Abstract
Background: Treatment of major depression with antidepressants is generally associated
with a delay in onset of clinical response. Functional brain correlates of this phenomenon
have not been previously characterized.
Methods: Time course of changes in brain glucose metabolism were measured using positron
emission tomography in hospitalized unipolar depressed patients treated with fluoxetine.
Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment.
Results: Changes were seen over time, and characterized by three distinct patterns:
1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks,
and 3) unique changes seen only after chronic treatment. Fluoxetine responders and
nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical
improvement was uniquely associated with limbic and striatal decreases (subgenual
cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases
(prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated
with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal
changes.
Conclusions: Chronic treatment and clinical response to fluoxetine was associated
with a reciprocal pattern of subcortical and limbic decreases and cortical increases.
Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific
brain regions over time in response to sustained serotonin reuptake inhibition. The
inverse patterns in responders and nonresponders also suggests that failure to induce
these adaptive changes may underlie treatment nonresponse.
Keywords
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References
- A role for somatosensory cortices in the visual recognition of emotion as revealed by three-dimensional lesion mapping.J Neurosci. 2000; 20: 2683-2690
- Basal ganglia-thalamocortical circuits.Prog Brain Res. 1990; 85: 119-146
- Reduction in serotonin transporter sites in prefrontal cortex is localized in suicide and widespread in major depression.Soc Neurosci Abstr. 1999; 25: 1798
- Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims.Brain Res. 1995; 688: 121-133
- Pindolol induces a rapid improvement of depressed patients with serotonin reuptake inhibitors.Arch Gen Psychiatry. 1994; 51: 248-251
- Primate serotonergic system.in: Fahn S Advances in Neurology. Vol 43, Myoclonus. Raven, New York1986: 407-468
- The interaction between mood and cognitive function studied with PET.Psychol Med. 1997; 27: 565-578
- Reduction of prefrontal cortex glucose metabolism common to three types of depression.Arch Gen Psychiatry. 1989; 46: 243-250
- Changes in regional cerebral blood flow on recovery from depression.Psychol Med. 1995; 25: 247-251
- Regional cerebral blood flow in depression measured by positron emission tomography.Psychol Med. 1993; 23: 579-590
- Early onset of therapeutic action in depression and greater efficacy of antidepressant treatments.Int Clin Psychopharmacol. 1997; 12: 21-28
- Selective activation of post-synaptic 5HT1A receptors produces a rapid antidepressant response.Neuropsychopharmacology. 1997; 16: 333-338
- Modulation of 5-HT release in the guinea-pig brain following long-term administration of antidepressant drugs.Br J Pharmacol. 1994; 113: 485-495
- Serotonergic but not noradrenergic neurons in rat CNS adapt to long-term treatment with MAOIs.Neuroscience. 1985; 16: 949-955
- Serotonin and drug-induced therapeutic responses in major depression, obsessive compulsive and panic disorders.Neuropsychopharmacology. 1999; 21: 170-178
- Cingulate metabolism predicts treatment response.Biol Psychiatry. 2000; 47: 107
- Brain metabolic changes in major depressive disorder from pre to post-treatment with paroxetine.Psychiatry Res. 1999; 99: 127-139
- Effect of sertraline on regional metabolic rate in patients with affective disorder.Biol Psychiatry. 1997; 41: 15-22
- Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys.J Comp Neurol. 1996; 371: 179-207
- Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments.Neuropsychopharmacology. 1991; 5: 219-229
- A PET study of visuospatial attention.J Neurosci. 1993; 13: 1202-1226
- Monoamine innervation of cingulate cortex.in: Vogt B.A Gabriel M The Neurobiology of Cingulate Cortex and Limbic Thalamus A Comprehensive Handbook. Birkhauser, Boston1993: 285-310
- Neural activity relating to generation and representation of galvanic skin conductance responses.J Neurosci. 2000; 20: 3033-3040
- Influence of ascending serotonergic pathways on glucose use in the conscious rat brain. II. Effects of electrical stimulation of the rostral raphé nuclei.Brain Res. 1988; 444: 227-246
- A suggestion for using powerful and informative tests of normality.Am Statistician. 1990; 44: 316-321
- The somatic marker hypothesis and the possible functions of the prefrontal cortex.Philos Trans R Soc Lond B Biol Sci. 1996; 351: 1413-1420
- Tricyclic antidepressants.Science. 1978; 202: 1303-1306
- Dissociation in prefrontal cortex of affective and attentional shifts.Nature. 1996; 380: 69-72
- Neuropsychological dysfunction in depression.Psychol Med. 1994; 24: 849-857
- Dorsolateral prefrontal cortex dysfunction in the major psychoses.J Neurol Neurosurg Psychiatry. 1993; 56: 1290-1294
- Serotonin in the basal ganglia.J Physiol Paris. 1981; 77: 393-403
- PET imaging of serotonin 1A receptor binding in depression.Biol Psychiatry. 1999; 46: 1375-1387
- Subgenual prefrontal cortex abnormalities in mood disorders.Nature. 1997; 386: 824-827
- A functional anatomical study of unipolar depression.J Neurosci. 1992; 12: 3628-3641
- Neural plasticity to stress and antidepressant treatment.Biol Psychiatry. 1999; 46: 1181-1191
- Functional classification of antidepressants based on antagonism of swim stress-induced fos-like immunoreactivity.J Pharmacol Exp Ther. 1996; 277: 1076-1089
- The neuropsychological profile in unipolar depression.Trends Cogn Sci. 1998; 2: 447-454
- Alterations of serotonin release in the guinea pig orbitofrontal cortex.Neuropsychopharmacology. 1995; 13: 117-127
- The neurobiological substrates of depression in Parkinson’s disease.Can J Neurol Sci. 1984; 11: 105-107
- Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H2150 tissue activity.J Nucl Med. 1989; 30: 141-149
- 5HT1a receptors and 5HT1a-mediated responses.Ann N Y Acad Sci. 1990; 600: 460-475
- Subcortical projections of area 25 (subgenual cortex) of the macaque monkey.J Comp Neurol. 2000; 421: 172-188
- Prefrontal rTMS reduces relative perfusion locally and trans-synaptically.Hum Psychopharmacol Clin Exp. 1999; 14: 161-170
- Topography of corticostriatal projections in nonhuman primates and implications for functional parcellation of the neostriatum.in: Jones E.G Peters A Cerebral Cortex. Plenum Press, New York1984: 447-466
- State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon emission tomography in major depression before and after treatment.J Affect Disord. 1993; 29: 243-253
- Neurotransmitter and neuromodulators in the basal ganglia.Trends Neurosci. 1990; 15: 244-254
- Long-term antidepressant treatments result in a tonic activation of forebrain 5HT1A receptors.J Neurosci. 1998; 18: 10150-10156
- A rating scale for depression.J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
- Arousal and emotions.in: Boller F Grafman J Handbook of Neuropsychology, Vol. 3. Elsevier, Amsterdam1989: 403-417
- Patterns of regional brain activity differentiate types of anxiety.J Abnorm Psychol. 1997; 106: 376-385
Henry ME, Schmidt ME, Matochik JA, Stoddard EP, Potter WZ (in press): The effects of ECT on brain glucose metabolism: A pilot FDG PET study. J ECT.
- Are antidepressants all the same? Surveying the opinions of Australian psychiatrists.Aust N Z J Psychiatry. 1999; 33: 642-649
- Initiation and adaptation.Am J Psychiatry. 1996; 153: 151-162
- Baseline cerebral hypermetabolism associated with carbamezepine response, and hypometabolism with nimodipine response in mood disorders.Biol Psychiatry. 1999; 46: 1364-1374
- Functions of the Cortico-Basal Ganglia Loop. Springer, Tokyo1995
- Primate cingulostriatal projection.J Comp Neurol. 1994; 350: 337-356
- A modality-independent approach to spatial normalization of tomographic images of human brain.Hum Brain MAPP. 1995; 3: 209-223
- Automated labeling of the human brain.Hum Brain Mapp. 1997; 5: 238-242
- Neural activation during selective attention to subjective emotional responses.Neuroreport. 1997; 22: 3969-3972
- The varieties of emotional experience.Psychol Rev. 1994; 101: 211-221
- Psychomotor retardation and anhedonia in depression.Acta Psychiatry Scand. 1999; 99: 252-256
- Interactive effects in the anterior cingulate of sadness and selective attention.Biol Psychiatry. 2000; 47: 125-126
- Right hemisphere sensitivity to arousal and depression.Brain Cogn. 1992; 18: 138-151
- Venlafaxine or buproprion responders but not non-responders show baseline prefrontal and paralimbic hypometabolism compared with controls.Psychopharmacol Bull. 1996; 32: 629-635
- Tentative limbic system models for certain patterns of psychiatric disorders.in: Laitinen V Livingstone K.E Surgical Approaches in Psychiatry. Medical and Technical Publishing, Lancaster, UK1973: 245-252
- Psychosomatic disease and the visceral brain. Recent developments bearing on the Papex theory of emotion.Psychosom Med. 1949; 194: 338-353
- The retrosplenial cortex and emotion.Trends Neurosci. 1999; 22: 310-316
- Neurocog. Neurocog Assessment Systems, Seattle1995
- Reduced midbrain serotonin transporter binding in depressed vs healthy subjects as measured by 123b-CIT SPECT.Biol Psychiatry. 1998; 44: 1090-1098
- Frontal lobes & neurosurgery for psychiatric disorders.J Psychopharmacol. 1997; 11: 179-187
- Protein kinase C in rat brain cortex and hippocampus.J Pharmacol. 1995; 115: 595-600
- A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide.Arch Gen Psychiatry. 2000; 57: 729-738
- Left prefrontal glucose hypometabolism in the depressed state.Am J Psychiatry. 1990; 147: 1313-1317
- Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors.Psychopharmacology. 1997; 133: 99-101
- Cingulate function in depression.Neuroreport. 1997; 8: 1057-1061
- Reciprocal limbic-cortical function and negative mood.Am J Psychiatry. 1999; 156: 675-682
- Frontal lobe dysfunction in secondary depression.J Neuropsychiatry Clin Neurosci. 1994; 6: 428-442
- Limbic-cortical dysregulation.J Neuropsychiatry Clin Neurosci. 1997; 9: 471-481
- Disease and state-specific effects of mood challenge on rCBF.Neuroimage. 1998; 7: S901
- PET imaging of cortical S2-serotonin receptors following stroke.Am J Psychiatry. 1988; 145: 937-943
- Mapping functional alterations in the CNS with C14-deoxyglucose.in: Iversen L.L Iversen S.D Snyder S.H Handbook of Psychopharmacology. Vol 15. Plenum Press, New York1982: 321-410
- Dissociation of autonomic and subjective responses to emotional slides in right hemisphere damaged patients.Neuropsychologia. 1994; 32: 847-856
- [F-18]-Altanserin binding to serotonin (5HT-2A) receptors in late-life depression and Alzheimer’s disease.Biol Psychiatry. 1999; 45: 61S
- Architecture of connectivity within a cingul-fronto-parietal neurocognitive network for directed attention.Arch Neurol. 1993; 50: 279-284
- 5-HT2A receptors in depression pre/post paroxetine.Biol Psychiatry. 2000; 47: 87S
- Prefrontal cortex 5-HT2 receptors in depression.Am J Psychiatry. 1999; 156: 1029-1034
- A highly accurate method of localizing regions of neuronal activation in the human brain with positron emission tomography.J Cereb Blood Flow Metab. 1989; 9: 96-103
- The serotonergic and noradrenergic systems of the hippocampus.Brain Res Rev. 1997; 23: 145-195
- Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention.Arch Neurol. 1993; 50: 279-284
- Circuitous connections linking cerebral cortex, limbic system, and corpus striatum.in: Doane B.K Livingston K.E The Limbic System Functional Organization and Clinical Disorders. Raven, New York1986: 43-54
- Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus.J Neurosci. 1996; 16: 2365-2372
Nobler MS, Ouendo M, Kegeles LS, Malone K, Campbell C, Sackeim JA, Mann JJ (1999): Effects of ECT on regional cerebral metabolic rate: A PET study. Presented at the 38th Annual Meeting of the ACNP, Acapulco.
- Regional cerebral blood flow in mood disorders, III. Treatment and clinical response.Arch Gen Psychiatry. 1994; 51: 884-897
- Antidepressant medication change in a clinical treatment setting.J Clin Psychiatry. 1999; 60: 574-579
- Glial reduction in the subgenual prefrontal cortex in mood disorders.Proc Natl Acad Sci U S A. 1998; 95: 13290-13295
- Comparison of prefrontal architecture and connections.Philos Trans R Soc Lond B Biol Sci. 1996; 351: 1423-1432
- The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm.Proc Natl Acad Sci U S A. 1990; 87: 256-259
- Localization of a human system for sustained attention by positron emission tomography.Nature. 1991; 349: 61-63
- Regional cerebral blood flow changes following chronic administration of antidepressant drugs.Prog Neuropsychopharmacol Biol Psychiatry. 1995; 19: 627-636
- Posttraumatic stress and depression. A neurochemical anatomy of the learned helplessness animal model.Ann N Y Acad Sci. 1997; 821: 529-532
- Tomographic measurement of local cerebral glucose metabolic rate in humans with (F18)2-fluoro-2-deoxydglucose.Ann Neurol. 1979; 6: 371-388
- The orbitofrontal cortex.Phil Trans R Soc Lond B Biol Sci. 1996; 351: 1433-1444
- Brain serotonin-1A receptor binding measured by PET with 11C-Way-100635.Arch Gen Psychiatry. 2000; 57: 174-180
- Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in OCD.Neuropsychopharmacology. 1999; 21: 683-693
- Hippocampal atrophy in recurrent major depression.Proc Natl Acad Sci U S A. 1996; 93: 3908-3913
- Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression.Am J Psychiatry. 1999; 156: 683-689
- Measurement of local glucose utilization and its use in localization of functional activity in the CNS of animal and man.Recent Prog Horm Res. 1983; 39: 75-126
- Manual for the Structured Clinical Interview for DSMIIIR (SCID). New York State Psychiatric Institute, Biometrics Research, New York1988
- Time course of improvement under antidepressant treatment.Eur Neuropsychopharmacol. 1993; 3: 127-135
- Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms.J Neurosci. 1999; 19: 610-618
- Co-Planar Stereotaxic Atlas of the Brain. Thieme, New York1988
- Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS.J Neuropsychiatry Clin Neurosci. 1999; 11: 426-435
- Treatment-resistant depression.in: Blood F.E Kupfer D.J Psychopharmacology The Fourth Generation of Progress. Raven, New York1995: 1081-1097
- 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex.J Neurosci. 1997; 17: 2785-2795
- Human cingulate cortex.J Comp Neurol. 1995; 359: 490-506
- Cingulate cortex of the rhesus monkey, II.J Comp Neurol. 1987; 262: 271-289
- The emotional counting Stroop paradigm.Biol Psychiatry. 1998; 44: 1219-1228
- Three dimensional statical analysis for CBF activation studies in human brain.J Cereb Blood Flow Metab. 1992; 12: 900-918
- Prediction of antidepressant effects of sleep deprivation on metabolic rates in ventral anterior cingulate and medial prefrontal cortex.Am J Psychiatry. 1999; 156: 1149-1158
- Effect of sleep deprivation on brain metabolism of depressed patients.Am J Psychiatry. 1992; 149: 538-543
- Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment.Arch Gen Psychiatry. 1999; 56: 705-711
Article info
Publication history
Accepted:
August 25,
2000
Received in revised form:
August 25,
2000
Received:
May 2,
2000
Identification
Copyright
© 2000 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
