SCZ, 17 HC | temporal lobes | SCZ > HC on left side | All patients medication naïve |
| Volz et al. (1998a) | 26 SCZ, 23 HC | frontal lobes | [PCr only] (1) SCZ = HC; (2) PCr correlates with frontal lobe task in controls only | Ongoing medication in all patients |
| Volz et al. (1998b) | 50 SCZ, 36 HC | DLPFC | (PCr) SCZ > HC | Ongoing medication in all patients |
| Volz et al. (1997) | 26 medicated SCZ, 10 drug-free SCZ, 36 HC | frontal lobes | [PCr only] medicated SCZ > drug-free = HC | Ongoing medication in all but ten patients |
| Kato et al. (1995) | 27 SCZ (14 high SANS, 13 low SANS), 26 HC | frontal lobes | [PCr only] left frontal: SCZ with high negative symptoms > SCZ low negative symptoms = HC | 10 patients were medication free (3 drug naïve), and ongoing medication in remainder |
| Deicken et al. (1995) | 18 SCZ, 14 HC | temporal lobes | [PCr only] temporal: SCZ asymmetry, right > left | Ongoing medication in all but 5 patients |
| Deicken et al. (1994) | 20 SCZ, 16 HC | frontal lobes, parietal lobes | [PCr only] frontal: SCZ < HC | Ongoing medications in all but 6 patients |
| Calabrese et al. (1992) | 11 SCZ, 9 HC | temporal lobes | [PCr only] (1) SCZ = HC; (2) PCr/ATP asymmetry: right lobe > left lobe | Two patients were medication free for 1 week prior to the study, ongoing treatment in 9 remaining patients |
| Fujimoto et al. (1992) | 16 SCZ, 20 HC | temporal lobes, frontoparietal region | [PCr only] left frontoparietal: SCZ < HC | Ongoing medication in all patients |
| Pettegrew et al. (1991) | 11 SCZ, 10 HC | DLPFC | SCZ = HC | All patients drug-naïve |
| (b) Major Depressive Disorder | ||||
| Merkl et al. (2011) | 25 MDD, 27 HC | DLPFC, ACC | All regions: MDD = HC | Ongoing psychotropic medication in all patients |
| Nery et al. (2009) | 37 MDD, 40 HC | DLPFC | Male MDD < Male HC; Female MDD > Female HC | All medication free for at least 2 weeks prior to scan |
| Ventkatramar et al. (2009) | 14 MDD, 12 HC (elderly) | medial PFC | MDD < HC | All but 1 patient on psychotropic meds at time of scan |
| Ende et al. (2007) | 11 MDD, 10 HC | HPC, putamen | All regions: MDD = HC | Ongoing psychotropic medication in all patients |
| Gabbay et al. (2007) | 14 MDD, 10 HC (adolescents) | Left/right caudate, putamen, thalamus | Left caudate: MDD > HC | 6 medication free (4 treatment naïve), 8 on psychotropic medications at time of scan |
| Caetano et al. (2005) | 14 MDD, 22 HC (all children/adolescents) | left DLPFC | MDD = HC | 8 medication free (6 treatment naïve), 6 on psychotropic meds |
| Hasler et al. (2005) | 16 remitted MDD, 15 HC | PFC (dorsal- medial/dorsal- anterolateral) | MDD = HC | All medication free for at least 3 months prior to study |
| Brambilla et al. (2004) | 19 MDD, 19 HC | left DLPFC | MDD = HC | All patients were free of psychotropic medications. |
| Mirza et al. (2004) | 14 MDD, 13 HC (children/adolescents) | ACC, occipital cortex | ACC: MDD < HC | All patients were psychotropic medication- naïve. |
| Sanacora et al. (2004) | 33 MDD, 38 HC | occipital cortex | MDD = HC | All medication free for at least 2 weeks prior |
| Gruber et al. (2003) | 17 MDD, 17 HC | frontal lobe | MDD > HC | All medication free for at least 4 weeks prior |
| Michael et al. (2003a) | 12 MDD, 12 HC | left DLPFC | (1) MDD = HC; (2) more severe depression negatively correlated with lower tCr | All medication free for at least 3–8 d |
| Michael et al. (2003b) | 28 MDD, 28 HC | left amygdalar region | MDD = HC | All medication free for at least 3–8 d |
| Pfleiderer et al. (2003) | 17 MDD, 17 HC | left ACC | MDD = HC | All but 1 patient off psychotropic medications for at least ~5 d |
| Kumar et al. (2002) | 20 MDD, 18 HC (elderly) | left DLPFC, ACC | All regions: MDD = HC | All medication free for at least 2 weeks, except Lorazepam |
| Farchione et al. (2002) | 11 MDD, 11 HC (all children/adolescents) | DLPFC | MDD = HC | All patients treatment-naïve |
| Auer et al. (2000) | 19 MDD, 18 HC | ACC, parietal WM | All regions: MDD = HC | 7 patients medication free, remainder on antidepressant therapy |
| Ende et al. (2000) | 17 MDD, 24 HC, 6 remitted MDD | hippocampus | MDD = remitted MDD = HC | Washout period unclear, but medications free at least 8 d prior to ECT treatment |
| Rosenberg et al. (2000) | 13 MDD, 13 HC (children/adolescents) | left caudate, occipital cortex | All regions: MDD = HC | All patients medication-naïve |
| Volz et al. (1998) | 14 MDD, 8 HC | frontal lobe | MDD = HC | All but 3 patients on psychotropic medications |
| (c) Bipolar Disorder | ||||
| Caetano et al. (2011) | 43 BP, 38 HC (children/adolescents) | mPFC, DLPFC, ACC, occipital lobes | Left mPFC, DLPFC: BP < HC | 12 patients medication free, remainder receiving treatment |
| Patel et al. (2008) | 28 BP, 10 HC (children/adolescents) | ACC, VLPFC | (1) VLPFC: BP > HC; (2) ACC: BP > HC (trend, p = .07) | All patients were medication free for ~ 18 d |
| Frey et al. (2007a) | 32 BP, 32 HC | DLPFC | Left side: BP < HC | All patients medication free for at least 2 weeks (6 weeks for fluoxetine) |
| Frey et al. (2007b) | 35 BP (24 val/val, 11 val/met), 40 HC | DLPFC (left) | (1) BP = HC; (2) val/met BP < val/val BP; (3) val/val BP > HC | Twenty-two patients received ongoing treatment, and 13 were unmedicated for at least 2 weeks |
| Frye et al. (2007) | 23 BP, 12 HC | ACC/mPFC | BP > HC | All subjects free of psychotropic medication except 5 patients using lithium |
| Frey et al. (2005) | 10 BP, 10 HC | DLPFC | BP = HC | Ongoing psychotropic medication in all patients |
| Sassi et al. (2005) | 14 BP, 18 HC | DLPFC (left) | BP < HC (trend, p = .08) | Ongoing psychotropic medication in all but two patients |
| Dager et al. (2004) | 32 BP, 26 HC | cingulate gyrus | (1) BP = HC; (2) inverse correlation with white matter tCr and HAMD scores | All patients medication free |
| Hamakawa et al. (1999) | 23 BP, 20 HC | frontal lobes | Depressive state BP < HC | Ongoing psychotropic medication in all patients. All patients scanned in euthymic stage, and 8 scanned again during depressive stage |
| Murashita et al. (2000) | 19 BP (9 responders, 10 resistant), 25 HC | occipital region | [PCr only] BP resistant < BP responder = HC (post-photic stimulation) | Ongoing psychotropic medications in all but 1 patient |
| Deicken et al. (1995) | 12 BP, 14 HC | temporal lobes | [PCr only] BP = HC | All patients medication free for at least 1 week |
| Kato et al. (1994) | 29 BP (15 BP-II, 14 BP-I), 59 HC | frontal lobes | [PCr only] BP II < BP I = HC | Ongoing medication in all patients, which changed on basis of psychiatric states (hypomanic, depressed, euthymic) |
| (d) Anxiety Disorders | ||||
| Coplan et al. (2006) | 15 GAD, 15 HC | centrum semiovale (cerebral WM) | GAD < HC | Six patients were medication-naïve, and all were off medication for at least 4 weeks |
| Yucel et al. (2008) | 20 OCD, 26 HC | ACC | OCD = HC | 12 patients on psychotropic medications |
| Massana et al. (2002) | 11 PD, 11 HC | medial temporal lobe, medial PFC | Medial temporal: PD < HC | All patients free of medications for at least 2 weeks |
| Shiori et al. (1996) | 18 PD, 18 HC | frontal lobes | [PCr only] asymmetry in PD, left lobe > right lobe | All patients on psychotropic medications |
| (e) Comparisons between disorders | ||||
| Öngür et al. (2010) | 15 BP, 15 SCZ, 20 HC | ACC, POC | ACC: BP < SCZ = HC | Differences reflect shorter metabolite T2 relation times. Ongoing medication in all but 1 BP patents and 1 SCZ patient |
| Öngür et al. (2009) | 15 BP, 15 SCZ, 22 HC | ACC, POC | All regions: BP = HC > SCZ | Ongoing medication in all patients |
| Mirza et al. (2006) | 18 MDD, 27 OCD, 18 HC (children/adolescents) | medial thalamus | OCD > MDD = HC | All patients medication free |
| Cecil et al. (2003) | 7 BP, 2 MDD, 10 HC (children/adolescents) | PFC, cerebellum | All regions: MDD/BP < HC (trend, p = .07) | All patients medication free except 1 |
| Hamakawa et al. (1998) | 22 MDD, 18 BP (11 depressive, 16 euthymic), 20 HC | basal ganglia | (1) MDD = BP = HC; (2) medicated BP (n = 7) > unmedicated BP (n = 11) | Ongoing psychotropic medication in majority of patients |
| Kato et al. (1992) | 12 MDD, 10 BP, 22 HC | frontal lobe | [PCr only] (1) BP = HC; (2) severe MDD < mild MDD | Ongoing psychotropic medication in all patients |
All comparisons refer to baseline spectroscopic analyses (pre-treatment, if applicable) of total creatine (creatine + phosphocreatine) except where noted. Greater-than (>) and less-than (<) signs represent statistically significant differences in creatine metabolism (p < .05) excluding if a trend is described. Correlations between total creatine, phosphocreatine and behavior were included only if these associations reached significance (p < .05). Studies reporting ratio calculations, as opposed to absolute metabolite values, were excluded due to limitations in interpreting the directionality of metabolite changes.
Abbreviations: [Metabolites] tCr, total creatine; PCr, phosphocreatine; [Diagnoses] HC, healthy controls; HR, high risk; MDD, major depression; BP, bipolar disorder; GAD, generalized anxiety disorder; OCD, obsessive-compulsive disorder; PTSD, post-traumatic stress disorder; PD, panic disorder; SCZ, schizophrenia; MZ, monozygotic; DZ, dizygotic; [Scales] BPRS, Brief Psychotic Rating Scale; [Brain regions] ACC, anterior cingulate cortex; DLPFC, dorsal-lateral prefrontal cortex; HPC, hippocampus; PCC, posterior cingulate cortex; POC, parietal-occipital cortex; VLPFC, ventro-lateral prefrontal cortex