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Persistent β 2 *-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder
Open accessAbstract
BACKGROUND: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subjects. METHOD: The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of β2*-nAChRs was quantified as VT/fP. Postmortem analysis of β2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects. RESULTS: The β2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, β2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in β2*-nAChR number between groups in the postmortem study. CONCLUSIONS: Depressed patients have lower β2*-nAChR availability than do healthy subjects. The difference between β2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.
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Written from the paper’s full text.
TL;DR
In medication-free, non-smoking patients with familial major depressive disorder (MDD), β2*-nicotinic acetylcholine receptor (β2*-nAChR) availability measured by [123I]5-I-A-85380 SPECT was lower in acutely depressed and recovered subjects than in controls, and lower in acutely depressed than recovered subjects. Postmortem prefrontal cortex showed no difference in β2*-nAChR number, suggesting lower in vivo availability may reflect increased endogenous acetylcholine rather than receptor loss.
Key findings
- Acutely depressed MDD subjects had decreased β2*-nAChR availability versus controls in 9 of 11 regions examined, except hippocampus and amygdala (all adjusted p<0.007); the omnibus model showed a significant group effect (F(3,42)=8.65, p<.0001) and group-by-region interaction (F(30,420)=1.82, p=.006).
- Recovered MDD subjects had lower β2*-nAChR availability than controls in frontal cortex (adjusted p=0.03), anterior cingulate (adjusted p=0.04), and thalamus (adjusted p=0.008); overall group effect F(1,28)=7.9, p=0.009.
- Acutely depressed subjects had lower overall β2*-nAChR availability than recovered subjects (F(1,21)=10.0, p=0.005), with no significant group-by-region interaction (F(10,210)=1.34, p=0.21).
- Postmortem prefrontal cortex showed no differences in β2*-nAChR number between 14 MDD subjects and age-matched controls; in vivo availability correlated positively with lifetime number of depressive episodes in combined MDD subjects for temporal cortex (r=0.46, p=0.049), occipital cortex (r=0.48, p=0.037), and striatum (r=0.49, p=0.034).
Methods
- Cross-sectional SPECT/MRI study: 23 medication-free, non-smoking subjects with recurrent familial MDD (8 acutely depressed, 15 recovered) and 23 age- and gender-matched non-smoking controls had one [123I]5-I-A-85380 SPECT scan and one MRI; β2*-nAChR availability was quantified as VT/fp.
- Postmortem study: [125I]5-I-A-85380 binding was analyzed in prefrontal cortex samples from 14 subjects with MDD and age-matched controls.
- Main analysis used linear mixed models with region as a within-subjects factor, diagnostic group as a between-subjects factor, and group-by-region interaction; post-hoc tests were Bonferroni-corrected for 11 regional comparisons (2-sided alpha=.0045). Clinical correlations, postmortem ANOVA, and voxel-based morphometry (SPM5, p<.05 uncorrected) were also performed.
Limitations
- The paper states the sample size is relatively small and composed nearly entirely of subjects without a past history of cigarette smoking; only 11 of 46 subjects had a past smoking history, so the relationship between past smoking and β2*-nAChR availability could not be adequately analyzed.
- The paper states SPECT limitations include absence of a quantifiable reference region and input function, absence of a measurement of non-displaceable binding in MDD patients, poor resolution for small regions such as the amygdala, and the need for a PET study to confirm results; use of current non-smokers limits generalizability.
- Evident from the text: the postmortem results are described as provided in the supplement, limiting detail in the main paper, and the cross-sectional design cannot establish whether cholinergic changes are a cause or effect of MDD.
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Claims the paper makes
14 Not checked yet · 10 Own method · 10 Own result · 7 Own interpretation
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was a significant overall group effect (F(1,21)=10.0, p=0.005) with lower overall β2*-nAChR availability observed among acute MDD patients compared to recovered patients.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Results for SPECT study
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Post hoc comparison revealed decreased β2*-nAChR availability in aMDD subjects compared to healthy controls in nine of the eleven ROIs examined (except hippocampus and amygdala, all adjusted p<0.007).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Results for SPECT study
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This was also observed in the rMDD group alone (temporal cortex r=0.54, p=0.036, occipital cortex r=0.56, p=0.03, thalamus r=0.54, p=0.038 and striatum r=0.58, p=0.022).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CTQ total score and emotional abuse subscale were negatively correlated with receptor availability in all ROIs studied except amygdala in the aMDD but not the rMDD group.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Post hoc comparisons showed lower β2*-nAChR availability among patients compared to controls in the frontal cortex (adjusted p=0.03), anterior cingulate (adjusted p=0.04), and thalamus (adjusted p=0.008).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Results for SPECT study
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When aMDD and rMDD groups were combined, there was a significant positive correlation between lifetime number of episodes and β2*-nAChR availability in temporal cortex (r=0.46, p=0.049), occipital cortex (r=0.48, p=0.037), and striatum (r=0.49, p=0.034).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NEO conscientiousness scores were significantly correlated with receptor availability in all ROIs studied except amygdala and brainstem (which showed a trend for significance) in the aMDD group but not the rMDD group.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no differences in β2*-nAChR number between groups in the human postmortem study.”
- Also stated in: § Postmortem studies · plain
“the postmortem samples show no change in receptor number in patients with MDD when compared with either controls.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > Abstract > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Postmortem brain samples are free of endogenous acetylcholine, so their β2*-nAChR binding reflects receptor number.
- Also stated in: § Postmortem studies · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“β2*-nAChR availability is decreased in patients with MDD.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > Abstract > Conclusion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“These results, together with the non-human primate study (27), suggest that when β2*-nAChR availability is measured in the absence of bound endogenous ACh, there is no evidence of a change in receptor number.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Postmortem studies
What the sources say
- Not checked yetcites [27] source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Postmortem brain samples are free of endogenous acetylcholine, so their β2*-nAChR binding reflects receptor number.
In the paper
“Finally observations of the relationship between childhood trauma and β2*-nAChR availability replicates a relationship that has been observed in previous studies of the association between trauma and MDD (45).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
What the sources say
- Not checked yetcites [45] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Assuming that the lower β2*-nAChR availability represents increased extracellular ACh levels, the correlation implies that the greater the number of episodes, the greater the amount of extracellular ACh.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we found that the lower β2*-nAChR availability in MDD patients had functional effects in that it was related to critical personality measures.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This suggests that, consistent with the cholinergic hypothesis of depression (4), the lower β2*-nAChR availability in vivo is likely better explained by increased levels of extracellular ACh in patients with MDD rather than by a decrease in the total number of receptors.”
- Also stated in: § Conclusion · hedged
“The difference between β2*-nAChR availability in vivo and in postmortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by increased endogenous acetylcholine.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion
What the sources say
- Not checked yetcites [4] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Postmortem brain samples are free of endogenous acetylcholine, so their β2*-nAChR binding reflects receptor number.
- Also stated in: § Conclusion · hedged
In the paper
“It has been shown previously in nonhuman primates that elevated ACh levels induced by a high dose of intravenous physostigmine, an acetylcholinesterase inhibitor, can compete effectively in vivo with [123I]5-IA binding at β2*-nAChRs (27).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
What the sources say
- Not checked yetcites [27] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally there were no differences in brain volume between the patients and controls suggesting that brain atrophy could not account for changes in receptor availability in this sample.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Use of [123I]5-IA to quantify β2*-nAChR availability
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“However, mice lacking the β2-nAChR subunit are insensitive to the antidepressant-like effects of mecamylamine (15) and amitriptyline (18).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that β2 subunit containing (β2*) nAChRs may be important for the potential antidepressant like effect in preclinical models of depression.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The recent development and use of [123I]5-I-A ([123I]-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine) as a SPECT radioligand to quantify β2*-nAChRs in vivo in the human brain now allows unparalleled access to this system in vivo (23–25).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
What the sources say
- Not checked yetcites [23] source
- Not checked yetcites [24] Fujita M, 2000, J Nucl Med
- Not checked yetcites [25] Staley JK, 2005, J Nucl Med
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 15
- Probably not a substantial claim. 15
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The STAI Trait subscale score was negatively correlated with receptor availability in anterior cingulate (r=−0.65, p=0.027), temporal (r=−0.64, p=0.026) and, occipital (r=−0.65, p=0.021) regions and showed a trend for significance in striatum (r=−0.51, p=0.09) in the rMDD group but not in the aMDD group.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An SPM analysis of brain volumes of all MDD subjects compared to all controls showed no significant changes in volume in this population even at the relatively generous threshold used in the analysis. Similarly, there were no significant changes in volume between the aMDD subjects and their respective controls, the rMDD subjects and their respective controls, or between the aMDD and rMDD subjects.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“nAChRs have a ubiquitous role in the modulation of multiple neurotransmitter systems considered crucial in the pathophysiology of MDD such as serotonin, noradrenaline, glutamate and GABA (43) and the observed dysfunction may reflect a cause or effect of dysfunction in these other systems.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Use of [123I]5-IA to quantify β2*-nAChR availability
What the sources say
- Not checked yetcites [43] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The continued, significant decrease in β2*-nAChR availability in fully recovered, euthymic, medication free rMDD subjects suggests that the changes in MDD are not an epiphenomenon of treatment or illness but may be associated with trait vulnerability to depression as demonstrated by us previously for other targets (26, 41, 42).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Use of [123I]5-IA to quantify β2*-nAChR availability
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Studies suggest that tobacco smokers have higher β2*-nAChR availability compared with non-smokers in non-psychiatric populations (34) which normalizes by 6–12 weeks of abstinence (44).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, lower binding of [123I]5-IA to the β2*-nAChR could reflect one of two processes: an actual, absolute change in the amount of receptor or a change in synaptic ACh levels, such that an increased amount of ACh would prevent the radioligand from binding to the receptor, resulting in low binding of the radioligand.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Notwithstanding the robust statistical significance of the SPECT binding results, the sample size of the population studied is relatively small and composed nearly entirely of subjects without a past history of cigarette smoking; only 11 of the 46 subjects studied had a past history of cigarette smoking.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
plainn = 46- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“First, cholinergic hyperactivity plays a role in the pathophysiology of depression (2–4) and can exacerbate depression-like symptoms in patients and controls (4–6).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Population-based studies show that smokers are twice as likely as nonsmokers to have a lifetime history of major depression (11–13).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Clinical and demographic characteristics of participants in each group are shown in Table 2; the groups were well matched on most parameters studied though there were significant differences in ethnicity and lifetime smoking history between the groups.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Results for SPECT study
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All data were approximately normal.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 2. Materials and Methods > 2.4 Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Inclusion of age and gender as co-variates did not alter results and were therefore dropped from the analysis.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 2. Materials and Methods > 2.4 Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The use of a population exclusively composed of current non-smokers while essential to interpretation of the results limits generalizability and should be examined in future studies.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This study was approved by the Yale University School of Medicine Human Investigation Committee and the Radiation Safety Committee. After complete description of the study to the subjects, written informed consent was obtained. The use of the radiotracer [123I]5-IA was approved by the US Food and Drug Administration.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 2. Materials and Methods > 2. 1. Methods for SPECT Study
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“While the amygdala is a crucial structure in the pathophysiology of depression, SPECT has poor resolution for small brain regions and the findings for the amygdala should be interpreted with caution a.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Second, tobacco dependence is highly prevalent in MDD populations (7) and MDD patients have a higher prevalence of smokers (8–10).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant differences in the total injected dose, bolus dose, infusion dose, and bolus to infusion ratio between depressed and control groups (Table 1).”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 2. Materials and Methods > 2. 1. Methods for SPECT Study
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Inter-rater variability for VT/fp was <10% across all regions, which was computed as percent difference between two raters via following equation [(VT/fp 1/VT/fp 2)−1]*100=% difference.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 2. Materials and Methods > 2. 1. Methods for SPECT Study
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The relationship between a history of past cigarette smoking and β2*-nAChR availability could not be studied because of the small and unbalanced number of subjects with a past history of cigarette smoking.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Correlation with clinical features
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs) and partial agonists and antagonists of nAChRs including nicotine (14), mecamylamine and dihydro-beta-erythroidine (DHβE) (15), cytisine (16) and varenicline (17), have antidepressant-like effects in preclinical studies.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Analogous to findings from radioligand based studies of dopamine in humans, it is critically important to note that changes in receptor availability in vivo could be due to a change in receptor number or a change in receptor occupancy.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 1. Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The difference between β2*-nAChR availability in vivo and in postmortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by increased endogenous acetylcholine.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > Abstract > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper relies on this without support.
Postmortem brain samples are free of endogenous acetylcholine, so their β2*-nAChR binding reflects receptor number.
“β2*-nAChR availability in the postmortem human samples, in the absence of endogenous acetylcholine, would help interpret the precise mechanism of potential changes in binding observed with [123I]5-IA in humans.”
“under conditions that washed out any endogenous bound ACh”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“supports the idea that the elevated ACh levels observed in human subjects who are actively depressed contributes to the disorder (Saricicek et al. 2012;Hannestad et al. 2013).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Saricicek et al. 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Notably, anomalies in the availability or expression of specific nAChR subunits have been implicated in depression [104] and schizophrenia patients [105, 106].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [104]
In the citing paper
“More recently, human imaging and post mortem studies suggested that there is increased occupancy of nAChRs by ACh that is highest in individuals who are actively depressed and intermediate in those who have a history of depression with no change in overall nAChR number (Saricicek et al., 2012).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Saricicek et al., 2012
In the citing paper
“Recent imaging studies have shown that availability of β2* nAChRs for tracer binding was greatly decreased in actively depressed patients but was intermediate in remitted subjects (Saricicek et al., 2012).”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Saricicek et al., 2012
Statistics that don’t add up
Each reported p-value recomputed from its test statistic and degrees of freedom.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“F(3,42)=8.65, p<.0001”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Results for SPECT study
Reported p < .0001 · recomputed p < .001
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- Doesn’t add upF(3, 42) = 8.65reported p < .0001 · recomputed p < .001
“F(3,42)=8.65, p < .0001”
- ConsistentF(30, 420) = 1.82reported p = .006 · recomputed p = .006
“F(30,420)=1.82, p = .006”
- ConsistentF(1, 14) = 15.8reported p = .0014 · recomputed p = .001
“F(1,14)=15.8, p = .0014”
- ConsistentF(10, 140) = 2.52reported p = .008 · recomputed p = .008
“F(10,140)=2.52, p = .008”
- ConsistentF(1, 28) = 7.9reported p = .009 · recomputed p = .009
“F(1, 28)=7.9, p = .009”
- ConsistentF(1, 21) = 10reported p = .005 · recomputed p = .005
“F(1,21)=10.0, p = .005”
- ConsistentF(10, 210) = 1.34reported p = .21 · recomputed p = .211
“F(10,210)=1.34, p = .21”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > Abstract > Results
“β2*-nAChR availability in aMDD and rMDD subjects was significantly lower across all brain regions than in respective controls”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 3. Results > Results for SPECT study
“Post hoc comparison revealed decreased β2*-nAChR availability in aMDD subjects compared to healthy controls in nine of the eleven ROIs examined (except hippocampus and amygdala, all adjusted p<0.007).”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
“Assuming that the lower β2*-nAChR availability represents increased extracellular ACh levels, the correlation implies that the greater the number of episodes, the greater the amount of extracellular ACh.”
§ Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder > 4. Discussion > Functional consequences of lower β2*-nAChR availability
“We observed a significant positive correlation between the number of depressive episodes and β2*-nAChR availability in the combined MDD sample and rMDD patients.”
Citations
Cites
The CES-D Scale: A Self-Report Depression Scale for Research in the General Population
Radloff, L. S. (1977) · Applied Psychological Measurement · doi:10.1177/014662167700100306 · Cited by 53,267
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817
Ashburner, J., & Friston, K. J. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2005.02.018 · Cited by 7,507
The link between childhood trauma and depression: insights from HPA axis studies in humans
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.03.008 · Cited by 1,704
Bunney, W. E., Hippius, H., Laakmann, G., & Schmauß, M. (1990) · Springer eBooks · doi:10.1007/978-3-642-74034-3 · Cited by 1,523
Grant, B. F., Hasin, D. S., Chou, S. P., Stinson, F. S., & Dawson, D. A. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.11.1107 · Cited by 1,262
A cholinergic-adrenergic hypothesis of mania and depression
Janowsky, D., Davis, J., El-Yousef, M. K., & Sekerke, H. J. (1972) · The Lancet · doi:10.1016/s0140-6736(72)93021-8 · Cited by 1,134
Prevalence of smoking among psychiatric outpatients
(1986) · American Journal of Psychiatry · doi:10.1176/ajp.143.8.993 · Cited by 1,058
Bora, E., Fornito, A., Pantelis, C., & Yücel, M. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.03.049 · Cited by 763
Cigarette smoking: implications for psychiatric illness
(1993) · American Journal of Psychiatry · doi:10.1176/ajp.150.4.546 · Cited by 723
Research works printed but not linked: 5
- Fujita M, 2000, J Nucl Med, 41, 1552
- Staley JK, 2005, J Nucl Med, 46, 1466
- First MB, 1997, Structured Clinical Interview for DSM-IV Axis I Disorders—Clinician Version (SCID-CV)
- Beck AT, 1996, Beck Depression Inventory, 2nd ed, Manual
- Costa PT, 1992, NEO PI-R Professional Manual
Cited by
Sorted by citations
Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior
Picciotto, M. R., Higley, M. J., & Mineur, Y. S. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.036 · Cited by 1,404
Self-citationMineur, Y. S., Obayemi, A., Wigestrand, M. B., Fote, G. M., Calarco, C. A., Li, A. M., & Picciotto, M. R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1219731110 · Cited by 375
Self-citationCholinergic regulation of mood: from basic and clinical studies to emerging therapeutics
Dulawa, S. C., & Janowsky, D. S. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0219-x · Cited by 187
Neuromodulation by acetylcholine: examples from schizophrenia and depression
Higley, M. J., & Picciotto, M. R. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.06.004 · Cited by 184
Self-citationDavis, M. T., Holmes, S. E., Pietrzak, R. H., & Esterlis, I. (2017) · Chronic Stress · doi:10.1177/2470547017710916 · Cited by 194
Self-citation
Metadata
- Authors
- Saricicek, A., Esterlis, I., Maloney, K. H., Mineur, Y. S., Ruf, B. M., Muralidharan, A., Chen, J. I., Cosgrove, K. P., Kerestes, R., Ghose, S., Tamminga, C. A., Pittman, B., Bois, F., Tamagnan, G., Seibyl, J., Picciotto, M. R., Staley, J. K., & Bhagwagar, Z.
- Affiliations
- From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
- Yale University (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2012-08
- Volume
- 169
- Issue
- 8
- Pages
- 851-859
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3494404
- OpenAlex
- W2012803743
- Semantic Scholar
- 509ecb3712492199234e49435e4fb63c5347c8ae
- Cited by
- 118
- References
- 49
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 9 · 2017: 14 · 2016: 5 · 2015: 10 · 2014: 11 · 2013: 12 · 2012: 5
- FWCI
- 4.89
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k23mh077914-02)
- National Institute of Mental Health (MH077681, K23-MH077914, P50MH096890, MH-077914, R01MH077681)
- National Center for Research Resources (UL1RR024139)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Keywords
- major depressive disorder, nicotinic acetylcholine receptors, beta2 subunit, receptor availability, prefrontal cortex, postmortem brain, endogenous acetylcholine, trauma, anxiety, depressive episodes, recovered depression
- MeSH terms
- Adult, Brain, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Magnetic Resonance Imaging, Male, Psychiatric Status Rating Scales, Receptors, Nicotinic, Tomography, Emission-Computed, Single-Photon, Case-Control Studies, Neuroimaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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