Psychiatry and Clinical Neurosciences 2016; 70: 34–41 doi:10.1111/pcn.

12335

Regular Article

Baseline symptom severity predicts serotonin

transporter change during psychotherapy in patients with
major depression
Mikko Joensuu, MD,1* Pasi Ahola, MD,2,3 Paul Knekt, PhD,7 Olavi Lindfors, PhD,7
Pirjo Saarinen, MD, PhD,3,5 Tommi Tolmunen, MD, PhD,3
Minna Valkonen-Korhonen, MD, PhD,2,3 Ritva Vanninen, MD, PhD,4 Tuija Jääskeläinen, MSc,7
Esa Virtala, SrSysAnal, BSc,7 Jyrki Kuikka, PhD,6† Jari Tiihonen, MD, PhD1,7,8 and
Johannes Lehtonen, MD, PhD3,7
1
Department of Forensic Psychiatry, 2University of Eastern Finland, 3Department of Psychiatry, 4Department of Clinical
Radiology, Kuopio University Hospital, 5Kuopio Psychiatric Center, 6Department of Clinical Physiology and Nuclear
Medicine, University of Kuopio, Kuopio, 7National Institute for Health and Welfare, Helsinki, Finland, and 8Department of
Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden

Aims: The role of the serotonin transporter (SERT) in list Depression Scale and the Symptom Checklist
the pathophysiology of depression is unclear and Global Severity Index. With cut-off values applied, it
only a few follow-up studies exist. Our aim was to was found that SERT availabilities increased in
measure changes in SERT availability during psycho- patients with high baseline symptoms, and decreased
dynamic psychotherapy in patients with major in patients with low baseline symptoms.
depression over a follow-up time of 12 or 18 months.
Conclusions: Together with our earlier finding of
Methods: The patients were studied with iodine-123 decreased SERT in patients with depression, these
labelled 2β-carbomethoxy-3β-(4-iodophenyl) serial results indicate a state-dependent and possibly a
single-photon emission tomography imaging and compensatory role of decreased SERT availability in
clinical rating scales of symptoms. depression.
Results: Changes in SERT availability had no correla-
Key words: follow-up, midbrain, psychodynamic
tion with the change of symptoms, but the change of
psychotherapy, serotonin transporter, serial single-
SERT availability during psychotherapy in the mid-
photon emission tomography.
brain was predicted by the baseline severity of the
clinical symptoms measured by the Symptom Check-

INDINGS CONCERNING SEROTONIN trans- have reported decreased SERT binding. Positron
F porter (SERT) in major depressive disorder
(MDD) are inconsistent. Several,1–4 but not all,5
emission tomography (PET) studies have reported
decrease,6–11 increase12–14 and no significant differ-
single-photon emission tomography (SPECT) studies ence15 in SERT availability of patients with MDD
compared with healthy subjects. A recent meta-
analysis indicated reduced SERT availability in the
*Correspondence: Mikko Joensuu, MD, Department of Forensic midbrain and amygdala in MDD patients compared
Psychiatry, University of Eastern Finland, Niuvankuja 65, 70240 with healthy subjects.16
Kuopio, Finland. Email: [email protected] In recovered MDD patients, SERT availabilities do
†
Deceased.
ClinicalTrials.gov Identifier: NCT00594711.
not significantly differ from those of healthy con-
Received 23 November 2014; revised 16 June 2015; accepted 30 July trols.17,18 A recent follow-up study19 reported
2015. increases in SERT availability during 12 weeks of cog-

34 © 2015 The Authors

Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2016; 70: 34–41 Baseline symptoms and SERT change 35

nitive behavioral therapy in MDD patients with

recovery. Table 1. Baseline characteristics
Our previous case studies,20–22 a naturalistic Number of patients 33
follow-up study23 and an analysis of the impact of Socioeconomic variables
atypical symptoms of depression,24 have suggested Age (years) 26.8 (7.4)
that SERT availability may change during psycho- Women 25/33
therapy, but probably only in subgroups of depres- Living alone 23/32
sion. The aim of the present study was to investigate Academic education 6/31
whether SERT availability changes in relation to psy- Employed or studying 21/33
chotherapy in an unselected sample of patients with Psychiatric diagnoses
MDD and whether there are correlations between the Major depressive disorder 33/33
One or more comorbid axis I 18/33
changes in SERT availability and the clinical severity
diagnoses
of depression.
One or more personality disorders 13/24†
Psychiatric background and health
First episode of depression < 20 years 16/29
of age
METHODS
Depression diagnosed for either or 18/32
both parents
Subjects Good or relatively good general health 19/30
Patients considered eligible for this study had to be Scores of clinical variables
drug naïve with no previous psychiatric treatment. GSI 1.32 (0.60)
They were required to meet DSM-IV-R criteria for ANX 1.24 (0.78)
BDI 25.68 (9.13)
moderate or severe depression. Psychotic symptoms,
DEP 2.23 (0.84)
bipolar disorder, substance abuse, severe personality
HDRS 17.96 (5.61)
disorders and somatic illnesses were exclusion TAS 62.72 (9.27)
criteria. †
Diagnosis assessed after 12 months of treatment.
Of the 60 referred patients, 54 were clinically
ANX, Anxiety scale of the Symptom Checklist; BDI,
assessed and 40 were found to satisfy the criteria.
Beck Depression Inventory; DEP, Depression scale of
During the waiting time, seven patients decided not the Symptom Checklist; GSI, Global Severity Index of
to participate. Altogether, 33 patients (25 female, Symptom Checklist; HDRS, Hamilton Rating Scale for
eight male) were included in the intention-to-treat Depression; TAS, Toronto Alexithymia Scale.
analysis (Table 1). In order to assess the efficacy of
psychotherapy, every second referred patient was
allocated to the direct therapy group (DG, n = 17),
starting psychotherapy directly after the assessment,
carried out to exclude somatic disorders and focal
and every other to the waiting group (WG, n = 16),
brain abnormalities.
starting psychotherapy after an average of 6-months’
waiting time. Five patients did not receive the allo-
cated intervention. A total of 14 DG patients and 10
WG patients completed the study. In the outpatient
Imaging procedure
clinic, where the treatments were carried out, a A dose of iodine-123 labelled 2β-carbomethoxy-3β-
6-month waiting time before psychotherapy treat- (4-iodophenyl) ([123I] nor-β-CIT) was slowly
ment was common. The subjects were not exposed injected into the right antecubital vein in a dimly lit
to extra suffering due to the experimental setting. and quiet room. SPECT scans (5 min, 6 h and 24 h)
The clinical safety and ethics of the study were also were performed on a Siemens MultiSPECT 3 gamma
supported by earlier findings from comparable clini- camera (Hoffman Estates, IL, USA).26,27 SPECT
cal research settings.25 All patients provided written imaging was performed for the women on the first
informed consent. The study was approved by the Wednesday after the end of menstruation, except for
ethics committee of the University of Eastern one patient who noted being pregnant after the
Finland. Clinical and laboratory examinations, as SPECT imaging and three controls whose menstrual
well as magnetic resonance imaging (MRI), were status was not controlled for technical reasons.

© 2015 The Authors

Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
36 M. Joensuu et al. Psychiatry and Clinical Neurosciences 2016; 70: 34–41

The midbrain (MB) and the medial prefrontal

cortex (MPC) were chosen as regions of interest Table 2. Correlation ratios† between SERT change and
(ROI) and manually drawn with the help of MRI its potential determinants (i.e. baseline SERT, baseline
symptoms, study group and symptom change)
data. The specific binding density for SERT was cal-
culated using the simplified reference tissue model Clinical SERT Symptom Baseline Baseline
with cerebellum as a reference region.28,29 Scale localization change SERT symptom
The reproducibility of MB SPECT scans had been GSI MB 0.08 0.18 0.58*
studied with 11 healthy subjects scanned twice with a MPC 0.19 0.40 0.49
12-month interval with a mean difference (mean ANX MB 0.01 0.17 0.40
± SD) of 0.00 ± 0.08. The intra-class correlation MPC 0.26 0.32 0.29
coefficient was 0.82 (P < 0.01) (A. Uusitalo, pers. DEP MB 0.10 0.20 0.60*
comm.). MPC 0.01 0.37 0.34
HDRS-17 MB 0.39 0.16 0.30
MPC 0.20 0.35 0.28
Psychotherapy and therapists BDI MB 0.22 0.07 0.38
The patients were offered psychodynamic psycho- MPC 0.26 0.36 0.44
therapy30 with the frequency of sessions twice a week TAS MB 0.45 0.08 0.50
for 1 year without medication by experienced psycho- MPC 0.24 0.46 0.46
dynamic psychotherapists with at least a 3-year post- *P < 0.05. †Statistical model: Change in
graduate professional training in the outpatient clinic SERT = change of symptom severity + study
of the Department of Psychiatry of Kuopio University group + baseline symptom severity + baseline SERT,
Hospital. n = 18 for all except HDRS-17 where n = 24.ANX,
Anxiety scale of the Symptom Checklist; BDI, Beck
Depression Inventory; DEP, Depression scale of the
Assessments Symptom Checklist; GSI, Global Severity Index of
Psychiatric diagnoses were made using the Structured Symptom Checklist; HDRS, Hamilton Rating Scale for
Clinical Interviews for DSM-IV-R (SCID-I and SCID- Depression; MB, midbrain; MPC, medial prefrontal
cortex; SERT, serotonin transporter; TAS, Toronto
II).31 Outcome measures of depression symptoms
Alexithymia Scale.
were the 17-item Hamilton Rating Scale for Depres-
sion (HDRS-17),32 the Beck Depression Inventory
(BDI)33 and the Depression scale of the Symptom
Checklist (SCL-90-DEP). The global, anxiety and
alexithymia symptoms were measured by the Global SERT change, from randomization to the end of
Severity Index of Symptom Checklist (SCL-90-GSI), follow-up, were estimated using two types of linear
the Anxiety scale of the Symptom Checklist (SCL-90- regression models. The dependent variable in both
ANX)34 and the Toronto Alexithymia Scale (TAS- types of models was the change in MB or MPC SERT
20),35 respectively. availability. In the first type of model, the indepen-
Outcome variables were obtained from each par- dent variables were baseline SERT (MB or MPC),
ticipant at recruitment and after 12 months of treat- study group, symptoms at baseline (SCL-90-GSI,
ment. Psychiatric diagnoses on axis I were assessed by SCL-90- DEP, SCL-90- ANX, BDI, or HDRS-17, or
an experienced psychiatrist at the recruitment to the TAS) and any subsequent symptom change in
study and then on axis II after 12 months of treat- respective symptom measure during follow-up.
ment for both groups. The socioeconomic data and Thus, 12 separate models were performed (Table 2).
information on psychiatric background (age at onset In the second type of model, the baseline symptom
of first episode of depression, diagnosis of depression variable was replaced by a dichotomized version
in either parent) and data on somatic health were (low, high) with the following cut-offs of the vari-
collected by a questionnaire. able: GSI, 1.7; ANX, 1.7; DEP, 1.7 (the mean of the
three SCL-90 scores in a Finnish psychiatric patient
sample);36 HDRS-17, 19; BDI, 17 (moderate level
Statistical methods symptoms of the HDRS and BDI);37,38 and TAS,
Determinants (i.e., baseline SERT, baseline symp- 60 (1 SD above mean)39 (Table S2, Supporting
toms, treatment group, and symptom change) of material).

© 2015 The Authors

Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2016; 70: 34–41 Baseline symptoms and SERT change 37

RESULTS 0.40

Change in SERT availability during follow up 0.30

SERT MB change
The SERT availability in the MB and the MPC was 0.20
measured at baseline for all 33 patients with an inten-
tion to treat. When their overall change was assessed, 0.10
from randomization to follow up (i.e., during 18
months in the waiting group and 12 months in the 0.00
direct therapy group), no statistically significant –0.10
changes were found; MB baseline, 1.14 (SD 0.1),
follow-up of psychotherapy, 1.16 (SD 0.17); and –0.20
MPC baseline, 0.25 (SD 0.07), follow-up of psycho-
therapy 0.25 (SD 0.07). Furthermore, no overall dif- –0.30
0.00 0.50 1.00 1.50 2.00 2.50 3.00
ferences were found between the distributions of MB SCL-90-GSI baseline
or MPC values for the two study groups during
follow-up (P-value for interaction = 0.33 for MB and Figure 1. Change in midbrain serotonin transporter (SERT)
0.89 for MPC). Accordingly, at the end of the follow- availability and the Global Severity Index of Symptom Check-
list (SCL-90-GSI) at baseline.
up, the MB difference between the groups, adjusted
for the baseline MB level, was negligible, 0.05 (–0.05,
0.15), while the corresponding value for MPC was
−0.004 (–0.059, 0.050). (Supporting information 1). The change in SERT for
the MB was predicted by the baseline severity of clini-
cal symptoms measured by SCL-90 GSI (R = 0.58,
Comparison and combination of
P = 0.02, n = 18) and DEP (R = 0.60, P = 0.02,
treatment groups
n = 18) (Table 2, Figs 1 and 2). Moreover in a
As no significant differences were observed between dichotomized analysis (Supporting information 2)
the two treatment groups in the changes of SERT with cut-off values (i.e., low vs high levels of the
availability in MB and MPC during follow up, these symptomology) applied, it was found that SERT
groups were combined for the analysis of the deter- availabilities increased in patients with baseline
minants for SERT changes (i.e., baseline SERT, symp-
toms at baseline and their clinical change at follow
up).
0.40
Baseline SERT
0.30
Baseline SERT did not significantly predict changes in
SERT MB change

MB or MPC, where correlations varied between 0.07 0.20

and 0.46 (Table 2).
0.10

Clinical change 0.00

Correlations between changes in clinical symptom –0.10

measures (SCL-90-GSI, SCL-90-DEP, SCL-90-ANX,
BDI, HDRS-17 and TAS) and the changes in MB and –0.20
MPC SERT varied between 0.01 and 0.45, with all
–0.30
associations being non-significant (Table 2). 0.00 1.00 2.00 3.00 4.00
SCL-90-DEP baseline
Symptom severity at baseline
Figure 2. Change in midbrain serotonin transporter (SERT)
There were no significant correlations between base- availability and Depression scale of Symptom Checklist (SCL-
line symptom levels and baseline SERT availabilities 90-DEP) at baseline.

© 2015 The Authors

Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
38 M. Joensuu et al. Psychiatry and Clinical Neurosciences 2016; 70: 34–41

GSI ≥ 1.7 (MPC +0.08, MB +0.17; n = 5) and tive to more comprehensive symptom burden and
decreased in patients with baseline GSI < 1.7 not only to depression. The lack of correlation
(MPC −0.03, MB −0.02; n = 13), p(MPC) = 0.003, between baseline HDRS-17 and BDI and SERT
p(MB) = 0.002). SERT MB availability increased in change further suggests that specific depressive symp-
patients with SCL-90 DEP > 1.7 (+0.07; n = 14) and toms are possibly not key factors in the relation
decreased in patients with SCL-90 DEP ≤ 1.7 (–0.11; between SERT and depression.
n = 4, P = 0.03). The severity of baseline TAS correlated with
SERT MB availability increased (P = 0.01) in changes in SERT. The connection of TAS with
patients with BDI > 17 (+0.07; n = 17) and decreased changes in SERT availability may be explained by its
in patients with BDI ≤ 17 (−0.12; n = 5). In patients connection to depression, as TAS is reduced together
with TAS > 60, SERT availability increased (MPC with the alleviation of depressive symptoms44
+0.05, MB +0.14; n = 10) and decreased in patients and with an improvement in cortical emotion
with TAS ≤ 60 (MPC −0.07, MB −0.10; n = 8), processing.45
p(MPC) = 0.01, p(MB) = 0.003. There were more significant findings connected
with SERT in MB than in MPC, which is in line with
decreased MB SERT in depression in our baseline
DISCUSSION study2 and other studies, compared with mixed find-
SERT changes during psychotherapy in the total ings in MPC.16
sample were not correlated with any symptomatic There was no healthy control group included in
change in depression, anxiety, general psychiatric our study, but the reproducibility of the SPECT
symptoms or alexithymia. imaging for MB was reliable (unpublished data). The
Our finding contradicts the results from Amster- lack of a significant correlation between symptom
dam et al.,19 who reported increases in SERT availabil- change and SERT change may be a result of the small
ity connected with recovery. The current study sample size. However, the possibility of a type II error
included a longer follow-up period than previous is small, given the low R-values. The use of multiple
studies by Laasonen-Balk et al.23 and Amsterdam tests without control for familywise error rate is a
et al.19 and some patients in those studies had previ- statistical limitation of the study. Only two tests out
ously used antidepressants, which may have affected of 12 were statistically significant, so it is possible that
the results. The therapeutic modality used by Amster- the associations are chance findings.
dam et al.19 may have been more oriented towards Drug-naïve patients willing to participate in a study
stress coping, which might have an effect on SERT that included a long period of non-pharmacological
availability. intervention and a possible waiting time may not
Decrease of MB SERT availability is connected represent an average patient group with depression.
with major depression, but the causal mechanism The combination of two follow-up groups (WG and
is unclear. If the downregulated MB serotonin DG) can be seen as a disadvantage making it difficult
reuptake system would represent a mechanism to conclude whether the changes in SERT and clinical
maintaining or increasing serotonin transmission, parameters were caused by psychotherapy or other
this endogenous compensatory effort may return factors, such as regression toward means. However,
toward normal when the stress load is lightened by there were no significant differences in the findings
treatment, as we found in patients with high between these groups.
symptom burden. This would be in line with recent As [123I] nor-β-CIT also binds to dopamine trans-
results showing a positive correlation of social porter (DAT) and noradrenaline transporter (NORT),
support and MB SERT availability.40 we cannot rule out the possibility that our findings
The role of stress in SERT regulation is supported may be partly caused by differences in DAT and
by the findings in animal41 and genetic studies,42 as NORT availability. However, according to autoradio-
well as correlations between SERT availability and the graphic studies, MPC does not contain significant
dexamethasone suppression test.43 densities of NORT or DAT.46,47 The noradrenergic
The correlation between baseline severity and SERT nucleus caeruleus and the dopamine cell body-rich
change was found not only in depression measures, substantia nigra are situated close to the MB. In the
but also in the global symptom measure SCL GSI, study by Hiltunen et al., one healthy male subject
suggesting that SERT availability may also be sensi- pre-treated with 30 mg citalopram had 52% lower

© 2015 The Authors

Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2016; 70: 34–41 Baseline symptoms and SERT change 39

MB [123I] nor-β-CIT binding than that of unmedi- 6. Parsey RV, Hastings RS, Oquendo MA et al. Lower sero-
cated subjects, indicating that the MB binding is also tonin transporter binding potential in the human brain
highly SERT-specific.26 during major depressive episodes. Am. J. Psychiatry 2006;
The long-term effects of earlier antidepressant use 163: 52–58.
7. Miller JM, Oquendo MA, Ogden RT, Mann JJ, Parsey RV.
on SERT expression are mainly unknown, and we
Serotonin transporter binding as a possible predictor of
consider the drug-naïvety of our patients to be a sig- one-year remission in major depressive disorder. J.
nificant strength in this study. Compared to the study Psychiatr. Res. 2008; 42: 1137–1144.
by Amsterdam et al.,19 we followed the patients for a 8. Miller JM, Kinnally EL, Ogden RT, Oquendo MA, Mann JJ,
considerably longer period of time. Parsey RV. Reported childhood abuse is associated with
As genetic polymorphism and ethnic heterogeneity low serotonin transporter binding in vivo in major depres-
may also influence the results,48 it may be of advan- sive disorder. Synapse 2009; 63: 565–573.
tage that our sample was homogeneous (i.e., all sub- 9. Reimold M, Batra A, Knobel A et al. Anxiety is associated
jects were Caucasians of Finnish origin). with reduced central serotonin transporter availability in
unmedicated patients with unipolar major depression: A
[11C]DASB PET study. Mol. Psychiatry 2008; 13: 606–613,
Conclusions 557.
10. Frokjaer VG, Vinberg M, Erritzoe D et al. High familial risk
Our finding of a correlation with baseline symptom for mood disorder is associated with low dorsolateral pre-
severity of depression and follow-up SERT change frontal cortex serotonin transporter binding. Neuroimage
during psychotherapy provides a new viewpoint on 2009; 46: 360–366.
the role of SERT in depression by suggesting a state- 11. Selvaraj S, Murthy NV, Bhagwagar Z et al. Diminished
dependent and compensatory mechanism for brain 5-HT transporter binding in major depression: A
decreased SERT availability in depression. positron emission tomography study with [11C]DASB.
Psychopharmacology 2011; 213: 555–562.
12. Ichimiya T, Suhara T, Sudo Y et al. Serotonin transporter
ACKNOWLEDGMENT binding in patients with mood disorders: A PET study with
[11C](+)McN5652. Biol. Psychiatry 2002; 51: 715–722.
M.J., P.I.S., and J.L. are recipients of a grant from the
13. Reivich M, Amsterdam JD, Brunswick DJ, Shiue CY. PET
Signe and Ane Gyllenberg Foundation. There is no brain imaging with [11C](+)McN5652 shows increased
conflict of interest. serotonin transporter availability in major depression. J.
Affect. Disord. 2004; 82: 321–327.
14. Cannon DM, Ichise M, Rollis D et al. Elevated serotonin
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Psychiatry and Clinical Neurosciences 2016; 70: 34–41 Baseline symptoms and SERT change 41

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low and high baseline symptom level.
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Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology