Depression is common and found in every country of the world.

The World Health Organization estimates that 3.8% of the world’s people suffer with depression. More than 75% of those in low to middle income countries receive no mental health benefits. Depression is one of these conditionsabout whicheveryone thinks they know what they’re talking until they take a deeper look. While the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders Version 5)(1) and earlier versions have been helpful in getting us to speak a similar language, it’s clear that the categorical-based approach is not sufficient if we are to move forward in our clinical understanding of depression. There is a tremendous range of symptom constellations all bearing the name depression. The current diagnostic system is based on symptoms. It is not pathology based.

For example, using the DSM-5 (1) diagnostic criteria for Major Depressive Disorder (Henderson, 2018; 2020), (2-3) there are over 20 possible distinct phenotypes of this single diagnosis.

 The failure of clinical trials to effectively treat depression has led experts to state, “that major depressive disorder is biologically heterogeneous, such that different treatments differ in the likelihood of achieving remission in different patients” (Rush, 2006). (4)

Moreover, the number of symptoms under the heading of depression may be expanding. A recent American Journal of Psychiatry paper (14 May 2006),with over 86,000 subjects explored the  importance ofdiet in causing inflammation and how inflammation contributes to depressive disorders(Pitharouli, 2021).

Since psychiatry has difficulty establishing correct diagnoses and therapies, it is not surprising that perfusion SPECT has not established pathognomonic perfusion patterns.That is not to say that there are no SPECT findings associated with depressive symptomatology, there are. But when one tries to correlate them with specific symptom constellations based on DSM 5 descriptions this doesn’t work so well.  Thomas Insel,formerly of(NIH/NIMH)in 2013, made it clearthat,“The diagnostic system has to be based on the emerging research data, not on the current symptom-based categories…We need to begin collecting the genetic, imaging, physiologic, and cognitive data to see how all the data – not just the symptoms – cluster and how these clusters relate to treatment response” (Insel 2013).

Hence, when we look at emerging research data concerningSPECT brain perfusion studies of “depression” there are some interesting observations.First it is important to recognize that over 150 studies of perfusion SPECT imaging in depression containing more than 12,100 subjects have been completed.

Next, it is important to look at some of the consistent findings noted from this body of research:

A consistent finding in early SPECT (Xenon or HMPAO) studies of depression found decreased perfusion in the frontal, and often temporal cortices, as well as the superior anterior cingulate gyri (Lesser 1994(7); Ito 1996(8); Ebmeier 1997(9); Galynker 1998(10);).

Later, two distinct patterns of perfusion were recognized – decreased perfusion in typical and melancholic depression and increased frontal lobe perfusion in atypical depression (Fountoulakis 2004(11); Pagani 2007(12); Nagafusa 2012(13); Li 2018(14);).

Increased perfusion in the subgenual anterior cingulate gyrus in treatment-resistant depression was first described by Goodwin and colleagues (Goodwin 1993 (15)), but has been recognized as a hallmark sign of treatment resistant depression, subsequently (Brockmann 2009(16); Drevets 2008(17); Li 2018 (14)).

Remission or response to treatment is characteristically followed by increased perfusion in the affected areas (Goodwin 1993(15); Ogura 1998(18); Loo 2003(19)). Response could be predicted by the degree of frontal hypoperfusion and of subgenual hyperperfusion.

Notably, response to serotonin reuptake inhibitors was predicted by higher frontal and cingulate perfusion (Brockmann 2009(16); Hanada 2013(20); Amen 2018(21)), while response to electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) was predicted by lower frontal and cingulate perfusion.

Increased metabolic activity and perfusion in the thalamus (Drevets 1998(22); Milak 2005(23)) is also a frequently reported finding in unipolar depression. Increased symmetrical perfusion of the thalamus has been consistently seen by clinicians on tens of thousands of perfusion SPECT scans.

Case Example 1: Persistent and Recurrent Depression Spanning Decades

A 71-year-old female presents with over 50 years of recurrent depression. She states she has tried dozens of medications, electroconvulsive shock therapy, transcranial magnetic stimulation, and numerous specialty retreats and programs. She describes a persistent low mood, free-floating guilt, intrusive thoughts of self-doubt, disrupted sleep, low energy, and a growing sense of hopelessness.

Reviewing the SPECT scan, it is evident that there is significant hypoperfusion in the frontal and temporal lobes. The subgenual anterior cingulate is not overactive. The scan appearance is similar to what is found in mild cognitive impairment of the frontotemporal type (MCI-FTD), but her performance on cognitive testing is excellent.

Based on the scan appearance, the patient was started on bupropion and intravenous ketamine therapy. She received four infusions of ketamine one time per week and experienced marked reduction of her symptoms. Six months later, she returned for two more ketamine infusion (again one week apart) after a romantic breakup. Now six years later, she reports she lives a joyful life, free of low mood, self-doubt, or intrusive thoughts.

A Repeat Scan at 18 months after Initiating Treatment Showed Marked Improvement.

Case Example 2: Patient Presenting With Complaint of Depression – the Role of Comorbidities

A 29-year-old single female presented because of death a friend who suicided eight months earlier. Patient stated “I don’t want to be depressed all the time.” The patient admitted using marijuana, cocaine and alcohol regularly. Family history included a father and brother who were alcoholics, and a sister who suffered from severe anxiety. Patient was estranged from the family.

The patient gave a history of prior treatment with multiple antidepressants over a period of 15 years, all of which were discontinued due to lack of efficacy or intolerable side effects. She was not taking any psychotropic medication at the time of evaluation and reported binge drinking up to 10 drinks once or twice a week. She also gave a history of having had a slip and fall, seven years prior to scan, in which she hit her head on the sidewalk. She experienced brief loss of consciousness and was admitted to hospital.

At the time of the scan, the patient’s primary symptoms were trouble focusing, headaches, fatigue, excessive drinking and persistent sadness. She also reported since her friend death, she felt her life fell apart. “I just haven’t recovered. I don’t like being alone as I feel hopeless. If I don’t drink I feel sober and I can’t hang out with others.” She worked in a bar and reported getting angry at work “I don’t like the people I serve.”

Figure 1: Sagittal tomograms of the case example.

Figure 2: Surface views and isocontours of the same patient.

Reviewing the SPECT scan at the surface 55% threshold

  • There is decreased perfusion to the high convexity {parietal lobes) bilaterally,
  • Perfusion in the left temporal lobe is moderately decreased,
  • Perfusion in the right temporal lobe is minimally decreased
  • Perfusion in the left infraorbital frontal lobe is minimally decreased.

Reviewing the 85%/90% perfusion: there is moderate to markedincreased perfusion to the right thalamus.

In this case, while depression is the primary presenting feature, the scan makes it clear that there’s a lot more happening than just a straightforward depression. The toxic effects of alcohol and substances of abuse are evident in the diffuse patchy hypoperfusion. Also, the hypoperfusion of the temporal lobes and right frontal cortex may be signs of a persistent brain injury, possibly related to the slip and fall. Of interest the patient did not respond well to antidepressants in the past – always having to stop them because of some side effect.

Based on the SPECT scan results, she was started on small doses of gabapentin (400 mg) which she was able to tolerate. She began attending CBT group for alcoholism and depression. Over time she became able to get involved in a relationship and was able to recognize that substance use was not beneficial for her. Subsequently, she was lost to follow-up.


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(2) Henderson, T.A. (2018). Brain SPECT imaging in neuropsychiatric diagnosis and monitoring. EPatient. 1:40-47.

(3) Henderson TA, van Lierop M, McLean M, Uszler JM, Thornton J, Siow Y-H, Pavel DG, Cardaci G, Cohen P. Functional Neuroimaging in Psychiatry – Aiding in Diagnosis and Guiding Treatment. What the APA Does Not Know. Front. Psychiatry, April 15; 11:276, 2020,

(4) Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D., et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry. 163(11):1905-17.

(5)Maria C. Pitharouli, M.Sc., Saskia P. Hagenaars, Ph.D., Kylie P. Glanville, Ph.D., Jonathan R.I. Coleman, Ph.D., Matthew Hotopf, Ph.D., F.R.C.Psych., …Et al.Elevated C Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank Published Online:14 May 2021

The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank.

(6)Thomas Insel, 2013, (

(7) Lesser IM, Mena I, Boone KB, Miller BL, Mehringer CM, Wohl M. Reduction of cerebral blood flow in older depressed patients. Arch Gen Psychiatry. 1994 Sep;51(9):677-86.

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(9) Ebmeier KP, Cavanagh JT, Moffoot AP, Glabus MF, O’Carroll RE, Goodwin GM. Cerebral perfusion correlates of depressed mood. Br J Psychiatry. 1997 Jan;170:77-81.

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(12) Pagani M, Salmaso D, Nardo D, Jonsson C, Jacobsson H, Larsson SA, Gardner A. Imaging the neurobiological substrate of atypical depression by SPECT. Eur J Nucl Med Mol Imaging. 2007 Jan;34(1):110-20.

(13) Nagafusa Y, Okamoto N, Sakamoto K, Yamashita F, Kawaguchi A, Higuchi T, Matsuda H. Assessment of cerebral blood flow findings using 99mTc-ECD single-photon emission computed tomography in patients diagnosed with major depressive disorder. J Affect Disord. 2012 Nov;140(3):296-9.

(14) Li J, Yang Y, Zhu Y, Zhou L, Han Y, Yin T, Cheng Z, Zhang G, Shen Y, Chen J. Towards characterizing the regional cerebral perfusion in evaluating the severity of major depression disorder with SPECT/CT. BMC Psychiatry. 2018 Mar 21;18(1):70.

(15) Goodwin GM, Austin MP, Dougall N, Ross M, Murray C, O’Carroll RE, Moffoot A, Prentice N, Ebmeier KP. 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 Dec;29(4):243-53.

(16) Brockmann H, Zobel A, Joe A, Biermann K, Scheef L, Schuhmacher A, von Widdern O, Metten M, Biersack HJ, Maier W, Boecker H. The value of HMPAO SPECT in predicting treatment response to citalopram in patients with major depression. Psychiatry Res. 2009 Aug 30;173(2):107-12.

(17) Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008 Aug;13(8):663-81.

(18) Ogura A, Morinobu S, Kawakatsu S, Totsuka S, Komatani A. Changes in regional brain activity in major depression after successful treatment with antidepressant drugs. Acta Psychiatr Scand. 1998 Jul;98(1):54-9.

(19) Loo CK, Sachdev PS, Haindl W, Wen W, Mitchell PB, Croker VM, Malhi GS. High (15 Hz) and low (1 Hz) frequency transcranial magnetic stimulation have different acute effects on regional cerebral blood flow in depressed patients. Psychol Med. 2003 Aug;33(6):997-1006.

(20) Hanada H, Imanaga J, Yoshiiwa A, Yoshikawa T, Tanaka Y, Tsuru J, Inoue A, Ishitobi Y, Okamoto S, Kanehisa M, Maruyama Y, Ninomiya T, Higuma H, Isogawa K, Kawasaki T, Fujioka T, Akiyoshi J. The value of ethyl cysteinate dimer single photon emission computed tomography in predicting antidepressant treatment response in patients with major depression. Int J Geriatr Psychiatry. 2013 Jul;28(7):756-65.

(21) Amen DG, Taylor DV, Meysami S, Raji CA. Deficits in Regional Cerebral Blood Flow on Brain SPECT Predict Treatment Resistant Depression. J Alzheimers Dis. 2018;63(2):529-538.

(22)Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49:341-61.

(23) Milak MS, Parsey RV, Keilp J, Oquendo MA, Malone KM, Mann JJ. Neuroanatomic correlates of psychopathologic components of major depressive disorder. Arch Gen Psychiatry. 2005 Apr;62(4):397-408.

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