Abstract
Impairment of serotonin receptor and transporter function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ). We conducted a PubMed search, which provided a total of 136 in vivo studies with PET and SPECT, in which 5-HT synthesis, 5-HT transporter binding, 5-HT1 receptor binding or 5-HT2 receptor binding in patients with the primary diagnosis of acute AD, MDD, BD or SZ was compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BD and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and receptor binding sites.
Introduction
In Europe, anxiety disorder (AD) is the most frequent affective disorder with a 1-year prevalence of 12%. The prevalence of major depressive disorder (MDD) and psychotic disorders including schizophrenia (SZ) amounts to 8% and 3%, respectively (Wittchen and Jacobi, 2005). Despite these incidences and their socioeconomic impact, pathophysiological mechanisms of psychiatric disorders are still not fully understood.
Among the neurotransmitters implicated in AD, MDD and SZ are catecholamines (AD, Stein et al., 2002; MDD, Willner, 1983; SZ, Seeman and Lee, 1975), glutamate (AD, Carlsson, 2001; MDD, Mitchell and Baker, 2010; SZ, Konradi and Heckers, 2003), acetylcholine (AD, Graef et al., 2011; MDD, Mineur and Picciotto, 2010; SZ, Hajós and Rogers, 2010) and γ-aminobutyric acid ([GABA]; AD, Nuss, 2015; MDD, Pehrson and Sanchez, 2015; SZ, Taylor and Tso, 2014).
A major role has also been ascribed to dysfunctions of the serotonin (5-HT)ergic system (AD, Lowry et al., 2005; MDD, Di Giovanni et al., 2006; SZ, Di Pietro and Seamans, 2007). 5-HTergic neurons arise in mesencephalic/pontine regions (MB) including dorsal, median and rostral raphe nucleus, caudal linear nucleus, interpeduncular nucleus, B9 5-HTergic cell group and reticular formation and project to virtually every part of the brain including prefrontal (PFC), frontal (FC), parietal (PC) and occipital cortex (OC), cingulate (CING), septum, hippocampus (HIPP), parahippocampal gyrus (PHG), amygdala (AMYG), entorhinal cortex (EC), neostriatum (STR), ventral striatum (VS), substantia nigra, ventral tegmental area, thalamus (THAL), hypothalamus (HT), locus caeruleus and tuberomammillary nucleus (for review, see Hale and Lowry, 2011).
In recent surveys of all in vivo imaging studies, which, so far, had been conducted on 5-HTergic neurotransmission in acute AD, MDD, bipolar disorder (BD) and SZ (Nikolaus et al., 2010, 2012, 2014a), we found (1) a significant reduction of SERT in the MB of patients with AD relative to controls; (2) significant reductions of SERT in THAL and MB and a significant elevation of SERT in the insula (INS) of patients with MDD relative to controls; (3) significant elevations of SERT in CING and INS of depressed patients with BD relative to controls; (4) significant reductions of 5-HT1A receptors (5-HT1R) in MB and CING of patients with AD relative to controls; (5) a significant reduction of 5-HT1R in the MB of patients with MDD relative to controls; (6) significant reductions of 5-HT1R in MB and temporal cortex (TC) of patients with SZ relative to controls; (7) significant reductions of 5-HT2A receptors (5-HT2R) in prefrontal (PFC), frontal (FC), occipital cortex (OC) and CING of patients with MDD relative to controls; and (8) significant reductions of 5-HT2R in FC and TC of patients with SZ relative to controls.
In these surveys, however, AD, MDD, BD and SZ had been considered separately, and no comparison of regional SERT, 5-HT1R and 5-HT2R binding had been performed between disorders. Thus, for the present study, a new PubMed search was conducted in order to update the pool of investigations. Since the number of available publications on SERT, 5-HT1R and 5-HT2R binding in AD, MDD, BD and SZ had increased by a total of 27 investigations (AD: SERT, n=4, 5-HT1R, n=1; 5-HT2R, n=2; MDD: SERT, n=10, 5-HT1R, n=3, 5-HT2R, n=3; BD: 5-HT1R, n=2; SZ: SERT, n=1, 5-HT2R, n=1), a novel analysis was performed comparing (A) regional 5_HT synthesis as well as SERT, 5-HT1R and 5-HT2R binding separately in patients with AD, MDD, BD (depressive state [BDdep], manic state [BDman]) and SZ relative to healthy controls; and (B) regional SERT, 5-HT1R and 5-HT2R binding between patients with AD, MDD, BDdep, BDman and SZ.
Method
Selection of studies
A PubMed search was performed using the keywords ‘anxiety disorder’, ‘depression’, ‘bipolar disorder’, ‘schizophrenia’, ‘schizoaffective disorder’ and ‘schizophreniform disorder’ in combination with either ‘SERT’, ‘5-HT1 receptor’, ‘5-HT2 receptor’ or ‘5-HT synthesis’ and either ‘PET’ or ‘SPE(C)T’.
The search provided a total of 25 investigations on acute AD [277 patients, age: 36±10 years (mean±standard deviation), duration of disease: 13±6 years, Yale-Brown Obsessive-Compulsive score (Ybocs): 24±5; Hamilton Anxiety (HAMA) Rating Scale score: 17±9; 360 controls, age: 36±10 years], 74 investigations on acute MDD [1295 patients, age: 38±8 years, duration of disease: 10±7 years, Hamilton Depression Rating Scale (HDRS) score: 24±6; 1375 controls, age: 36±10 years], 12 investigations on acute BD [BDdep, n=10; BDman, n=2, 174 patients, age: 34±6 years, duration of disease: 14±8 years, HDRS score: 20±6; Young Mania Rating Scale (YMRS) score: 11±9; 211 controls, age: 33±3 years] and 25 investigations on acute SZ [345 patients, age: 25±10 years, duration of disease: 5±3 years, Positive and Negative Syndrome Scale (PANSS) score: 62±12; 286 controls, age: 28±10 years] published in peer-reviewed journals between 1991 and January 2015, in which patients with the primary diagnosis of AD [obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder (PD), phobia], MDD, BDdep, BDman or SZ were compared to healthy individuals, and in which quantitative data were communicated (Tables 1–4). Studies on subjects with post-traumatic stress disorder (PTSD; Bonne et al., 2005; Sullivan et al., 2013) were not included in this analysis, because – in contrast to endogenous AD such as OCD, PD, GAD or phobia – patients with PTSD per definition are exposed to a single or long-term extrinsic trauma (see the Discussion section). Rating scale scores, employed radioligand, comorbidities, smoking habits, medication prior to the investigation, disease duration, medication state at the time of the in vivo investigation and withdrawal times are listed in Tables 1–4, if specified in the individual scientific reports.
All in vivo investigations of synaptic constituents (SERT, 5-HT1A receptor, 5-HT2A receptor, 5-HT synthesis) on patients with acute anxiety disorder (AD) with either PET or SPECT.
| Study | Subtype | Mean anxiety score±SD | Constituent | Ligand | Comorbidity | Premedication | Smoking | Patients (m/f) | Mean age±SD (years) | Controls (m/f) | Mean age±SD (years) | Mean duration±SD (years) | Medication at the time of scanning | Duration of withdrawal (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adams et al., 2005 | OCD | YBOCS: 29±7 HDRS: n.s. | 5-HT2A | [18F]altanserin | None, MDD, GAD, phobia, migraine, personality disorder | None, psychotropics | n.s. | 7/8 | 38±16 | 7/8 | 39±n.s. | 1±0.8 | n | 28 |
| Cannon et al., 2006 | OCD | Ybocs: n.s. MADRS: n.s. HAMA: n.s. IDS-c: n.s. | SERT | [11C]DASB | BD | None, psychotropics, incl. sodium channel blockers, lithium | n.s. | 9 (gender n.s.) | 30±n.s. | 37 (gender n.s.) | 32±n.s. | n.s. | n | 21 |
| Hasselbalch et al., 2007 | OCD | Ybocs: 22±6 HDRS: 1±2 HAMA: 1±2 | SERT | [123I]β-CIT | None, MDD | None, psychotropics | n.s. | 4/5 | 32±11 | 3/6 | 33±8 | 14±10 | n | 28 |
| Hesse et al., 2005 | OCD | Ybocs: 25±9 BDI: 7±4 | SERT | [123I]β-CIT | None | None, psychotropics | n.s. | 8/7 | 32±12 | 7/3 | 40±13 | 16±9 | n | 168 |
| Hesse et al., 2011 | OCD | Ybocs: 21±4 BDI: 13±2 | SERT | [11C]DASB | None | None | n.s. | 11/8 | 36±13 | 10/11 | 38±13 | 13±8 | n | n.a. |
| Lanzenberger et al., 2007 | Social phobia | TSC: 51±9 SPS: 47±8 | 5-HT1A | [11C]WAY-10635 | None, agoraphobia | None, psychotropics, incl. SSRIs | 12/0 | 30±6 | 18/0 | 27±10 | n.s. | n | 21 | |
| Marksteiner et al., 2003 | OCD | Ybocs: 29 HDRS: 9 MMS: 17 | SERT | [123I]β-CIT | M. Alzheimer | Psychotropics, incl. SARI, bezodiazepines | n.s. | 0/1 | 82 | 5 (gender n.s.) | 76±4 | 2 | n | 8 |
| Maron et al., 2004b | PD | HAMA: 17±5 PDSS: 9±3 VAS: 49±25 | SERT | [123I]β-CIT | None, agoraphobia | None, psychotropics | n.s. | 1/7 | 35±16 | 1/7 | 34±7 | 12±13 | n | 14 |
| Maron et al., 2004a | GAD | MADRS: 12±3 HAMA: 25±6 VAS: n.s. | SERT | [123I]β-CIT | None | None, psychotropics | n.s. | 4/3 | 39±12 | 4/3 | 37±12 | n | 14 | |
| Maron et al., 2011 | PD | HAMA: 22±5 PDSS: 14±5 | SERT | [11C]MADAM | None, MDD, social anxiety disorder | None, psychotropics, incl. benzodiazepines | y/n | 5/6 | 31±9 | 12/12 | 37±7 | 4±3 | n | 14 |
| Matsumoto et al., 2010 | OCD | Ybocs: 22±7 | SERT | [11C]DASB | None | None, psychotropics, incl. SSRIs and SRIs | n.s. | 4/6 | 30±8 | 7/11 | 30±n.s. | 10±9 | n | 35 |
| Müller-Vahl et al., 2005 | OCD | STSS: 3±1 TSGSSMT: 3±1 TSGSCMT: 2±1 TSGSSVT: 2±1 TSGSCVT: 2±1 Customary rating scale: 2±1 | SERT | [123I]β-CIT | TS | SSRIs, neuroleptics | n.s. | 12/0 | 35±n.s. | 37 (gender n.s.) | 32±n.s. | n.s. | y/n | 0 |
| Nash et al., 2008 | PD | HAMA: 21±7 HDRS: 10±4 BDI: 14±9 | 5-HT1A | [11C]WAY-100635 | None, agoraphobia, MDD | None, psychotropics | n.s. | 9/0 | 38±11 | 19/0 | 41±13 | 5±5 | n | 21 |
| Neumeister et al., 2004 | PD | MADRS: 19±10 PDSS: 14±5 | 5-HT1A | [18F]FCWAY | None, MDD | None, psychotropics | n.s. | 6/10 | 35±10 | 5/10 | 35±10 | n.s. | n | 84 |
| Perani et al., 2008 | OCD | YBOCS: 29±4 YBOCSobs: 14±2 YBOCScomp: 15±n.s NIMHgocs: 11±1 CGI:5±1 | 5-HT2A | [11C]MDL100907 | None | None, benzodizepines | y/n | 6/3 | 31±7 | 12/3 | 21–75 | 2±0.05 | n | 5 half-lives |
| Pogarell et al., 2003 | OCD | HDRS: 23±8 | SERT | [123I]β-CIT | None | None, psychotropics | n | 5/4 | 34±12 | 9/1 | 28±5 | 12±n.s. | n | 84 |
| Reimold et al., 2007a | OCD | Ybocs: 21±9 BDI: 15±12 | SERT | [11C]DASB | None | None, SSRI, D3/4/ 5-HT2A/2B/2C/6/7/ M1/4/H1 antagonist | y/n | 5/4 | 44±9 | 11/8 | 44±10 | 22±8 | n | 70 |
| Simpson et al., 2003 | OCD | Ybocs: 20±4 HDRS: 6±4 | SERT | [11C]McN5652 | None, MDD, PTSD, phobia, anorexia, substance abuse | Psychotropics, incl. SSRIs | n.s. | 6/5 | 31±12 | 6/5 | 31±10 | 14±n.s. | n | 21 |
| Stengler-Wenzke et al., 2004 same subjecs as Stengler-Wenzke et al., 2006 (see below) | OCD | Ybocs: 32±3 BDI: 7±4 | SERT | [123I]β-CIT | None | None, psychotropics | n.s. | 4/6 | 29±9 | 7 (gender n.s.) | 30±10 | 14±4 | n | 168 |
| Stengler-Wenzke et al., 2006 same subjecs as Stengler-Wenzke et al., 2004 (see above) | OCD | Ybocs: 32±3 BDI: 7±4 | SERT | [123I]β-CIT | None | n.s. | n.s. | 4/6 | 29±9 | 7 (gender n.s.) | 30±10 | 14±4 | n | 168 |
| Van der Wee et al., 2004 | OCD | Ybocs: 23±4 Ybocsobs: 12±2 Ybocscomp: 11±3 HDRS: 8±4 LSAS: 74±14 | SERT | [11C]β-CIT | None | None, psychotropics | y/n | 11/4 | 31±9 | 11/4 | 32±10 | 12±7 | n | n.a. |
| Van der Wee et al., 2008 | GAD | HDRS: 8±2 | SERT | [11C]β-CIT | None | n.s. | y/n | 7/5 | 39±13 | 7/5 | 33±10 | 24±15 | n | n.s. |
| Wong et al., 2008 same subjects | OCD OCD | Ybocs: 17±7 BPRS: 23±3 YGTSSmt: 14±8 YGTSSpt: 10±7 Ybocs: 17±7 BPRS: 23±3 YGTSSmotor: 14±8 YGTSSphonic: 10±7 | SERT 5-HT2A | [11C]McN5652 [11C]MDL100907 | TS TS | None, psychotropics None, psychotropics | n.s. n.s. | 9 (gender n.s.) 9 (gender n.s.) | 34±9 34±9 | 9 (gender n.s.) 9 (gender n.s.) | 32±8 32±8 | n.s. n.s. | n n | 168 168 |
| Zitterl et al., 2007 | OCD | Ybocs: 25±5 | SERT | [123I]β-CIT | None | None, psychotropics | n.s. | 13/11 | 38±12 | 13/11 | 36±14 | 16±11 | n | 168 |
Given are the reference (in alphabetical order), the assessed disorder, mean rating scale scores (±SD), employed radioligands comorbidities, premedication, cigarette smoking habits, numbers of (male and female) patients and controls, mean age of patients and controls (±SD; years), mean duration of disease (±SD; years), medication state at the time of the investigation and duration of withdrawal (days).
BD, bipolar disorder; BDI, Beck’s Depression Inventory; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression Scale; D3/4, dopamine D3/4 receptor subtype; GAD, generalized anxiety disorder; H1, histamine H1 receptor subtype; HAMA, Hamilton Anxiety Rating Scale; HDRS, Hamilton Depression Rating Scale; IDS-c, Inventory of Depressive Symptoms-Clinician Rated; LSAS, Liebowitz Social Anxiety Scale; M1/4, muscarinic M1/4 receptor subtype; M., Morbus; MADRS, Montgomery Asberg Depression Rating Scale; MDD, major depressive disorder; MMS, Mini-Mental State Inventory; n, no; n.a., not applicable; n.s., not specified in the original investigation; NIMHgocs, NIMH Obsessive-Compulsive Rating Scale; OCD, obsessive-compulsive disorder; PD, panic disorder; PDSS, Shears Panic Disorder Severity Scale; PTSD, post-traumatic stress disorder; SARI, 5-HT receptor antagonist plus 5-HT transporter inhibitor; SERT, Serotonin Transporter; SPS, State Spielberger Scale; SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; STSS, Shapiro Tourette Syndrome Severity Scale; TS, Tourette syndrome; TSC, Trait Spielberger Scale; TSGSCMT, Tourette Syndrome Global Scale – Complex Motor Tics; TSGSCVT, Tourette Syndrome Global Scale – Complex Vocal Tics; TSGSCVT, Tourette Syndrome Global Scale – Simple Vocal Tics; TSGSSMT, Tourette Syndrome Global Scale – Simple Motor Tics; VAS, Visual Analogue Scale of Anxiety; y, yes; y/n, yes as well as no; Ybocs, Yale-Brown Obsessive-Compulsive Score; Ybocscomp, Yale-Brown Obsessive-Compulsive Score – Compulsive Score; Ybocsobs, Yale-Brown Obsessive-Compulsive Score – obsessive score; YGTSSmotor, Yale Global Tic Severity Scale – Motor Tics; YGTSSphonic, Yale Global Tic Severity Scale – Phonic tics; 5-HT1A, serotonin 5-HT1A receptor; 5-HT2A, serotonin 5-HT2A receptor; 5-HT2A/2B/2C/6/7, serotonin 5-HT2A/2B/2C/6/7 receptor subtype.
All in vivo investigations of synaptic constituents (SERT, 5-HT1A receptor, 5-HT2A receptor, 5-HT synthesis) on patients with acute major depressive disorder (MDD) with either PET or SPECT.
| Study | Subtype | Mean depression score±SD | Constituent | Ligand | Comorbidity | Premedication | Smoking | Patients (m/f) | Mean age±SD (years) | Controls (m/f) | Mean age±SD (years) | Mean duration±SD (years) | Medication at the time of scanning | Duration of withdrawal (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Agren et al., 1991 partly the same subjects as Agren et al., 1992 (see below) | MDD | HDRS: 21±4 | 5-HTsyn | [11C]HTP | n.s. | None, TCAs, SSRI, lithium | n.s. | 3/2 | 39±4 | 8/0 | 33±6 | n.s. | n | 10 |
| Agren et al., 1992 partly the same subjects as Agren et al., 1991 (see above) | MDD | n.s. | 5-HTsyn | [11C]HTP | n.s. | n.s. | n.s. | 6 (n.s.) | 40±9 | 8 (n.s.) | 35±7 | n.s. | n.s. | n.s. |
| Agren et al., 1993 | MDD | HDRS: 23±6 | 5-HTsyn | [11C]HTP | n.s. | TCAs, TeCA, lithium | n.s. | 5/3 | 38±6 | 11/0 | 33±6 | n.s. | n | 23 |
| Agren and Reibring, 1994 | MDD | n.s. | 5-HTsyn | [11C]HTP | n.s. | n.s. | n.s. | 8 (n.s.) | n.s. | 11 (n.s.) | n.s. | n.s. | n.s.. | n.s. |
| Attar-Lévy et al., 1999 same subjects | MDD MDD | HDRS: 54±6 MDRS: 34±7 BPRS: 45±10 HDRS: 34±2 BDI: 10±6 | 5-HT2A 5-HT2A | [18F]setoperone [18F]setoperone | n.s. n.s. | Antidepressants (incl. benzodiazepines) TCAs for 21–39 days | n.s. n.s. | 3/4 3/4 | 40±11 40±11 | 16/16 16/16 | 39±10 39±10 | 11±n.s. n.s. | y/n y | 0 0 |
| Amsterdam et al., 2013 partly the same subjects as Newberg et al., 2012 (see below) | MDD | HDRS: 20±3 | SERT | [123I]ADAM | None, substance abuse | Antipsychotics | n.s. | 15/5 | 41±13 | 7/3 | 45±11 | 20±n.s. | n | 365 |
| Audenaert et al., 2001 partly the same subjects as van Heeringen et al., 2003, (see below) | self-harm | HDRS: 16±10 | 5-HT2A | [123I]5-I-R91150 | MDD, brief psychotic disorder, adjustment disorder | Psychotropics (incl. benzodiazepines, barbiturates, anticonvulsants) | n.s. | 7/2 | 32±12 | 6/6 | 29 | n.s. | n | 180 |
| Baeken et al., 2011 partly the same subjects as Baeken et al., 2012 (see below) | MDD | HDRS: 26±4 | 5-HT2A | [123I]5-I-R91150 | n.s. | SSRIs, SNRIs, benzodizepines | n.s. | 8/13 | 45±12 | 8/13 | 42±13 | n.s. | y/n | 0 |
| Baeken et al., 2012 partly the same subjects as Baeken et al., 2011 (see above) | MDD MDD | HDRS: 27±3 HDRS: 22±7 | 5-HT2A 5-HT2A | [123I]5-I-R91150 [123I]5-I-R91150 | n.s. n.s. | TCAs, SNRIs, benzodiazepines n.s., presently medication-free | n.s. n.s. | 6/9 6/9 | 39±10 36±10 | 6/9 6/9 | 36±10 36±10 | 5±3 n.s. | y n | 0 n.s. |
| Bah et al., 2008 partly the same subjects as Ryding et al., 2006 (see below) | Self-harm | BSIC: >18 | SERT | [123I]β-CIT | None, MDD adjustment disorder | Antidepressants, antipsychotics | y/n | 9/0 | 41±15 | 9/0 | 41±15 | n.s. | n | 180 |
| Biver et al., 1997 | MDD | HDRS: 32±7 | 5-HT2A | [18F]altanserin | None, melancholia | Antidepressants (incl. benzodiazepines) | n.s. | 2/6 | 48±10 | 12/10 | 38±12 | n.s. | n | 10 |
| Cannon et al., 2007 | MDD | MADRS: 26±7 IDS-C: 33±9 | SERT | [11C]DASB | None, PD, substance abuse | Antidepressants (incl. SSRI and herbal preparations) | y/n | 5/13 | 35±9 | 9/25 | 33±8 | 19±10 | n | 21 |
| Catafau et al., 2006 | MDD | HDRS: >18 | SERT | [123I]ADAM | None | Antidepressants (incl. benzodiazepines) | n.s. | 4/6 | 36±11 | 7/3 | 36±11 | n.s. | n | n.a. |
| Dahlström et al., 2000 | MDD | n.s. | SERT | [123I]β-CIT | None, dysthymia, psychosis, separation anxiety disorder, GAD, OCD, ADHD, CD, PDD,TS, BPD, GID, anorexia | None, enhancers of DA and/or NA release | n.s. | 22/9 | 14±3 | 5/5 | 12±3 | n.s. | n | 900 |
| D’haenen et al., 1992 | MDD | HDRS: 23±5 | 5-HT2A | [123I]ketanserin | n.s. | Psychotropics | n.s. | 6/13 | 45±14 | 5/5 | 36±11 | n.s. | n | 21 |
| Drevets et al., 1999 | MDD | HDRS: 25±7 | 5-HT1A | [11C]WAY-100635 | None, BD, substance abuse | Psychotropics (incl. SSRIs) | y/n | 8 (n.s.) | n.s. | 4/4 | 35±14 | n.s. | n | 14 |
| Drevets et al., 2000 | MDD | HDRS: 27±7 | 5-HT1A | [11C]WAY-100635 | None, BD, substance abuse | Psychotropics (incl. SSRIs) | y/n | 5/7 | 36±10 | 4/4 | 35±14 | n.s. | n | 14 |
| Drevets et al., 2007 | MDD | HDRS: 21±8 STAI: 23±10 | 5-HT1A | [11C]WAY-100635 | None, substance abuse | Psychotropics | y/n | 5/6 | 31±8 | 4/4 | 32±12 | n.s. | n | 21 |
| Frey et al., 2010 | MDD | HDRS: 26±5 | 5-HTsyn | [11C]MT | None | Antidepressants | n | 12/13 | 40±10 | 12/13 | 36±11 | n.s. | n | 14 |
| Hammoud et al., 2010 | MDD | n.s. | SERT | [11C]DASB | HIV | SSRIs | n.s. | 9 (n.s.) | 42±6 | 9 (n.s.) | 47±4 | n.s. | n | 365 |
| Hasler et al., 2007 | MDD | BDI: 14±13 | 5-HT1A | [18F]FCWAY | Epilepsy, GAD, PD, phobia, OCD, substance abuse | n.s. | n.s. | 7/9 | 39±12 | 15/6 | 35±12 | 212 | n.s. | n.s. |
| Herold et al., 2006 | MDD | HDRS: 28±10 | SERT | [123I]ADAM | n.s. | Antidepressants, benzodiazepines | n.s. | 15/6 | 42±12 | 5/8 | 36±13 | n.s. | n | 60 |
| Hesse et al., 2009 | MDD | BDI: n.s. | SERT | [123I]FP-CIT | M. Parkinson | Antiparkinsonian medication, SSRIs | n.s. | 13/17 | 64±10 | 8/10 | 62±11 | n.s. | y | 0 |
| Hirvonen et al., 2008 partly the same subjects as Karlsson et al., 2010 and Karlsson et al., 2011 (see below) | MDD | HDRS: 18±3 BDI: 23±7 | 5-HT1A | [11C]WAY-100635 | None | Benzodiazepines, nonbenzodiazepine, GABAA agonists | n.s. | 8/13 | 40±9 | 7/8 | 33±8 | n.s. | n | 120 |
| Ho et al., 2013 | MDD | HDRS: 29±7 | SERT | [123I]ADAM | None | None, antidepressants, benzodiazepine | y/n | 13/27 | 36±13 | 8/4 | 32±10 | n.s. | y/n | 0 |
| Ichimiya et al., 2002 | MDD | HDRS: 19±8 BDI: 19±14 | SERT | [11C]McN 5652 | None | TCAs | n.s. | 7/0 | 44±14 | 21/0 | n.s. | n.s. | n | 42 |
| Joensuu et al., 2007 | MDD | HDRS: 19±6 MADRS: 28±7 | SERT | [123I]nor-β-CIT | None | n.s. | y/n | 5/24 | 28±9 | 3/16 | 31±9 | n.s. | y | 0 |
| Karlsson et al., 2010 partly the same subjects as Karlsoon et al., 2011 (see below) and Hirvonen et al., 2008 (see above) | MDD | HDRS: 18±3 BDI: 23±7 | 5-HT1A | [11C]WAY-100635 | n.s. | SSRIs | n.s. | 10/13 | 40±9 | 11/9 | 26±6 | n.s. | n | 1825 |
| Karlsson et al., 2011 same subjects as Karlsoon et al., 2010 (see above)and Partly the same subjects as Hirvonen et al., 2008 (see above) | MDD | HDRS: 18±3 BDI: 23±7 | 5-HT1A | [11C]WAY-100635 | n.s. | None, SSRI | n.s. | 10/13 | 40±9 | 11/9 | 26±6 | n.s. | n | 1825 |
| Kraus et al., 2014 | MDD | HDRS: 20±4 | SERT | [11C]WAY-100635 | n.s. | n.s. | n.s. | 4/12 | 44±8 | 16/9 | 32±11 | n.s. | n.s. | n.s. |
| Lehto et al., 2006 | MDD | HDRS: 30±8 | SERT | [123I]nor-β-CIT | None | None | n.s. | 5/24 | 29±9 | 2/16 | 31±9 | n.s. | n | n.a. |
| Lehto et al., 2008 | MDD | HDRS: 19±5 | SERT | [123I]nor-β-CIT | None, dysthymia | None | y/n | 2/17 | 27±5 | 3/16 | 31±9 | n.s. | n.a. | |
| Liik et al., 2013 | MDD | BDI: 15±4 EST-q: 16±3 | SERT | [123I]ADAM | Epilepsy | None | n.s. | 4/3 | 38±10 | 3/2 | 34±6 | n.s. | n | n.a. |
| Lothe et al., 2012 | MDD | n.s. | 5-HT1A | [11C]WAY-100635 | n.s. | None | n.s. | 1/5 | 37±8 | 3/15 | 23–48 years | n.s. | n | n.a. |
| Lundgren et al., 2009 | MDD | HDRS: 16±n.s. CGIS: 4–6 | SERT | [123I]ADAM | None | None, SSRIs | n.s. | 3/4 | 38±9 | 3/3 | 38±11 | .8±n.s. | n | 21 |
| Malison et al., 1998 | MDD | YDI: >17 | SERT | [123I]β-CIT | None, dysthymia, PD, ADHD substance abuse | None, TCAs, SSRIs, 5-HT2A antagonists, NA/DA reuptake inhibitors | n.s. | 7/8 | 44±10 | 7/8 | 45±11 | n.s. | n | 21 |
| Meltzer et al., 1999 partly the same subjects as Meyer et al., 2001 (see below) | MDD | HDRS: 20±4 | 5-HT2A | [18F]altanserin | Epilepsy, GAD, PD, phobia, OCD, substance abuse | None | n.s. | 4/7 | 66±6 | 4/6 | 70±5 | n.s. | n | n.a. |
| Messa et al., 2003 | MDD | HDRS: 23 ±6 | 5-HT2A | [18F]FESP | n.s. | None | n.s. | 7/12 | 39 | 11/9 | 36 | 2±n.s. | n | n.a. |
| Meyer et al., 1999 partly the same subjects as Meyer et al., 2001 (see below) | MDD | HDRS: 23±4 | 5-HT2A | [18F]setoperone | None | None, antidepressants, psychotropics | n.s. | 12/2 | 32±6 | 8/11 | 32±7 | n.s. | y/n | 180 |
| Meyer et al., 2001 partly the same subjects as Meyer et al., 1999 (see above) | MDD | HDRS: 22±4 | 5-HT2A | [18F]setoperone | None | None, antidepressants, psychotropics | n.s. | 12/7 | 31±6 | 8/11 | 32±7 | n.s. | n | 180 |
| Meyer et al., 2003 different patient cohorts | MDD self-harm | HDRS: >17 n.s. | 5-HT2A 5-HT2A | [18F]setoperone [18F]setoperone | n.s. BPD, MDD | None, antidepressants n.s. | n.s. n.s. | 22 (n.s.) 18 (n.s.) | 31±6 31±7 | 29 (n.s.) 29 (n.s.) | 31±7 31±7 | n.s n.s. | n n | 28 28 |
| Meyer et al., 2004a | MDD | HDRS: 20±4 | SERT | [11C]DASB | None | None, antidepressants | n | 9/11 | 35±11 | 10/10 | 35±11 | n.s. | n | 180 |
| Meyer et al., 2004b | MDD | n.s. | SERT | [11C]DASB | None,OCDPD | None, antidepressants | n.s. | 45 (n.s.) | n.s. | 37 (n.s.) | n.s. | n.s. | n | 30 |
| Miller et al., 2008 | MDD | HDRS: 24±9 | SERT | [11C]McN 5652 | None, AD | n.s. | n.s. | 2/10 | 42±15 | 21/20 | 39±16 | n.s. | n | 14 |
| Miller et al., 2009a partly the same subjects as Parsey et al., 2006a (see below) | MDD | HDRS: 26±8 BDI: 27±8 GAS: 53±13 BHS: 10±6 | 5-HT1A | [11C]WAY-100635 | Dysthymia, PD, PTSD, phobia | None | n.s. | 3/10 | 36±12 | 22/29 | 37±15 | n.s. | n | n.a. |
| Miller et al., 2009b | MDD | HDRS: 25±7 BDI: 23±11 GAS: 50±13 | SERT | [11C]McN 5652 | AD,PTSD | SSRIs, neuroleptics (incl. benzodiazepines) | n.s. | 6/17 | 39±14 | 22/21 | 39±16 | n.s. | n | 3 |
| Miller et al., 2013a | MDD | HDRS: 26±6 BDI: 26±9 | SERT | [11C]DASB | None, AD, anorexia nervosa, bulimia nervosa, substance abuse | Antidepressants, antipsychotics (incl. benzodiazepines) | n.s. | 23/28 | 40±11 | 15/16 | 33±11 | 21±n.s. | n | 3 |
| Miller et al., 2013b | MDD | HDRS: 25±5 BDI: 16±3 GAS: 60±6 | 5-HT1A | [11C]WAY-100635 | None, AD, anorexia nervosa, bulimia nervosa, substance abuse | Antidepressants (incl. 5-HTergic compounds, benzodiazepines) | n.s. | 7/17 | 35±14 | 22/29 | 37±14 | 0.9±n.s. | n | 3 |
| Mintun et al., 2004 partly the same subjects as Sheline et al., 2004 (see below) | MDD | HDRS: 23±4 | 5-HT2A | [18F]altanserin | None | Antidepressants (incl. SNRIs) | n.s. | 16/30 | 50±16 | 9/20 | 46±15 | n.s. | n | 28 |
| Murrough et al., 2011 | MDD | MADRS: 24±5 | 5-HT1B | [11C]P943 | None | n.s. | y/n | 5/5 | 31±10 | 5/5 | 31±11 | 14±n.s. | n.s. | n.s. |
| Newberg et al., 2005 | MDD | HDRS: >16 | SERT | [123I]ADAM | None | None, antidepressants (incl.MAOIs,SSRIs) | n.s. | 3/4 | 38 | 2/4 | 37±n.s. | 10±n.s. | n | 14 |
| Newberg et al., 2012 partly the same subjects as Amsterdam et al., 2013 (see above) | MDD | HDRS: 20±2 | SERT | [123I]ADAM | None, substance abuse | Antipsychotics | n.s. | 15/5 | 39±12 | 6/3 | 45±12 | n.s. | n | 168 |
| Nye et al., 2013 | MDD | HDRS: 18±4 | SERT | [11C]ZIENT | Self-harm, substance abuse | None, antidepressants (incl. SSRIs and TCAs), neuroleptics (incl. D2 antagonists and α1/2/D1–4/5-HT1/2/M1/2/H1 antagonists), St. John’s wort | n.s. | 7/4 | 38±13 | 64 | 21±2 | n.s. | n | 42 |
| Parsey et al., 2006a partly the same subjects as Miller et a., 2009a (see above) | MDD | HDRS: 26±7 BDI: 27±9 GAS: 52±11 | 5-HT1A | [11C]WAY-100635 | None, melancholic depression, PD, PTSD | None, benzodiazepines, SSRIs, SNRIs, TCAs, NA/DA reuptake inhibitors, MAOIs | n.s. | 7/21 | 38±13 | 19/24 | 38±15 | 15±n.s. | n | 3 |
| Parsey et al., 2006b | MDD | HDRS: 24±7 BDI: 23±12 GAS: 53±11 | SERT | [11C]McN 5652 | None, melancholic depression, dysthymia, PD, PTSD, GAD, phobia, BED | None, benzodiazepines, antidepressants | n.s. | 7/18 | 38±13 | 22/21 | 39±16 | 17±n.s. | n | 14 |
| Parsey et al., 2006c | MDD | HDRS: 23±9 | 5-HT1A | [11C]WAY-100635 | None,melancholic depression, PD, PTSD | Antidepressants | n.s. | 2/15 | 42±15 | 19/24 | 38±15 | n.s. | n | 14 |
| Politis et al., 2010 | MDD | HDRS: 17±3 BDI: 19±1 | SERT | [11C]DASB | M. Parkinson | n.s. | n.s. | 6/4 | 61±9 | 20/4 | 67±7 | 10±5 | n.s. | n.s. |
| Reimold et al., 2008 | MDD | BDI: 24±8 STAI: 58±14 | SERT | [11C]DASB | None | Antidepressants (incl. TCAs, SSRIs, TeCAs) | y/n | 5/5 | 48±10 | 11/8 | 44±10 | n.s. | n | 5 |
| Reivich et al., 2004 | MDD | HDRS: >16 | SERT | [11C]McN 5652 | None | Psychotropics (incl. SSRIs, MAOIs) | n.s. | 3/1 | 45±16 | 1/3 | 44±18 | n.s. | n | 14 |
| Rosa-Neto et al., 2004 | MDD | HDRS: 27±6 BDI: 30±9 | 5-HTsyn | [11C]MTrp | None, BD | n.s. | n.s. | 8/9 | 41±11 | 8/9 | 35±13 | n.s. | n | 14 |
| Ruhé et al., 2009 | MDD | HDRS: 24±5 | SERT | [123I]β-CIT | AD, dysthymia, Substance abuse | None, antidepressants | n.s. | 17/32 | 43±8 | 17/32 | 43±8 | 7±n.s. | n | 28 |
| Ryding et al., 2006 partly the same subjects as Bah et al.,2004 (see above) | Self-harm | BSIC: >18 | SERT | [123I]β-CIT | None, MDD adjustment disorder, substance abuse | Antidepressants, antipsychotics | n.s. | 10/2 | 39±14 | 10/2 | 39±14 | n.s. | n | 180 |
| Saarinen et al., 2005 | MDD | HDRS: 18 MADRS: 21 | SERT | [123I]nor-β-CIT | Dysthymia | None | n.s. | 0/1 | 20 | 10 (n.s.) | 26 | 9±n.s. | n | n.a. |
| Sargent et al., 2000 | MDD | HDRS: 17±3 BDI: 23 | 5-HT1A | [11C]WAY-100635 | None | None, antidepressants | n.s. | 15/0 | 38±14 | 17/1 | 36±8 | 5±n.s. | n | 441 |
| Sheline et al., 2004 partly the same subjects as Mintun et al., 2004 (see above) | MDD | HDRS: 23±4 | 5-HT2A | [18F]altanserin | None | Antidepressants (incl. SNRIs, 5-HT2A antagonists) | n.s. | 7/9 | 66±10 | 2/7 | 65±9 | n.s. | n | 14 |
| Smith et al., 2009 | MDD | HDRS: 25±6 BDI: 7±8 | H1,α2, 5-HT2A | [11C]mirtazepine | n.s. | TCAs, TeCAs, SSRIs, SNRIs, MAOIs, anticonvulsants, DA reuptake inhibitors, NA reuptake inhibitors, NA/DA reuptake inhibitors, 5-HT2A antagonists, HT2A/D2 antagonists, enhancers of DA and/or NA release, lithium | n.s. | 4/11 | 41±13 | 8/10 | 31±10 | n.s. | n | 450 |
| Staley et al., 2006 | MDD | BDI: 28±7 YDI: 25±5 | SERT | [123I]β-CIT | n.s. | None, benzodiazepines | y/n | 16/16 | 39±10 | 16/16 | 39±10 | 11±n.s. | n.s. | n.s. |
| Theodore et al., 2007 | MDD | BDI: 10±10 | 5-HT1A | [18F]FCWAY | Epilepsy | Anticonvulsants | n.s. | 30/15 | 35±11 | 7/3 | 32±9 | n.s. | n | 1 |
| Tolmunen et al., 2004 | MDD | HDRS: 15 | SERT | [123I]nor-β-CIT | n.s. | n.s. | n.s. | 0/6 | 27±6 | 10 (n.s.) | 26±6 | 0.9±0.6 | n.s. | n.s. |
| Uebelhack et al., 2006 | MDD | HDRS: 25±11 | SERT | [123I]ADAM | SAD | Antidepressants, antipsychotics (incl. benzodizepines, antihypertensives | n.s. | 18/12 | 44±14 | 6/8 | 37±21 | n.s. | n | 60 |
| van Heeringen et al., 2003 partly the same subjects as Audenaert et al., 2001 (see above) | Self-harm | HDRS: 16±10 | 5-HT2A | [123I]5-I-R91150 | MDD, brief psychotic disorder, adjustment disorder | Psychotropics (incl. benzodiazepines, barbiturates, anticonvulsants | n.s. | 7/2 | 32±11 | 7/6 | 29±8 | n.s. | n | 180 |
| Viinamäkki et al., 1998 | MDD | HDRS: 27 | SERT | [123I]β-CIT | BPD, substance abuse | Benzodiazepines | n.s. | 1/0 | 33 | 5/0 | 34±1 | n.s. | y | n.s. |
| Willeit et al., 2000 | SAD | GSS: 16±72 | SERT | [123I]β-CIT | None | None, SSRIs | n.s. | 2/9 | 31±8 | 2/9 | 29±6 | n.s. | n | 180 |
| Yatham et al., 2000 | MDD | HDRS: 27±6 | 5-HT2A | [18F]setoperone | n.s. | None, SSRIs, SARIs, SNRIs, NA/DA reuptake inhibitors | n.s. | 9/11 | 40±10 | 8/12 | 37±13 | n.s. | n | 14 |
| Yeh et al., 2014 | MDD | HDRS: 25±5 BSIC: 14±11 | SERT | 4-[18F]ADAM | None, self-harm | None | y/n | 8/9 | 35±8 | 8/9 | 35±7 | 5±n.s. | n | n.a. |
Given are the reference (in alphabetical order), the assessed disorder, mean rating scale scores (±SD), employed radioligands comorbidities, premedication, cigarette smoking habits, numbers of (male and female) patients and controls, mean age of patients and controls (±SD; years), mean duration of disease (±SD; years), medication state at the time of the investigation and duration of withdrawal (days).
AD, anxiety disorder; ADHD, attention-deficit hyperactivity disorder; BD, bipolar disorder; BDI, Beck Depression Inventory; BED, binge eating disorder; BPD, borderline personality disorder; BSIC, Beck Suicidal Intent Scale; CD, conduct disorder; CGIS, Clinical Global Impression Scale; D1–5, dopamine D1–5 receptor subtype; D2, dopamine D2 receptor; DMSloc, Depressive Mood Scale – loss of control subscale score; EST-q, Emotional State Questionnaire; GABA, μ-amino butyric acid; GAD, generalized anxiety disorder; GAS, Endicott’s Global Assessment Scale; GID, gender identity disorder; GSS, Global Seasonality Score; H1, histamine H1 receptor; HDRS, Hamilton Depression Rating Scale; HIV, human immunodeficiency virus; IDS-C, Inventory of Depressive Symptoms Clinician Rated; M1/2, muscarinic M1/2 receptor subtype; M., Morbus; MADRS, Montgomery-Asberg Depression Rating Scale; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; n, no; n.a., not applicable; n.s. not specified; NA, noradrenaline; OCD, obsessive-compulsive disorder; PD, panic disorder; PDD, pervasive developmental disorder; PTSD, posttraumatic stress disorder; SAD, schizoaffective disorder; SARI, 5-HT receptor antagonists plus SERT inhibitors; selective serotonin reuptake inhibitors; SERT, serotonin transporter; SNRI, 5-serotonin/noradrenaline reuptake inhibitors; SSRI; STAI, Spielberger State-Trait Anxiety Inventory; TCA, tricyclic antidepressants; TeCA, tetracyclic antidepressants; TS, Tourette syndrome; y, yes; y/n, yes/no; YDI, Yale Depression Inventory; α1/2, noradrenaline α1/2 receptor; 5-HT, serotonin; 5-HT1A, serotonin 5-HT1A receptor; 5-HT1B, serotonin 5-HT1B receptor; 5-HT2A, serotonin 5-HT2A receptor; 5-HTsyn, serotonin synthesis.
All in vivo investigations of synaptic constituents (SERT, 5-HT1A receptor, 5-HT2A receptor, 5-HT synthesis) on patients with acute bipolar disorder in depressive (BDdep) or manic (BDman) state with either PET or SPECT.
| Study | Disorder | Mean depression score±SD | Constituent | Ligand | Comorbidity | Premedication | Smoking | Patients (m/f) | Mean age±SD (years) | Controls (m/f) | Mean age±SD (years) | Mean duration±SD (years) | Medication at the time of scanning | Duration of withdrawal (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cannon et al., 2006 | BDdep | MADRS: 27±10 YMRS: 7±6 | SERT | [11C]DASB | None, OCD | None, lithium | n.s. | 6/12 | 30±9 | 13/24 | 32±9 | n.s. | n.s. | n.s. |
| Cannon et al., 2007 | BDdep | MADRS: 27±10 IDS-C: 33±12 | SERT | [11C]DASB | None, PD, psychosis, substance abuse | Antidepressants (incl. SSRI and herbal preparations) | y/n | 6/12 | 30±9 | 9/25 | 33±8 | 17±10 | n | 21 |
| Drevets et al., 1999 | BDdep | HDRS: 25±7 | 5-HT1A | [11C]WAY-100635 | None, substance abuse | Psychotropics, incl. SSRIs | n.s. | 8 (gender n.s.) | n.s. | 4/4 | 35±14 | n.s. | n | 14 |
| Drevets et al., 2007 | BDdep | HDRS: 21±8 STAI: 23±10 | 5-HT1A | [11C]WAY-100635 | None, substance abuse | Psychotropics | y/n | 1/4 | 36±14 | 4/4 | 32±12 | n.s. | n | 21 |
| Ichimiya et al., 2002 | BDdep | HDRS: 8±8 BDI: 6±7 | SERT | [11C] (+)-McN 5662 | None | None, TeCAs, D2 antagonist, DA/5-HT, antagonist plus NA reuptake inhibitor, SARI | n.s. | 6/0 | 42±9 | 21/0 | n.s. | n.s. | n | 14 |
| Lan et al., 2013 | BDdep | HDRS: 28±7 YMRS: 7±8 | 5-HT1A | [11C]WAY-100635 | None | Antidepressants, incl. SSRIs, benzodiazepines | y/n | 14/27 | 39±4 | 51 (gender n.s.) | n.s. | n.s. | n | 3 |
| Moses-Kolko et al., 2008 | BDdep/PPD | HDRS: 22±8 EPDS: 13±3 | 5-HT1A | [11C]WAY-100635 | None, PMDD, PD, GAD, OCD | None, psychotropics (incl. SRRIs) | y/n | 0/9 | 27±8 | 0/7 | 33±4 | n.s. | y/n | n.s. |
| Nugent et al., 2013 | BDdep | MADRS: 23±10 YMRS: 7±5 HAMA: 13±6 | 5-HT1A | [18F]FC-WAY | n.s. | Antidepressants | n.s. | 7/19 | 33±10 | 11/26 | 33±10 | 16±n.s. | y | 21 |
| Oquendo et al., 2007 | BDdep | HADRS: 24±6 BDI: 29±10 GAS: 49±10 | SERT | [11C] (+)-McN 5662 | None | None, MAOIs, DA reuptake inhibitors, 5-HT2A antagonists, anticonvulsants, atypical antipsychotics, neuroleptics, antiepileptics, benzodiazepines, GABA, analogues, lithium | n.s. | 10/8 | 39±16 | 22/19 | 38±10 | 20±n.s. | n | 1 |
| Sullivan et al., 2009 | BDdep | HDRS: 18±5 BDI: 26±11 YMRS: 6±7 GAS: 48±11 | 5-HT1A | [11C]WAY-100635 | None | Antidepressants, mood stabilizers (incl. SSRIs, benzodiazepines) | n.s. | 13/19 | 38±10 | 20/27 | 38±15 | 18±10 | n | 3 |
| Tolmunen et al., 2004 | BDman | HDRS: 15 | SERT | [123I]nor-β-CIT | n.s. | n.s. | n.s. | 0/1 | 25 | 10 (n.s.) | 26±6 | n.s. | n.s. | n.s. |
| Yatham et al., 2010 | BDman | YMRS: 27±8 | 5-HT2A | [18F]setoperone | None | Anticonvulsants for 6 weeks | n.s. | 3/7 | 34±12 | 3/7 | 34±6 | n.s. | n | 14 |
Given are the references (in alphabetical order), the assessed disorder, mean rating scale scores (±SD), employed radioligands, comorbidities, premedication, cigarette smoking habits, numbers of (male and female) patients and controls, mean age of patients and controls (±SD; years), mean duration of disease (±SD; years), medication state at the time of the investigation and duration of withdrawal (days).
BDdep, bipolar depression – depressive state; BDI, Beck’s depression inventory; BDman, bipolar depression – manic state; DA, dopamine; GABA, μ-amino butyric acid; GAD, generalized anxiety disorder; GAS, Endicott’s Global Assessment Scale; HAMA, Hamilton Anxiety Rating Scale; HDRS, Hamilton Depression Rating Scale; IDS-C, Inventory of Depressive Symptoms Clinician Rated; MADRS, Montgomery-Asberg Depression Rating Scale; MAOI, monoamine oxidase inhibitor; n, no; n.s.. not specified; NA, noradrenaline; OCD, obsessive-compulsive disorder; PD, panic disorder; PMDD, premenstrual dysphoric disorder; PPD, post partum depression; SARI, 5-HT receptor antagonists plus SERT inhibitors; TeCA, tetracyclic antidepressants; y, yes; y/n, yes/no; YMRS, Young Mania Rating Scale; 5-HT, serotonin; 5-HT2A, serotonin 5-HT2A receptor.
All in vivo investigations of synaptic constituents (SERT, 5-HT1A receptor, 5-HT2A receptor) on patients with acute psychosis with either PET or SPECT.
| Study | Subtype of Psychosis | Mean rating scale score±SD | Constituent | Ligand | Comorbidity | Medication | Smoking | Patients (m/f) | Mean age±SD (years) | Controls (m/f) | Mean age±SD (years) | Mean duration±SD (years) | Medication at the time of scanning | Duration of withdrawal (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bantick et al., 2004 same controls | SZ, SFD SZ, SAD | BPRS: 26±7 BDI: 9±7 STAI: 41±14 BPRS: 37±13 BDI: 15±6 STAI: 51±14 | 5-HT1A 5-HT1A | [11C]WAY-100635 [11C]WAY-100635 | None None | None, typical and atypical neuroleptics Current: clozapine | n.s. n.s. | 11/0 11/0 | 42±12 37±11 | 11/0 11/0 | 37±8 37±8 | 11±11 14±9 | y/n y | 0 0 |
| Catafau et al., 2011 | SZ | n.s. | 5-HT2A | [123I]R91150 | n.s. | Previous: n.s. Current: SB-773812 for 16–days | n.s. | 10/4 | 33±7 | 27/0 | 26±5 | n.s. | y | 0 |
| Erritzoe et al., 2008 | SZ | PANSS: 77±n.s. PANSSpos: 19±5 PANSSneg: 21±7 PANSSgen: 37±7 | 5-HT2A | [18F]altanserin | None, substance abuse | None, SSRIs, benzodiazepines | n.s. | 11/4 | 28±5 | 11/4 | 29±6 | n.s. | n | 1 |
| Frankle et al., 2005 | SZ, SAD | SAPS: 23±26 SANS: 42±18 HDRS: 14±12 | SERT | [11C]DASB | None | None, antipsychotics, incl.SSRI and benzodiazepine | n.s. | 9/1 | 34±10 | 9/1 | 31±8 | n.s. | y/n | 0 |
| Frankle et al., 2006 | SZ, SAD | PANSS: 60±14 PANSSpos: 16±5 PANSSneg: 15±7 HDRS: 14±7 | 5-HT1A | [11C]WAY-100635 | None | None, antipsychotics, incl. SSRI and benzodiazepine | n.s. | 16/6 | 32±10 | 15/3 | 32±8 | 7±n.s. | y/n | 0 |
| Gefvert et al., 1998 | SZ, SFD | PANSS: 56±n.s CGI: 4±n.s | 5-HT2A | [11C]MSP | n.s. | Previous: neuroleptics, incl. clozapine, benzodiazepines; current: quetiapine for 29 days | n.s. | 11/0 | 34±n.s | n.s. | n.s. | n.s.. | n | 1 |
| Jones et al., 2000 | SZ, SAD | n.s. | 5-HT2A | [123I]5-I-R91150 | Orofacial dyskinesia, akathisia | Previous: typical neuroleptics; current: quetiapine for at least 7 weeks | n.s. | 2/0 | 29±11 | 4/1 | 32±5 | n.s. | y | 0 |
| Jones et al., 2001 | SZ | SAPS: 16±25 SANS: 45±27 MADRS: 8±6 AIMS: 7±8 SA: 5±5 | 5-HT2A | [123I]5-I-R91150 | None | Previous: none, typical antipsychotics; current: quetiapine for at least 5 weeks | n.s. | 5/1 | 29±6 | 5/1 | n.s. | n.s. | y | 0 |
| Kim et al., 2015 | SZ | PANSSpos: n.s. PANSSneg: n.s. PANSSgen: n.s. CDSS: n.s. SWN: n.s. | SERT | [11C]DASB | n..s. | None, antipsychotics, incl. benzodiazepines | n.s. | 9/3 | 30±10 | 10/5 | 31±8 | 3±2 | n | 14 |
| Laruelle et al., 2000 | SZ | PANSSpos: 18±6 PANSSneg: 17±7 | SERT | [123I]β-CIT | None | None, antipsychotics, benzodiazepines | n.s. | 22/2 | 41±8 | 20/2 | 39±8 | n.s. | n | 142 |
| Lerond et al., 2013 same controls | SZ SZ | PANSS: 67±11 PANSSpos: 17±6 PANSSneg: 19±5 PANSSgen: 32±5 PANSS: 75±17 PANSSpos: 17±7 PANSSneg: 20±4 PANSSgen: 37±8 | 5-HT1A 5-HT1A | [18F]MPPF [18F]MPPF | n.s. n.s. | Current: risperidone, olanzapine for >3 months Current: aripiprazole for >3 months | n.s. n.s. | 6/3 4/6 | 29±8 26±5 | 10/9 10/9 | 27±7 27±7 | 5±5 5±3 | y y | 0 0 |
| Lewis et al., 1999 | SZ | n.s. | 5-HT2A | [18F]setoperone | n.s. | None, neuroleptics, benzodiazepines | n.s. | 10/3 | 31±7 | 11/15 | 31±7 | ±4 | y/n | 0 |
| Mamo et al., 2007 same patients and controls | SZ, SAD SZ, SAD | PANSS: 51±12 AIMS: 1±5 SA: 0±1 BAS: 0±1 CGI: 3±1 PANSS: 51±12 AIMS: 1±5 SA: 0±1 BAS: 0±1 CGI: 3±1 | 5-HT1A 5-HT2 | [11C]WAY-100635 [18F]setoperone | n.s. n.s. | Previous: typical and atypical neuroleptics; current: aripiprazole for at least 14 days Previous: typical and atypical neuroleptics; current: aripiprazole for at least 14 days | n.s. n.s. | 9/3 9/3 | 31±7 31±7 | 60 (gender n.s.) 60 (gender n.s.) | n.s. n.s. | 8±n.s. 8±n.s. | y y | 0 0 |
| Ngan et al., 2000 | SZ | SAPS: 8±n.s. SANS: 10±n.s. | 5-HT2A | [18F]setoperone | n.s. | None, benzodiazepines | n.s. | 5/1 | 22±n.s. | 4/3 | 23±n.s. | 1±2 | y | 0 |
| Okubo et al., 2000 | SZ | n.s. | 5-HT2 | [11C]MSP | n.s. | None, neuroleptics | n.s. | 17/0 | 27±6 | 18/0 | 28±6 | 6±n.s. | n | 14 |
| Reimold et al., 2007a,b | SZ, SAD | PASS: 50±10 PANSSpos: 11±3 PANSSneg: 14±4 PANSSgen: 26±5 EPS: 0±0 | 5-HT2A | [11C]MSP | None | Previous: psychotropics, SSRIs; current: flupenthixol, haloperidol or risperidone for at least 14 days; co-medication: benzodiazepines, anticholinergics | n.s. | 20/15 | 40±9 | 26 (gender n.s.) | n.s. | n.s. | n.s. | n.s. |
| Rasmussen et al., 2011 | SZ | PASS: 80±3 PANSSpos: 20±1 PANSSneg: 22±1 PANSSgen: 39±1 | 5-HT2A | [18F]altanserin | None, substance abuse | None, SSRIs, benzodiazepines | y/n | 30 (gender n.s.) | 26±6 | 30 (gender n.s.) | 26±6 | 6±n.s. | n | 1 |
| Tauscher et al., 2002 | SZ | n.s. | 5-HT1A | [11C]WAY-100635 | None | None, benzodiazepines | n.s. | 8/6 | 26±5 | 6/8 | 28±5 | n.s. | y/n | 0 |
| Travis et al., 1998 | SZ | PANSS: 67±18 SANS: 45±20 AIMS: 5±3 SA: 4±3 BAS: 3±4 GAF: n.s. | 5-HT2A | [123I]5-I-R91150 | n.s. | Current: clozapine or haloperidol for at least 6 weeks; co-medication: anticholinergics | n.s. | 10/1 | 28±7 | 5/1 | 30±3 | 8±7 | y | 0 |
| Trichard et al., 1998 | SZ, SFD | n.s. | 5-HT2A | [18F]setoperone | n.s. | None, neuroleptics, benzodiazepines | n.s. | 10/4 | 27±9 | 7/8 | 29±5 | 2±n.s. | n.s. | n.s. |
| Verhoeff et al., 2000 | SZ | PANSS: n.s. | 5-HT2A | [18F]setoperone | None | None, antipsychotics, benzodiazepines | n.s. | 11/2 | 31±7 | 15/20 | 30±7 | n.s. | n | 210 |
| Yasuno et al., 2004 | SZ, SFD | PANSS: 47±11 PANSSpos: 15±5 PANSSneg: 21±7 | 5-HT1A | [11C]WAY-100635 | None | None, antipsychotics, benzodiazepines | n.s. | 9/2 | 31±9 | 18/4 | 31±9 | 0.1–5 years | n | 30 |
Given are the reference (in alphabetical order), the assessed disorder, mean rating scale scores (±SD), employed radioligand(s), comorbidities, premedication, cigarette smoking habits, numbers of (male and female) patients and controls, mean age of patients and controls (±SD; years), mean duration of disease (±SD; years), medication state at the time of the investigation and duration of withdrawal (days).
AIMS, Abnormal Involuntary Movement Scale; BAS, Barnes Scale for Drug-induced Akathisia; BDI, Beck’s Depression Inventory; BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Rating Scale for Schizophrenia; CGI, Clinical Global Impression Scale; EPS, Extrapyramidal Symptoms Scale; HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery Asberg Depression Rating Scale; n, no; n.s., not specified in the original investigation; PANSS, Positive and Negative Syndrome Scale; PANSSgen, Positive and Negative Syndrome Scale – general psychopathology score; PANSSneg, Positive and Negative Syndrome Scale – negative syndrome scale; PANSSpos, Positive and Negative Syndrome Scale – positive syndrome scale; SAD, schizoaffective disorder; SANS, Andreasen’s Scale for Assessment of Negative Symptoms; SAPS, Andreasen’s Scale for Assessment of Positive Symptoms; SFD, schizophreniform disorder; SSRI, selective serotonin reuptake inhibitor, STAI, State-Trait Anxiety Inventory; SWN, Subjective Well-being under Neuroleptics Scale; SZ, schizophrenia; y, yes; y/n, yes/no; 5-HT1A, serotonin 5-HT1A receptor; 5-HT2A, serotonin 5-HT2A receptor.
Our analysis included all available in vivo investigations on patients with AD, MDD, BDdep, BDman and SZ in the acute stage of disease irrespective of the medication state (Tables 1–4). Data were evaluated as previously described (Nikolaus et al., 2010, 2012, 2014a,b). Percentual differences of SERT binding, 5-HT1R binding, 5-HT2R binding or 5-HT synthesis to the respective control groups of healthy individuals were computed for the following brain regions: STR (nucleus caudate, putamen), VS, globus pallidus (GP), THAL, HT, PFC (Brodmann areas 9–12, 46, 47 and 49), FC (PFC plus Brodmann areas 4 and 6), PC (Broadmann areas 3, 5, 7, 8, 39 and 40), TC (Brodmann areas 20–22, 38, 41 and 42), OC (Brodmann areas 17–19), CING, HIPP, PHG, AMYG, INS, EC, fusiform gyrus (FG), periaqueductal gray (PAG), MB (midbrain, pons) and cerebellum (CER). Left and right radioactivity accumulations were pooled if given separately in the original publication. If the authors had analyzed more than one area within STR, PFC, FC, PC, TC, OC and CING, the mean values of these data were computed for patients with AD, MDD, BDdep, BDman and SZ and the respective controls before calculating percentual differences.
Statistic calculations were performed using IBM SPSS Statistics 22 (IBM Germany, Ehningen, Germany). In the majority of cases, the Kolmogorov-Smirnov test for the normal distribution could not be performed, since the sum of weighted cases per disorder and brain region fell short of 5. Therefore, medians of percentual differences of SERT binding, 5-HT1R binding, 5-HT2R binding or 5-HT synthesis in the individual brain regions relative to controls were computed for patients with AD, MDD, BDdep, BDman and SZ. Differences between patients with AD, MDD, BDdep, BDman and SZ and the respective controls were assessed with the non-parametric Wilcoxon signed-rank test (α=0.05) for paired samples. Differences between the individual disorders (AD vs. MDD, AD vs. BDdep, AD vs. BDman, AD vs. SZ, MDD vs. BDdep, MDD vs. BDman, MDD vs. SZ, SZ vs. BDdep, SZ vs. BDman) were assessed with the non-parametric Mann-Whitney U-test (α=0.05) for unrelated samples. No corrections were made for multiple comparisons. As implied by the outcome of our previous surveys on AD, MDD and SZ (Nikolaus et al., 2009, 2010, 2012, 2014a,b), significance tests were performed one-sidedly.
Results
Comparison between patients and controls
AD
Significant reductions of SERT (Figure 1) were observed in THAL (-10%, p, 0.0265), AMYG (-7%, p, 0.0185) and MB (-13%, p, 0.014) relative to healthy individuals. In the TC, a decrease was detected, which marginally failed to reach statistical significance (-21%, p, 0.0605). 5-HT1R (Figure 2) were significantly lowered in FC (-13%, p, 0.051), CING (-24%, p, 0.0185), HIPP (-15%, p, 0.051), AMYG (-22%, p, 0.051), INS (-23%, p, 0.051) and MB (-29%, p, 0.0185). In turn, 5-HT2R (Figure 3) were significantly elevated in the TC (+8%, p, 0.051).
State of in vivo findings on SERT binding in anxiety disorder (AD), major depressive disorder (MDD), the depressive state of bipolar disorder (BDdep), the manic state of bipolar disorder (BDman) and schizophrenia (SZ). Considered were 19 studies on AD (207 patients, age: 36±12 years; 269 controls, age: 37±11 years), 38 studies on MDD (694 patients, age: 38±9 years; 700 controls, age: 37±10 years), 4 studies on BDdep (60 patients, age: 35±6 years; 133 controls, age: 34±3 years), 1 study on BDman (1 patient, age: 25 years; 1 control, age: 26 years) and 3 studies on SZ (46 patients, age: 35±6 years; 47 controls, age: 34±5 years), in which SERT was assessed in neostriatum (STR), ventral striatum (VS), hypothalamus (HT), thalamus (THAL), prefrontal cortex (PFC), frontal cortex (FC), parietal cortex (PC), temporal cortex (TC), occipital cortex (OC), cingulate (CING), hippocampus (HIPP), amygdala (AMYG), insula (INS), entorhinal cortex (EC), midbrain/pons (MB), periaqueductal gray (PAG) and cerebellum (CER). The box plots give medians, 25-/75-percentiles and 5-/95-percentiles of the individual synaptic constituents in the investigated brain regions expressed as percentages of control values. The circles represent the percentages of control values in the individual investigations (white circles, percentual difference relative to controls not significant in the original investigation; black circles, percentual difference relative to controls significant in the original investigation with a probability of at least 0.05). Asterisks indicate significant differences of the pooled samples of AD, MDD, BDdep, BDman or SZ patients relative to the pooled samples of controls (Wilcoxon signed-rank test, one-sided, α=0.05) and significant differences between pooled samples of AD, MDD BDdep, BDman or SZ (Mann-Whitney U-test, one-sided, α=0.05).
State of in vivo findings on 5-HT1R binding in anxiety disorder (AD), major depressive disorder (MDD), the depressive state of bipolar disorder (BDdep), and schizophrenia (SZ). Considered were 3 studies on AD (37 patients, age: 34±4 years; 52 controls, age: 34±7 years), 14 studies on MDD (245 patients, age: 37±3 years; 316 controls, age: 32±10 years), 5 studies on BDdep (95 patients, age: 35±6 years; 121 controls, age: 35±3 years), and 8 studies on SZ (100 patients, age: 32±5 years; 144 controls, age: 31±4 years), in which 5-HT1R were assessed in neostriatum (STR), globus pallidus (GP), prefrontal cortex (PFC), frontal cortex (FC), parietal cortex (PC), temporal cortex (TC), occipital cortex (OC), cingulate (CING), hippocampus (HIPP), amygdala (AMYG), insula (INS), parahippocampal gyrus (PHG), fusiform gyrus (FG), midbrain/pons (MB) and cerebellum (CER). The box plots give medians, 25-/75-percentiles and 5-/95-percentiles of the individual synaptic constituents in the investigated brain regions expressed as percentages of control values. The circles represent the percentages of control values in the individual investigations (white circles, percentual difference relative to controls not significant in the original investigation; black circles, percentual difference relative to controls significant in the original investigation with a probability of at least 0.05). Asterisks indicate significant differences of the pooled samples of AD, MDD, BDdep or SZ patients relative to the pooled samples of controls (Wilcoxon signed-rank test, one-sided, α=0.05) and significant differences between pooled samples of AD, MDD BDdep or SZ (Mann-Whitney U-test, one-sided, α=0.05).
State of in vivo findings on 5-HT2R binding in anxiety disorder (AD), major depressive disorder (MDD), the manic state of bipolar disorder (BDman), and schizophrenia (SZ). Considered were 3 studies on AD (33 patients, age: 34±4 years; 39 controls, age: 35±5 years), 19 studies on MDD (287 patients, age: 39±9 years; 279 controls, age: 37±10 years), 1 study on BDman (10 patients, age: 34±12 years; 10 controls, age: 34±6 years), and 14 studies on SZ (199 patients, age: 30±4 years; 216 controls, age: 28±3 years), in which 5-HT2R were assessed in neostriatum (STR), globus pallidus (GP), prefrontal cortex (PFC), frontal cortex (FC), parietal cortex (PC), temporal cortex (TC), occipital cortex (OC), cingulate (CING), hippocampus (HIPP), amygdala (AMYG), insula (INS), parahippocampal gyrus (PHG), fusiform gyrus (FG), midbrain/pons (MB) and cerebellum (CER). The box plots give medians, 25-/75-percentiles and 5-/95-percentiles of the individual synaptic constituents in the investigated brain regions expressed as percentages of control values. The circles represent the percentages of control values in the individual investigations (white circles, percentual difference relative to controls not significant in the original investigation; black circles, percentual difference relative to controls significant in the original investigation with a p of at least 0.05). Asterisks indicate significant differences of the pooled samples of AD, MDD, BDman or SZ patients relative to the pooled samples of controls (Wilcoxon signed-rank test, one-sided, α=0.05) and significant differences between pooled samples of AD, MDD, BDman or SZ (Mann-Whitney U-test, one-sided, α=0.05).
MDD
Significant reductions of SERT (Figure 1) were found in STR (-6%, p, 0.05), THAL (-12%, p, 0.002), PFC (-15%, p, 0.054), AMYG (-15%, p, 0.02) and MB (-8%, p, 0.0025) relative to healthy individuals, whereas in the INS (+9%, p, 0.0185), a significant elevation was detected. A significant increase of 5-HT1R (Figure 2) was observed in the GPH (+23%, p, 0.048), whereas in the MB (-17%, p, 0.038), HT1R were significantly diminished. Significant decreases of 5-HT2R (Figure 3) were detected in PFC (-6%, p, 0.0055), FC (-6%, p, 0.003), OC (-4%, p, 0.0145) and CING (-7%, p, 0.0045). No significant alterations of 5-HT synthesis were observed relative to controls (data not shown).
BDdep
Significant elevations of SERT (Figure 1) were observed in CING (+19%, p, 0.051) and INS (+13%, p, 0.051) relative to healthy individuals. 5-HT1R were significantly augmented in HIPP (+21%, p, 0.051), AMYG (+19%, p, 0.051) and PHG (+32%, p, 0.051). No investigation of 5-HT2R was conducted on patients with BDdep.
BDman
In patients with BDman, SERT binding was assessed merely once yielding a significant 18% elevation in MB relative to controls. Also 5-HT2R binding was determined in merely one investigation showing significant 20% decreases in FC, PC, TC, OC, CING, INS and FG. No investigation of 5-HT1R was conducted in BDman.
SZ
SERT (Figure 1) was not significantly different between patients and controls. Significant decrements of 5-HT1R were observed in TC (-6%, p, 0.02), OC (-5%, p, 0.051), AMYG (-12%, p, 0.051) and MB (-5%, p, 0.0035). 5-HT2R (Figure 3) were significantly diminished in FC (-25%, p, 0.0005), TC (-19%, p, 0.0105) and OC (-5%, p, 0.0475).
Comparison between disorders
SERT
SERT (Figure 1) was reduced in the TC (-14%, p, 0.076) of patients with AD compared to patients with MDD; the difference, however, marginally failed to reach statistical significance. Further decrements were observed in the THAL (-28%, p, 0.078) of patients with AD compared to patients with BDdep and in the MB (-31%, p, 0.074) of patients with AD compared to patients with BDman, which also did not reach statistical significance. There was neither a significant difference of SERT binding between AD and SZ, nor between MDD and SZ and SZ and BDman.
5-HT1R
5-HT1R (Figure 2) were significantly diminished in FC (-11%, p, 0.0485), CING (-8%, p, 0.0385), AMYG (-49%, p, 0.0215) and INS (-21%, p, 0.02) of patients with AD compared to patients with MDD. The decrease in the PHG (-17%, p, 0.072) failed to reach statistical significance. Moreover, 5-HT1R were significantly lowered in FC (-16%, p, 0.023), CING (-6%, p, 0.025) and MB (-19%, p, 0.0195) of patients with AD compared to patients with SZ, while the decrease in the AMYG (-8%, p, 0.065) marginally failed to reach statistical significance. 5-HT1R were elevated in the TC (+7%, p, 0.067) of patients with AD compared to patients with SZ; the observed difference, however, did not reach statistical significance. 5-HT1R in the INS (-24%, p, 0.0415) of patients with AD were significantly decreased compared to those with BDdep, while decrements in HIPP (-32%, p, 0.0605) and AMYG (-39%, p, 0.0605) did not reach statistical significance. Furthermore, a decline of 5-HT1R was found in the AMYG (-31%, p, 0.065) of patients with SZ compared to those with BDdep, which, likewise, failed to reach statistical significance. There were no significant differences of 5-HT1R binding between MDD and SZ.
5-HT2R
5-HT2R (Figure 3) were significantly increased in the TC (+10%, p, 0.025) of patients with AD compared to those with MDD, while the elevation in the CING (+9%, p, 0.058) marginally failed to reach statistical significance. In patients with AD, 5-HT2R binding in FC (+27%, p, 0.026) and TC (+27%, p, 0.034) was significantly increased compared to patients with SZ. The elevation in the OC (+10%, p, 0.0715) did not reach statistical significance. Moreover, 5-HT2R binding in the FC (+20%, p, 0.025) was significantly augmented in patients with MDD compared to those with SZ.
Discussion
Summary of findings
SERT
The most extensive decline of SERT relative to controls was observed in MDD involving both neocortical (PFC) and subcortical regions (MB, STR, THAL, AMYG). In AD, SERT decline relative to controls was confined to MB, THAL and AMYG, whereas no decline of SERT binding was observed in SZ. Moreover, in contrast to AD and SZ, increases of SERT relative to healthy individuals were detected in the INS of patients with MDD and in CING and INS of patients with BDdep, while investigations on BDman yielded evidence of increased mesencephalic SERT.
A comparison between disorders yielded no significant differences of SERT binding. However, there was a trend towards a reduction of SERT in the TC of patients with AD compared to those with MDD, in the THAL of patients with AD compared to those with BDdep, in the MB of patients with AD compared to those with BDman, and in THAL and HIPP of patients with MDD compared to those with SZ.
5-HT1R
The most extensive decline of 5-HT1R relative to controls was observed in AD involving neocortex (FC), CING, MB and various limbic regions (HIPP AMYG, INS). In SZ, decreases of 5-HT1R relative to controls were observed in the MB. In contrast to AD, however, 5-HT1R were reduced in TC and OC, but not in the FC. Limbic reductions, moreover, were less extensive, merely affecting the AMYG. Similar to AD and SZ, mesencephalic 5-HT1R were lowered in MDD relative to controls. In contrast to AD and SZ, however, no reductions of limbic 5-HT1R were detected. Rather, 5-HT1R were found to be elevated in the PHG relative to controls. Augmentations of limbic 5-HT1R relative to normal subjects were more extensive in BDdep compared to MDD with increases additionally involving HIPP and AMYG. No investigations of 5-HT1R were conducted on BDman.
A comparison between disorders revealed significant reductions of 5-HT1R in the FC, CING, AMYG and INS of patients with AD compared to those with MDD, in the INS of patients with AD compared to those with BDdep and in the FC, CING, MB and AMYG of patients with AD compared to those with SZ, whereas 5-HT1R were elevated in the TC of patients with AD compared to those with SZ. Moreover, there was a trend towards a reduction of 5-HT1R in the PHG of patients with AD compared to those with MDD, in the HIPP of patients with MDD compared to those with BDdep and in the AMYG of patients with SZ compared to those with BDdep.
5-HT2R
The most extensive decline of 5-HT2R relative to controls was found in BDman involving the whole neocortex (FC, PC, TC, OC) as well as CING, INS and FG. Evidence, however, is limited, since findings were obtained in merely one study. In SZ, 5-HT2R reductions relative to normal subjects were confined to the neocortex (FC, TC, OC), while in MDD, no reductions were detected in the TC. In contrast to SZ, however, 5-HT2R, additionally, were diminished in PFC and CING. Contrary to MDD, BDman and SZ, an elevation of temporal 5-HT2R relative to controls was observed in AD. No investigations of 5-HT2R were available on BDdep.
A comparison between disorders revealed increases of 5-HT2R in the TC of patients with AD compared to those with MDD, in the FC and TC of patients with AD compared to those with SZ and in the FC of patients with MDD compared to those with SZ. Moreover, there was a trend towards the elevation of 5-HT2R in the CING of patients with AD compared to those with MDD and in the OC of patients with AD compared to those with SZ.
5-HT synthesis
5-HT synthesis was merely assessed in patients with MDD. No alterations were detected relative to healthy controls.
Role of 5-HT in neuropsychiatric disorders
AD
Patients with AD displayed significant reductions of SERT in THAL, AMYG and HIPP, reductions of 5-HT1R in FC, CING, MB, HIPP, AMYG and INS, and a significant elevation of 5-HT2R in TC. In addition, a previous analysis of DA and GABA function in AD had revealed significant decreases of D2R in STR and GABAAR in STR, FC, TC, OC, CING, AMYG and INS (Nikolaus et al., 2010, 2014b).
If we proceed from the assumption that regulatory mechanisms aim to maintain functional homeostasis throughout the central nervous system (Andrews et al., 2011), we may tentatively surmise the following interactions between 5-HT, DA and GABA in acute AD: first, DA is known to inhibit the release of GABA via D2R action (Girault et al., 1986). Consequently, the observed desensitization of inhibitory striatal D2R may lead to an increase of available GABA in the STR as well as in the projection areas of striatothalamocortical GABAergic neurons; this is consistent with the detected decreases of striatal, neocortical and limbic GABAAR in AD.
Secondly, GABA exerts inhibitory effects on both DA (Grace and Bunney, 1979) and 5-HT neurons (Luparini et al., 2004). The desensitization of GABAAR in STR, FC, TC, OC, CING, AMYG and INS, thus, will diminish the inhibitory GABAergic input to DA and 5-HT neurons leading to an elevation of both DA and 5-HT concentrations throughout the mesolimbocortical system.
The desensitization of (inhibitory) D2 heteroreceptors in striatal tissues of AD may be interpreted as an adaptive response to the increase of available DA. Likewise, the desensitization of 5-HT1 heteroreceptors in MB, FC, CING, HIPP, AMYG and INS can be conceived to compensate for the increase of 5-HT concentrations. Since 5-HT acts to facilitate DA release via several subtypes including 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT3R and 5-HT4R (for review, see Alex and Pehek, 2007), the 5-HT1R desensitization in MB, FC, CING, HIPP, AMYG and INS is likely to elicit an adaptive decline of DA efflux in these regions. Moreover, the decrease of available inhibitory D2 in the STR and of 5-HT1 autoreceptors in FC, CING, HIPP, AMYG and INS can be presumed to entail a reduction of feedback inhibition resulting in a further enhancement of striatal DA and midbrain, frontal, cingulate and limbic 5-HT release, which is likely to fuel DAergic neurotransmission in the target regions of ascending DAergic striatothalamocortical fibers as well as 5-HTergic neurotransmission in both ascending and descending fibers of the mesolimbocortical system. Conversely, the decrease of (inhibitory) D2 and 5-HT1 heteroreceptors may be assumed to counterbalance the increase of DAergic/5-HTergic activity by reducing the inhibitory actions exerted by these binding sites. This is likely to result in a net overweight of excitatory input to the target regions of DAergic and 5-HTergic projections.
Taken together, 5-HTergic function in acute AD may be characterized by an abundance of 5-HT and a net overweight of excitatory input (due to the desensitization of inhibitory 5-HT1R binding sites) to the target regions of ascending and descending 5-HTergic projections. This is consistent with the 5-HT hypothesis of AD proposing increased 5-HTergic activity (for review, see Lowry et al., 2005). In particular, the Deakin/Graeff theory (Deakin and Graeff, 1991) surmises different pathways controlling behavioral responses to aversive stimuli. Thereby, the dorsal raphe periventricular tract is supposed to inhibit ‘fight-or-flight’ responses by stimulation of 5-HT1AR and/or 5-HT2AR. Disinhibition of this pathway is believed to result in bouts of sympathetic and behavioral arousal comparable to PD (for review, see Paul and Lowry, 2013). The mesencephalic 5-HT1R desensitization observed in the present analysis and the resulting disinhibition, thus, are in line with the hypothesized 5-HT1AR dysfunction in the dorsal raphe periventricular tract. Moreover, according to the Deakin/Graeff hypothesis, risk assessment and avoidance behaviors are facilitated by the dorsal raphe forebrain bundle tract via activation of the 5-HT2A/2CR and 5-HT3R binding sites, which is in agreement with the net overweight of excitatory input to the neocortical and limbic target regions of mesencephalic efferents.
In the present analysis, SERT binding was found to be decreased in MB, THAL and AMYG. This implies that SERT dysfunction in these regions at least may add to the increased availability of 5-HT caused by the desensitization of the D2R and GABAAR binding sites. Moreover, 5-HT2R binding was unaltered throughout most part of the neocortex with a significant elevation in the TC. Although the latter finding must be viewed with caution, since it was obtained on a pool of merely two studies, it may not be dismissed that sensitization/desensitization mechanisms of 5-HT2R binding sites are basically disturbed impeding adaptation to altered neocortical 5-HT levels. This possibility is underlined by the results of several experiments indicating an association between HTR2A gene variants and psychiatric disorders including AD (for review, see Serretti et al., 2007).
As follows from Table 1, all but one study had been conducted on patients who were drug-free at the time of scanning. Withdrawal times had not always been specified; according to the reports in which they had been given, they lay between 8 and 168 days. Thus, the effect of precedent anxiolytic treatment on the outcome of the present analysis is difficult to gauge. Further in vivo investigations are needed, in which SERT, 5-HT1R and/or 5-HT2R binding are measured before, under and after acute medication with anxiolytic compounds in order to assess the effect of treatment(s) on receptor/transporter regulation states and to relate it to the acute or remitted stage of the disease.
MDD and BD
Patients with MDD displayed significant reductions of SERT in STR, THAL, PFC, MB and AMYG, a significant elevation of SERT in the INS, a significant reduction of 5-HT1R in the MB, a significant elevation of 5-HT1R in the PHG and significant reductions of 5-HT2R in CING, PFC, FC and OC. Previous analyses had revealed no alterations of DA and GABA receptor binding sites in any of the investigated brain regions but an increase of DA synthesis in the FC (Nikolaus et al., 2012, 2014b). Patients with BDdep showed significant increases of cingulate and insular SERT as well as hippocampal, amygdalar and parahippocampal 5-HT1R binding sites, whereas in patients with BDman, 5-HT2R were significantly diminished in FC, PC, TC, OC, CING, INS and FG. Previous analysis of both BDdep and BDman, in addition, had shown a trend towards elevated striatal D2R and reduced frontal D1R binding (Nikolaus et al., 2012). GABAAR binding has so far neither been assessed in patients with BDdep nor in those with BDman.
In the present study, 5-HT synthesis did not differ between patients with MDD and healthy controls. Moreover, since no impairment of D2R or GABAAR function was detected, no elevation of 5-HT release due to D2R and GABAAR desensitization can be inferred. Still, however, SERT binding was reduced in MB as well as STR, THAL, PFC and AMYG of patients with MDD. Given the known association between MDD and variations of the SERT gene SLC6A4 (for review, see Serretti and Mandelli, 2008), it is not unlikely that SERT hypofunction constitutes the initial deficit in MDD leading to an abundance of 5-HT throughout the mesolimbocortical system.
First, the observed desensitization of mesencephalic 5-HT1 heteroreceptors may be conceived to compensate for the increase of 5-HT levels by reducing inhibitory neurotransmission, which – as in AD – is likely to result in a net overweight of excitatory input to the target regions of ascending 5-HTergic projections. Secondly – as in AD – the desensitization of mesencephalic 5-HT1 autoreceptors can be assumed to lead to a reduction of feedback inhibition resulting in an enhancement of 5-HT release and a further elevation of mesencephalic 5-HT levels. In contrast to AD, however, the resulting net overweight of excitatory 5-HTergic input to the neocortical and cingulate projection areas causes an adaptive desensitization of 5-HT2R in PFC, FC, OC and CING leading to a compensatory reduction of excitatory neocortical and cingulate neurotransmission.
As mentioned above, 5-HT stimulates DA release via several subtypes including the 5-HT2AR (for review, see Alex and Pehek, 2007). Since 5-HT2R are desensitized in PFC, FC, OC and CING, it may be concluded that DA efflux is diminished in these regions in acutely depressed patients. Given the higher expression of D1R relative to D2R in neocortical tissues (Palacios et al., 1988), the reduction of available DA can be inferred to induce a net reduction of excitatory action in the descending corticothalamostriatal fibers, which may be conceived to reflect an additional adaptation to the elevation of excitatory neurotransmission.
Our previous analysis of in vivo imaging studies on patients with BDdep had revealed an elevation of striatal D2R as well as a reduction of frontal D1R binding sites. Moreover, muscarinic M2R were found to be diminished in PFC, FC, OC as well as CING (Nikolaus et al., 2012). DA inhibits 5-HT efflux via the D2R binding site (Ferré et al., 1994), whereas acetylcholine facilitates 5-HT release via both muscarinic and nicotinic receptors (Marchi et al., 1988). Thus, it may be concluded that the striatal increase of D2R and the neocortical and cingulate decrease of M2R jointly act to decrease 5-HT concentrations throughout the mesolimbocortical system.
In the CING and INS of patients with BDdep, SERT binding was elevated relative to controls, which, for one, may be interpreted in terms of the increased availability of 5-HT in these regions. If this be the case, the reduction of 5-HT efflux effected by the decrease of the D2R and M2R binding sites would reflect an adaptive mechanism compensating for the abundance of 5-HT. This is unlikely, however, since the sensitization of hippocampal, amygdalar and parahippocampal 5-HT1 auto- and hetereoreceptors, rather, indicates a shortage of available 5-HT. The sensitization of limbic 5-HT1 heteroreceptors, for one, may be conceived to counteract this shortage by increasing inhibitory neurotransmission, which is likely to result in a net reduction of excitatory input to the target regions of ascending and descending 5-HTergic fibers. Secondly, however, the sensitization of limbic 5-HT1 autoreceptors may enhance feedback inhibition entailing a reduction of 5-HT release and a further decline of limbic 5-HT levels. As a matter of fact, this effect is likely to be aggravated in the INS by the observed elevation of SERT binding sites. Since 5-HT action stimulates DA release, and 5-HT1R binding sites are sensitized in HIPP, AMYG and PHG, it, furthermore, may be surmised that DA efflux is increased in these regions leading to an augmentation of DAergic activity in ascending limbocortical fibers. This conjecture is supported by the desensitization of D1R in the FC of patients with BDdep.
Strikingly, in MDD, the desensitization of mesencephalic 5-HT1A auto- and heteroreceptors was accompanied by a sensitization of parahippocampal 5-HT1R binding sites. This corresponds to the increase of 5-HT1R, which was observed in the limbic system of patients with BDdep. Thus, the same line of events – sensitization of parahippocampal 5-HT1 heteroreceptors leading to an increase of inhibitory input and sensitization of parahippocampal 5-HT1 autoreceptors leading to a decline of 5-HT levels – also may be assumed to take place in MDD. Altogether, this implies an interaction of limbic and mesencephalic 5-HT function in MDD, which is not present in BDdep. Thereby, it can be hypothesized that, in MDD, the net excitatory influence of 5-HTergic projections ascending from the MB to limbic and neocortical target regions counterbalances the inhibitory influence of 5-HTergic fibers projecting from the limbic system to the neocortex. Thereby, it remains inconclusive, to which degree the net excitation exerted by the MB on the neocortex counteracts the inhibition exerted by the limbic system, and to which degree the excitatory effects exerted by the MB on the limbic system, rather, enhance the inhibitory actions of the limbocortical efferents. Possibly, the mesencephalic-limbic loop even acts in conjunction with the desensitization of neocortical 5-HT2R binding sites resulting in a net inhibition of the neocortex.
In contrast to BDdep, where mesencephalic SERT binding was unaffected, patients with BDman displayed an increase of SERT in this region. Although this finding must be viewed with caution, since it was obtained in merely one investigation, it may be tentatively interpreted in terms of an increased availability of 5-HT in the MB resulting in an augmentation of 5-HTergic activity in the neocortical and limbic target regions of 5-HTergic efferents. This is also reflected by the (compensatory) desensitization of 5-HT2R in both neocortical and limbic areas. Unfortunately, no in vivo investigations have been conducted, so far, on 5-HT1R binding in BDman, while in BDdep no investigations are available on 5-HT2R. Thus, at present, it may only be hypothesized that mesencephalic and neocortical 5-HT levels are increased in BDman, whereas BDdep is characterized by a shortage of limbic 5-HT.
As mentioned above, a previous analysis of BDman had revealed a trend towards elevated striatal D2R and reduced frontal D1R binding sites (Nikolaus et al., 2012). Since 5-HT stimulates DA release, and 5-HT2R binding sites are desensitized in neocortex, CING and limbic regions, it may be surmised that DA efflux is decreased in these areas and in the target regions of corticothalamostriatal projections. This conjecture is supported by the sensitization of D2R in the STR but not by the desensitization of D1R in the FC of patients with BDman. Since, however, findings on D1R and D2R binding were obtained in merely three studies (D1R: n=1, D2R: n=2), future investigations are needed to shed further light on this matter.
Taken together, it may be hypothesized that acute MDD and BDman are associated with abundance of 5-HT, whereas BDdep may be characterized by a shortage of this neurotransmitter. In MDD, the net overweight of excitatory 5-HTergic input (due to the desensitization of mesencephalic 5-HT1R) – in contrast to AD – is compensated by a desensitization of 5-HT2R binding sites in the target regions of ascending 5-HTergic projections. This also holds for BDman, with the constraint that, presently, information on the regulation state of HT1R is lacking. In BDdep, the sensitization of limbic 5-HT1 heteroreceptors counteracts the decrease of available 5-HT by increasing inhibitory neurotransmission, which is likely to result in a net reduction of excitatory input to the target regions of ascending and descending 5-HTergic projections. Moreover, in both MDD and BDdep, limbic 5-HT1R are sensitized, which may be hypothesized to enhance the inhibitory action of limbocortical efferents. In MDD, however, the inhibitory actions exerted by the limbic system may be balanced by net excitatory influence from the MB.
The 5-HT hypothesis of MDD proceeds from the notion of reduced activity in the 5-HTergic system (for review, see Di Giovanni et al., 2006) and is supported by the antidepressant effects of selective 5-HT reuptake inhibitors (SSRIs) and 5-HT1AR agonists (for review, see Stein et al., 2002; Savitz et al., 2009). At first glance, the outcome of the present analysis does not seem to agree with this hypothesis, since the observed desensitizations of both mesencephalic 5-HT1R and neocortical and cingulate 5-HT2R binding sites, rather, reflect an increased availability of 5-HT. On the other hand, 5-HT1AR sensitization in the PHG of patients with MDD and in the HIPP, AMYG and PHG of the patients with BDdep argues in favor of lowered 5-HT levels in the limbic system. Conversely, the reduction of SERT in the MB, STR, THAL, PFC of patients with MDD supports the 5-HT hypothesis, which, however, does not hold for the increased amount of SERT in the CING and INS of subjects with BDdep.
As follows from Tables 2 and 3, the majority of studies on MDD and BD had been conducted on patients who were drug-free at the time of scanning. However, in a total of 17 studies on MDD and in a total of 4 studies on BD, the medication state had either not been specified, or the investigations had been conducted entirely or partly on acutely medicated subjects. In the studies on drug-free individuals, withdrawal times had not always been specified; according to those reports in which they had been given, they lay between 3 days and 5 years. Thus, the effect of precedent antidepressant treatment on the outcome of the present analysis is difficult to gauge. Antidepressants act by a variety of mechanisms including 5-HT and noradrenaline (NA) reuptake inhibition, 5-HTR antagonism, α2 adrenoreceptor antagonism and GABAAR agonism. As a consequence, a variety of actions are conceivable. Without prejudice to the 5-HT hypothesis, the abundance of 5-HT implied by the present analysis, for instance, may – partially or wholly – be due to treatment with tricyclics, SSRIs and 5-HT/NA reuptake inhibitors (SNRIs). 5-HT1R and 5-HT2R antagonist treatment, on the other hand, at least may have contributed to the observed decrease of available 5-HTR binding sites, while GABAAR agonistic benzodiazepines may have counteracted 5-HT affluence by inhibiting 5-HT release. It is interesting, however, that – notwithstanding the likely effects of tricyclics, SSRIs and SNRIs in augmenting synaptic 5-HT levels – SERT binding was found to be reduced. This may be accounted for either by the fact that the majority of studies had not been conducted on acutely medicated patients, or by a basic dysfunction of SERT regulation. Taken together, also in MDD and BD, further in vivo investigations are needed, in which SERT, 5-HT1R and/or 5-HT2R binding are determined before, under and after acute medication in order to assess the effect of treatment(s) on the regulation states of binding sites and to relate it to the acute or remitted stage of either disease.
SZ
Patients with SZ displayed significant reductions of 5-HT1R in TC, OC, MB and AMYG, while 5-HT2R were significantly lowered in FC, TC and OC. Previous findings, additionally, had evidenced significant elevations of DA synthesis and release, and significant reductions of striatal D1R, striatal, thalamic, frontal and parietal D2R, and striatal DA transporter (DAT) as well as frontal and temporal GABAAR binding (Nikolaus et al., 2014a,b).
Since D2R inhibit the release of GABA (Girault et al., 1986), D2R desensitization in STR, THAL, FC and TC is likely to induce a disinhibition resulting in an elevation of available GABA in both the STR and the projection areas of ascending striatothalamocortical GABAergic neurons. This conjecture is in agreement with the detected decreases of neocortical GABAAR in SZ.
Since GABA exerts inhibitory effects on both DA (Grace and Bunney, 1979) and 5-HT neurons (Luparini et al., 2004), the desensitization of GABAAR in FC and TC, in turn, can be presumed to diminish the inhibitory GABAergic input to DA and 5-HT neurons leading to an elevation of both DA and 5-HT concentrations throughout the mesolimbocortical system.
The desensitization of striatal D1R and striatal, thalamic, frontal and parietal D2R may be interpreted as an adaptive response to the overall increase of available DA. Likewise, the desensitization of 5-HT1R in MB, TC, OC and AMYG and 5-HT2R in FC, TC and OC can be conceived to compensate for the augmentation of 5-HT concentrations. Moreover, since 5-HT stimulates DA release (for review, see Alex and Pehek, 2007) and 5-HT1R and 5-HT2R are desensitized in MB, neocortex and AMYG, DA concentrations are likely to be additionally diminished via desensitization of 5-HTR binding sites.
The decrease of available D2 autoreceptors in STR, THAL, FC and PC and 5-HT1 autoreceptors in STR and MB, TC, OC and AMYG can be presumed to lead to a reduction of feedback inhibition resulting in a further augmentation of DA and 5-HT release, which is likely to enhance DAergic and 5-HTergic neurotransmission in both ascending and descending fibers of the mesolimbocortical system. In turn, the decrease of D2 and 5-HT1 heteroreceptors may be assumed to counterbalance the increase of DAergic/5-HTergic activity by reducing the inhibitory actions exerted by these binding sites. As in AD and MDD, this is likely to result in a net overweight of excitatory input to the target regions of ascending and descending DAergic as well as 5-HTergic neurons. As in MDD, but unlike AD, the net overweight of excitatory 5-HTergic input to neocortical projection areas is compensated by a desensitization of 5-HT2R in FC, OC and CING leading to a reduction of excitatory input to the mesolimbic target regions of neocortical afferents. Interestingly, in AD and SZ – unlike MDD and BDdep – no elevation of limbic 5-HT1R was observed implying entirely different modes of limbic 5-HT action.
Taken together, acute SZ is characterized by an abundance of 5-HT, which is compensated by the desensitization of mesencephalic, limbic and neocortical 5-HT1R as well as neocortical 5-HT2R binding sites. The increased availability of 5-HT is likely to be caused by the desensitization of the D2R and GABAAR binding sites throughout the brain. We have previously hypothesized that SZ in unmedicated patients may be associated with an impaired mechanism of both D2 auto- and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA (Nikolaus et al., 2014a,b). The basal increase of available presynaptic D2 autoreceptors may constitute an adaptive mechanism, which, however, remains ineffective in decreasing DA synthesis/release. Moreover, the sensitization of postsynaptic D2 heteroreceptors enhances the inhibitory actions exerted by these binding sites. This can be hypothesized to cause a decrease of GABA efflux in the neostriatum as well as in the thalamic and neocortical target regions of GABAergic projections, ultimately resulting in a reduction of inhibitory input to the target regions of descending corticothalamostriatal efferents.
As follows form Table 4, the majority of investigations had been conducted on acutely medicated patients. With the onset of neuroleptic treatment both excitatory and inhibitory DA and 5-HT binding sites become functionally desensitized. D2 antagonistic medication causes a disinhibition of the (inhibitory) DA actions mediated by this receptor subtype leading to an – at least partial – restoration of inhibitory GABAergic input to the STR and to the target regions of striatothalamocortical projections. 5-HT1AR and 5-HT2AR antagonistic compounds block excitatory and inhibitory 5-HTergic neurotransmission (including neocortical DA release elicited via both neocortical 5-HT1AR and 5-HT2AR binding sites) resulting in a decrease of both 5-HTergic and DAergic excitatory input to the mesolimbic target regions of neocortical afferents.
Appraisal of results
Findings evidenced that AD, MDD, BD and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and receptor binding sites. The outcome of the present analysis, which included findings obtained in 27 additional investigations, complements previous results on SERT, 5-HT1R and 5-HT2R function in AD, MDD, BD and SZ (Nikolaus et al., 2009, 2010, 2012, 2014a,b).
Acute AD is associated with increased 5-HT levels and a net overweight of excitatory input due to the desensitization of inhibitory mesencephalic, limbic, cingulate and frontal 5-HT1R. Also in acute MDD and BDman, an abundance of 5-HT can be inferred. In contrast to AD, however, the net overweight of excitatory 5-HTergic input (due to the desensitization of mesencephalic 5-HT1R) is compensated by a desensitization of limbic, cingulate and neocortical 5-HT2R. BDdep can be related to 5-HT shortage. In this condition, the sensitization of limbic 5-HT1 heteroreceptors may be surmised to counteract the decrease of available 5-HT by increasing inhibitory neurotransmission ultimately leading to a net reduction of excitatory input to the target regions of 5-HTergic projections. Moreover, in both MDD and BDdep, limbic 5-HT1R are sensitized, which can be hypothesized to strengthen the inhibitory action of limbocortical efferents. In MDD – in contrast to BDdep – these inhibitory actions may be balanced by a net excitatory influence from the MB. Also in acute SZ, an abundance of 5-HT can be surmised. Since the majority of investigations on SZ were conducted on acutely medicated patients, it may be assumed, however, that mesencephalic, limbic and neocortical 5-HT1AR as well as neocortical 5-HT2AR were functionally desensitized resulting in a decrease of both inhibitory and excitatory input to the target regions of 5-HTergic projections.
Comparisons between disorders revealed that, in AD, frontal 5-HT1R were not only significantly decreased relative to healthy individuals but also relative to MDD and SZ (where they were unaltered). Moreover, in AD, frontal, cingulate, amygdalar and mesencephalic 5-HT1R were not only significantly lowered relative to controls but also relative to SZ – thereby, in SZ, frontal and cingulate 5-HT1R binding were unaltered, whereas amygdalar and cingulate 5-HT1R were decreased relative to controls. Additionally, in AD, temporal 5-HT1R were not different from healthy individuals but significantly elevated compared to patients with SZ (where they were unaltered). Conversely, in AD, temporal 5-HT2R were not only significantly elevated relative to healthy individuals but also relative to MDD (where they were unaltered) and to SZ (where they were decreased compared to controls). Moreover, frontal 5-HT2R were not only significantly elevated in AD compared to normal subjects but also relative to SZ (where they were decreased compared to controls). Additionally, in MDD, frontal 5-HT2R were significantly reduced relative to healthy individuals and significantly elevated relative to SZ (where they were decreased compared to controls).
From this it may be inferred that frontal and limbic ‘inhibition’ – as exerted via 5-HT1R binding sites – is lower in AD relative to MDD and SZ, whereas temporal ‘inhibition’ is augmented (at least relative to SZ). Furthermore, it may be conjectured that frontal and temporal ‘excitation’ – as exerted via 5-HT2R binding sites – is higher in AD relative to MDD and SZ, and higher in MDD relative to SZ (at least as much as the frontal cortex is concerned). Limbic regions such as the amygdala play a major role in the mediation of fear (for review, see Herry and Johansen, 2014). Furthermore, prefrontal/frontal areas are involved in associative learning (for review, see Hélie et al., 2015), while the hippocampus and medial temporal structures mediate the formation and consolidation of declarative memory (for review, see Huijgen and Samson, 2015). Thus, it can be hypothesized that region-specific alterations of 5-HT1R and 5-HT2R may be related to specific disturbances in the processing of emotion and memory in the individual disorders. This is also likely to hold for BDdep and BDman, although the alterations observed in these conditions are difficult to position in relation of AD, MDD and SZ. With trends towards an elevation of hippocampal 5-HT1R in BDdep relative to MDD (where it is unaltered) and of amygdalar 5-HT1R relative to SZ (where it is reduced compared to controls), it may be speculated, however, that limbic ‘inhibition’ – as exerted via 5-HT1R binding sites – is elevated in BDdep relative to MDD and SZ.
Although the conjecture of region-specific alterations of 5-HT1R, 5-HT2R and SERT is intriguing, it must be put into perspective: first, investigations of some individual synaptic constituents in individual diseases are scarce with merely three studies of 5-HT2R in AD (Table 1), three studies on SERT in SZ (Table 4) and one study, each, on SERT and 5-HT2R in BDman (Table 3). Moreover, so far, no study has been conducted on 5-HT1R in BDman, and on 5-HT synthesis in AD, BDdep, BDman and SZ. In numerous cases, furthermore, the number of available studies per brain region is limited (Figures 1–3). If, in addition, the number of investigated subjects is comparatively small, findings are difficult to interpret as to their portability.
Secondly, the individual findings underlying the obtained differences between patients with AD, MDD, BDdep, BDman and SZ and the respective controls were rather inconsistent with reports of no alterations and both significant and non-significant increases as well as decreases of SERT, 5-HT1R and 5-HT2R binding (Figures 1–3). Thereby, inconclusive results may be due to varying subtypes of either disease, varying comorbidities, varying disease durations and varying disease severities, which, in addition, have been assessed with a variety of different inventories (Tables 1–4). All of these variables are likely to influence the regulation states of neurotransmitters and their receptive sites, and, therefore, may lead to results, which are incomparable not only between individual patients but also between the patient cohorts of different studies. Further factors bearing an effect on the comparability of in vivo findings are differences in methodology: results cannot be expected to be entirely consistent, when they were obtained with different imaging tools such as SPECT and the higher resolving PET, with radioligands differing as to their affinity for the respective binding sites, and – last but not least – with quantification methods ranging from the determination of simple count rates to statistical parametric mapping of distribution volumes.
Thirdly, it must be taken into account that in the majority of original investigations, patients had undergone previous and/or current treatment with anxiolytics, antidepressants and neuroleptics acting, among others, on pre- and postsynaptic DA, 5-HT, NA and GABA binding sites (Tables 1–4). As of yet, far too little investigations are available on 5-HT function in medication-naïve patients to permit meaningful conclusions on the potential effects of pharmacological compounds within the frameworks of 5-HT1R, 5-HT2R and SERT action and their relation to other neurotransmitter systems.
In order to advance our understanding of 5-HTergic neurotransmission in neuropsychiatric disorders, future efforts must be directed towards investigating 5-HT2R in AD and BDdep as well as 5-HT1R in BDman. Moreover, it may be surmised that regional differences of SERT, 5-HT1R and 5-HT2R not only exist between disorders but also between the subtypes of AD and MDD, BDdep, BDman and SZ, and that they are related to the predominance of the respective key symptoms.
As to AD, SERT binding was nearly exclusively assessed in patients with OCD (14 studies) supplemented by 2 studies each on PD and GAD, respectively (Table 1). Similarly, 5-HT1R was determined in patients with PD (3 studies) and social phobia (1 study), while 5-HT2R was solely investigated in patients with OCD (3 studies). In a previous paper, we have reported differences of SERT and 5-HT1R binding between individual subtypes of AD with reductions of SERT in MB and THAL of individuals with OCD and PD but not in patients with GAD, and reductions of 5-HT1R in the TC – in addition to decrements in FC and limbic regions – of individuals with PD but not in patients with phobia (Nikolaus et al., 2010). This may indicate patterns of 5-HT (dys)function, which not only differ between AD and the other disorders, but also between the individual subtypes of AD. In this context, it is interesting that patients with PTSD – in contrast to patients with PD and phobia – display no reduction of inhibitory 5-HT1R binding sites in any of the assessed neocortical and subcortical regions including PFC, FC, PC, TC, OC, CING, HIPP, AMYG, INS, PHG and MB (Bonne et al., 2005; Sullivan et al., 2009). Since PTSD per definition involves the singular or repeated infliction of an extrinsic (physical) trauma, 5-HT (and, for that matter, also DA and GABA) function may be basically altered in this subtype by interaction with neurotransmitters relevant for the mediation of nociception and acute and/or chronic stress such as substance P (for review, see Nikolaus et al., 2013), noradrenaline (for review, see Yamamoto et al., 2014), endocannabinoids (for review, see Hu et al., 2014) and endogenous opiates (for review, see Spetea, 2013).
Therefore, future investigations are needed, which explicitly address 5-HT (as well as DA and GABA) function in patients with the primary (and preferably exclusive) diagnosis of individual subtypes of AD (OCD, PD, GAD, phobia, PTSD), MDD (melancholic, atypical and catatonic depression, postpartum depression, seasonal affective disorder, etc.), BP (bipolar I disorder, bipolar II disorder, cyclothymia, etc.) or SZ (paranoid, disorganized, catatonic, undifferentiated, residual subtype, etc.). Correlation of in vivo imaging findings on 5-HT1R, 5-HT2R, GABAA, D1R and/or D2R and the occurrence of specific symptoms, then, would be the next step in unraveling the neurochemical mechanisms underlying behavioral manifestations of anxiety, compulsive behavior, delusion, hallucination, anhedonia or mania.
References
Adams, K.H., Hansen, E.S., Pinborg, L.H., Hasselbalch, S.G., Svarer, C., Holm, S., Bolwig, T.G., and Knudsen, G.M. (2005). Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei. Int. J. Neuropsychopharmacol. 8, 391–401.10.1017/S1461145705005055Search in Google Scholar
Agren, H. and Reibring, L. (1994). PET studies of presynaptic monoamine metabolism in depressed patients and healthy volunteers. Pharmacopsychiatry 27, 2–6.10.1055/s-2007-1014265Search in Google Scholar
Agren, H., Reibring, L., Hartvig, P., Tedroff, J., Bjurling, P., Hörnfeldt, K., Andersson, Y., Lundqvist, H., and Långström, B. (1991). Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers. Acta Psychiatr. Scand. 83, 449–455.10.1111/j.1600-0447.1991.tb05574.xSearch in Google Scholar
Agren, H., Reibring, L., Hartvig, P., Tedroff, J., Bjurling, P., Lundqvist, H., and Långström, B. (1992). PET studies with L-[11C]5-HTP and L-[11C]dopa in brains of healthy volunteers and patients with major depression. Clin. Neuropharmacol. 15(Suppl 1, Pt A), 235–236.10.1097/00002826-199201001-00123Search in Google Scholar
Agren, H., Reibring, L., Hartvig, P., Tedroff, J., Bjurling, P., Lundqvist, H., and Langstrom B. (1993). Monoamine metabolism in human prefrontal cortex and basal ganglia. Pet studies using [β-11C] l–5-hydroxytryptophan and [β-11C] L-dopa in healthy volunteers and patients with unipolar major depression. Depression 1, 71–83.10.1002/depr.3050010203Search in Google Scholar
Alex, K.D. and Pehek, E.A. (2007). Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol. Ther. 113, 296–320.10.1016/j.pharmthera.2006.08.004Search in Google Scholar
Amsterdam, J.D., Newberg, A.B., Newman, C.F., Shults, J., Wintering, N. and Soeller, I. (2013). Change over time in brain serotonin transporter binding in major depression: effects of therapy measured with [(123) I]-ADAM SPECT. J. Neuroimaging. 23, 469–476.10.1111/jon.12035Search in Google Scholar
Andrews, P.W., Kornstein, S.G., Halberstadt, L.J., Gardner, C.O., and Neale, M.C. (2011). Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression. Front Psychol. 2, 159.10.3389/fpsyg.2011.00159Search in Google Scholar
Attar-Lévy, D., Martinot, J.L., Blin, J., Dao-Castellana, M.H., Crouzel, C., Mazoyer, B., Poirier, M.F., Bourdel, M.C., Aymard, N., Syrota, A., and Féline, A. (1999). The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol. Psychiatry 45, 180–186.10.1016/S0006-3223(98)00007-9Search in Google Scholar
Audenaert, K., Van Laere, K., Dumont, F., Slegers, G., Mertens, J., van Heeringen, C., and Dierckx, R.A. (2001). Decreased frontal serotonin 5-HT 2a receptor binding index in deliberate self-harm patients. Eur. J. Nucl. Med. 28, 175–182.10.1007/s002590000392Search in Google Scholar PubMed
Baeken, C., De Raedt, R., Bossuyt, A., Van Hove, C., Mertens, J., Dobbeleir, A., Blanckaert, P., and Goethals, I. (2011). The impact of HF-rTMS treatment on serotonin(2A) receptors in unipolar melancholic depression. Brain Stimul. 4, 104–111.10.1016/j.brs.2010.09.002Search in Google Scholar
Baeken, C., De Raedt, R., and Bossuyt, A. (2012). Is treatment-resistance in unipolar melancholic depression characterized by decreased serotonin A receptors in the dorsal prefrontal – anterior cingulate cortex? Neuropharmacology 62, 340–346.10.1016/j.neuropharm.2011.07.043Search in Google Scholar
Bah, J., Lindström, M., Westberg, L., Mannerås, L., Ryding, E., Henningsson, S., Melke, J., Rosén, I., Träskman-Bendz, L., and Eriksson, E. (2008). Serotonin transporter gene polymorphisms: effect on serotonin transporter availability in the brain of suicide attempters. Psychiatry Res. 162, 221–229.10.1016/j.pscychresns.2007.07.004Search in Google Scholar
Bantick, R.A., Montgomery, A.J., Bench, C.J., Choudhry, T., Malek, N., McKenna, P.J., Quested, D.J., Deakin, J.F., and Grasby, P.M. (2004). A positron emission tomography study of the 5-HT1A receptor in schizophrenia and during clozapine treatment. J. Psychopharmacol. 18, 346–354.10.1177/026988110401800304Search in Google Scholar
Biver, F., Wikler, D., Lotstra, F., Damhaut, P., Goldman, S., and Mendlewicz, J. (1997). Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br. J. Psychiatry 171, 444–448.10.1192/bjp.171.5.444Search in Google Scholar
Bonne, O., Bain, E., Neumeister, A., Nugent, A.C., Vythilingam, M., Carson, R.E., Luckenbaugh, D.A., Eckelman, W., Herscovitch, P., Drevets, W.C., and Charney, D.S. (2005). No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder. Am. J. Psychiatry 162, 383–385.10.1176/appi.ajp.162.2.383Search in Google Scholar
Cannon, D.M., Ichise, M., Fromm, S.J., Nugent, A.C., Rollis, D., Gandhi, S.K., Klaver, J.M., Charney, D.S., Manji, H.K., and Drevets, W.C. (2006). Serotonin transporter binding in bipolar disorder assessed using [11C]DASB and positron emission tomography. Biol. Psychiatry 60, 207–217.10.1016/j.biopsych.2006.05.005Search in Google Scholar
Cannon, D.M., Ichise, M., Rollis, D., Klaver, J.M., Gandhi, S.K., Charney, D.S., Manji, H.K., and Drevets, W.C. (2007). Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol. Psychiatry 62, 870–877.10.1016/j.biopsych.2007.03.016Search in Google Scholar
Carlsson, M.L. (2001). On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 25, 5–26.10.1016/S0278-5846(00)00146-9Search in Google Scholar
Catafau, A.M., Perez, V., Plaza, P., Pascual, J.C., Bullich, S., Suarez, M., Penengo, M.M., Corripio, I., Puigdemont, D., Danus, M., Peric, J., and Alvarez, E. (2006). Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study. Psychopharmacology (Berl.) 189, 145–153.10.1007/s00213-006-0540-ySearch in Google Scholar PubMed
Catafau, A.M., Bullich, S., Nucci, G., Burgess, C., Gray, F., Merlo-Pich, E., and Barcelona Clinical Imaging in Psychiatry Group. (2011). Contribution of SPECT measurements of D2 and 5-HT2A occupancy to the clinical development of the antipsychotic SB-773812. J. Nucl. Med. 52, 526–534.10.2967/jnumed.110.081885Search in Google Scholar
D’haenen, H., Bossuyt, A., Mertens, J., Bossuyt-Piron, C., Gijsemans, M., and Kaufman, L. (1992). SPECT imaging of serotonin2 receptors in depression. Psychiatry Res. 45, 227–237.10.1016/0925-4927(92)90018-YSearch in Google Scholar
Dahlström, M., Ahonen, A., Ebeling, H., Torniainen, P., Heikkila, J., and Moilanen, I. (2000). Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents. Mol. Psychiatry 5, 514–522.10.1038/sj.mp.4000766Search in Google Scholar
Deakin, J.F. and Graeff, F.G. (1991). 5-HT and mechanisms of defence. J. Psychopharmacol. 5, 305–315.10.1177/026988119100500414Search in Google Scholar
Di Giovanni, G., Di Matteo, V., Pierucci, M., Benigno, A., and Esposito, E. (2006). Central serotonin2C receptor: from physiology to pathology. Curr. Top. Med. Chem. 6, 1909–1925.10.2174/156802606778522113Search in Google Scholar
Di Pietro, N.C. and Seamans, J.K. (2007). Dopamine and serotonin interactions in the prefrontal cortex: insights on antipsychotic drugs and their mechanism of action. Pharmacopsychiatry 40(Suppl 1), S27–S33.10.1055/s-2007-992133Search in Google Scholar
Drevets, W.C., Frank, E., Price, J.C., Kupfer, D.J., Holt, D., Greer, P.J., Huang, Y., Gautier, C., and Mathis, C. (1999). PET imaging of serotonin 1A receptor binding in depression. Biol. Psychiatry 46, 1375–1387.10.1016/S0006-3223(99)00189-4Search in Google Scholar
Drevets, W.C., Frank, E., Price, J.C., Kupfer, D.J., Greer, P.J., and Mathis, C. (2000). Serotonin type-1A receptor imaging in depression. Nucl. Med. Biol. 27, 499–507.10.1016/S0969-8051(00)00119-0Search in Google Scholar
Drevets, W.C., Thase, M.E., Moses-Kolko, E.L., Price, J., Frank, E., Kupfer, D.J., and Mathis, C. (2007). Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl. Med. Biol. 34, 865–877.10.1016/j.nucmedbio.2007.06.008Search in Google Scholar PubMed PubMed Central
Erritzoe, D., Rasmussen, H., Kristiansen, K.T., Frokjaer, V.G., Haugbol, S., Pinborg, L., Baaré, W., Svarer, C., Madsen, J., Lublin, H., Knudsen, G.M., and Glenthoj, B.Y. (2008). Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 33, 2435–2441.10.1038/sj.npp.1301656Search in Google Scholar PubMed
Ferré, S., Cortés, R., and Artigas, F. (1994). Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats. J. Neurosci. 14, 4839–4846.10.1523/JNEUROSCI.14-08-04839.1994Search in Google Scholar
Frankle, W.G., Narendran, R., Huang, Y., Hwang, D.R., Lombardo, I., Cangiano, C., Gil, R., Laruelle, M., and Abi-Dargham, A. (2005). Serotonin transporter availability in patients with schizophrenia: a positron emission tomography imaging study with [11C]DASB. Biol. Psychiatry 57, 1510–1516.10.1016/j.biopsych.2005.02.028Search in Google Scholar
Frankle, W.G., Lombardo, I., Kegeles, L.S., Slifstein, M., Martin, J.H., Huang, Y., Hwang, D.R., Reich, E., Cangiano, C., Gil, R., Laruelle, M., and Abi-Dargham, A. (2006). Serotonin 1A receptor availability in patients with schizophrenia and schizo-affective disorder: a positron emission tomography imaging study with [11C]WAY 100635. Psychopharmacology (Berl.) 189, 155–164.10.1007/s00213-006-0543-8Search in Google Scholar
Frey, B.N., Skelin, I., Sakai, Y., Nishikawa, M., and Diksic, M. (2010). Gender differences in α-[11C]MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: a positron emission tomography study. Psychiatry Res. 183, 157–166.10.1016/j.pscychresns.2010.05.005Search in Google Scholar
Gefvert, O., Bergström, M., Långström, B., Lundberg, T., Lindström, L., and Yates, R. (1998). Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology (Berl.) 135, 119–126.10.1007/s002130050492Search in Google Scholar
Girault, J.A., Spampinato, U., Glowinski, J., and Besson, MJ. (1986). In vivo release of [3H]γ-aminobutyric acid in the rat neostriatum – II. Opposing effects of D1 and D2 dopamine receptor stimulation in the dorsal caudate putamen. Neuroscience 19, 1109–1117.10.1016/0306-4522(86)90127-2Search in Google Scholar
Grace, A.A. and Bunney, B.S. (1979). Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons. Eur. J. Pharmacol. 59, 211–218.10.1016/0014-2999(79)90283-8Search in Google Scholar
Graef, S., Schönknecht, P., Sabri, O., and Hegerl, U. (2011). Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings. Psychopharmacology (Berl.) 215, 205–229.10.1007/s00213-010-2153-8Search in Google Scholar PubMed
Hajós, M. and Rogers, B.N. (2010). Targeting α7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr. Pharm. Des. 16, 538–554.10.2174/138161210790361434Search in Google Scholar PubMed
Hammoud, D.A., Endres, C.J., Hammond, E., Uzuner, O., Brown, A., Nath, A., Kaplin, A.I., and Pomper, M.G. (2010). Imaging serotonergic transmission with [11C]DASB-PET in depressed and non-depressed patients infected with HIV. Neuroimage 49, 2588–2595.10.1016/j.neuroimage.2009.10.037Search in Google Scholar PubMed PubMed Central
Hale, M.W. and Lowry, C.A. (2013). Functional topography of midbrain and pontine serotonergic systems: implications for synaptic regulation of serotonergic circuits. Psychopharmacology (Berl). 213, 243–264.10.1007/s00213-010-2089-zSearch in Google Scholar PubMed
Hasler, G., Bonwetsch, R., Giovacchini, G., Toczek, M.T., Bagic, A., Luckenbaugh, D.A., Drevets, W.C., and Theodore, W.H. (2007). 5-HT1A receptor binding in temporal lobe epilepsy patients with and without major depression. Biol. Psychiatry 62, 1258–1264.10.1016/j.biopsych.2007.02.015Search in Google Scholar PubMed PubMed Central
Hasselbalch, S.G., Hansen, E.S., Jakobsen, T.B., Pinborg, L.H., Lønborg, J.H., and Bolwig, T.G. (2007). Reduced midbrain-pons serotonin transporter binding in patients with obsessive-compulsive disorder. Acta Psychiatr. Scand. 115, 388–394.10.1111/j.1600-0447.2006.00940.xSearch in Google Scholar PubMed
Hélie, S., Ell, S.W., and Ashby, F.G. (2015). Learning robust cortico-cortical associations with the basal ganglia: an integrative review. Cortex 64C, 123–135.10.1016/j.cortex.2014.10.011Search in Google Scholar PubMed
Herold, N., Uebelhack, K., Franke, L., Amthauer, H., Luedemann, L., Bruhn, H., Felix, R., Uebelhack, R., and Plotkin, M. (2006). Imaging of serotonin transporters and its blockade by citalopram in patients with major depression using a novel SPECT ligand [123I]-ADAM. J. Neural. Transm. 113, 659–670.10.1007/s00702-005-0429-7Search in Google Scholar PubMed
Herry, C. and Johansen, J.P. (2014). Encoding of fear learning and memory in distributed neuronal circuits. Nat. Neurosci. 17, 1644–1654.10.1038/nn.3869Search in Google Scholar PubMed
Hesse, S., Müller, U., Lincke, T., Barthel, H., Villmann, T., Angermeyer, M.C., Sabri, O., and Stengler-Wenzke, K. (2005). Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Res. 140, 63–72.10.1016/j.pscychresns.2005.07.002Search in Google Scholar PubMed
Hesse, S., Meyer, P.M., Strecker, K., Barthel, H., Wegner, F., Oehlwein, C., Isaias, I.U., Schwarz, J., and Sabri, O. (2009). Monoamine transporter availability in Parkinson’s disease patients with or without depression. Eur. J. Nucl. Med. Mol. Imaging 36, 428–435.10.1007/s00259-008-0979-7Search in Google Scholar PubMed
Hesse, S., Stengler, K., Regenthal, R., Patt, M., Becker, G.A., Franke, A., Knüpfer, H., Meyer, P.M., Luthardt, J., Jahn, I., Lobsien, D., Heinke, W., Brust, P., Hegerl, U. and Sabri, O. (2011). The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder. Int. J. Neuropsychopharmacol. 14, 606–617.10.1017/S1461145710001604Search in Google Scholar PubMed
Hirvonen, J., Karlsson, H., Kajander, J., Lepola, A., Markkula, J., Rasi-Hakala, H., Någren, K., Salminen, J.K., and Hietala, J. (2008). Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int. J. Neuropsychopharmacol. 11, 465–476.10.1017/S1461145707008140Search in Google Scholar PubMed
Ho, P.S., Ho, K.K., Huang, W.S., Yen, C.H., Shih, M.C., Shen, L.H., Ma, K.H., and Huang, S.Y. (2013). Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression. Psychiatry Res. 212, 216–222.10.1016/j.pscychresns.2012.04.005Search in Google Scholar
Hu, S.S., Ho, Y.C., and Chiou, L.C. (2014). No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids. Eur. J. Neurosci. 39, 467–484.10.1111/ejn.12475Search in Google Scholar
Huijgen, J. and Samson, S. (2015). The hippocampus: a central node in a large-scale brain network for memory. Rev. Neurol. (Paris) 17, 204–216.10.1016/j.neurol.2015.01.557Search in Google Scholar
Ichimiya, T., Suhara, T., Sudo, Y., Okubo, Y., Nakayama, K., Nankai, M., Inoue, M., Yasuno, F., Takano, A., Maeda, J., and Shibuya, H. (2002). Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+)McN5652. Biol. Psychiatry 51, 715–722.10.1016/S0006-3223(01)01351-8Search in Google Scholar
Joensuu, M., Tolmunen, T., Saarinen, P.I., Tiihonen, J., Kuikka, J., Ahola, P., Vanninen, R., and Lehtonen, J. (2007). Reduced midbrain serotonin transporter availability in drug-naïve patients with depression measured by SERT-specific [123I] nor–CIT SPECT imaging. Psychiatry Res. 154, 125–131.10.1016/j.pscychresns.2006.08.001Search in Google Scholar PubMed
Jones, H.M., Travis, M.J., Mulligan, R., Visvikis, D., Gacinovic, S., Ell, P.J., Kerwin, R.W. and Pilowsky, L.S. (2000). In vivo serotonin 5-HT(2A) receptor occupancy and quetiapine. Am J Psychiatry. 157, 148.10.1176/ajp.157.1.148Search in Google Scholar PubMed
Jones, H.M., Travis, M.J., Mulligan, R., Bressan, R.A., Visvikis, D., Gacinovic, S., Ell, P.J, and Pilowsky, L.S. (2001). In vivo 5-HT2A receptor blockade by quetiapine: an R91150 single photon emission tomography study. Psychopharmacology (Berl). 157, 60–66.10.1007/s002130100761Search in Google Scholar PubMed
Karlsson, H., Hirvonen, J., Kajander, J., Markkula, J., Rasi-Hakala, H., Salminen, J.K., Någren, K., Aalto, S., and Hietala, J. (2010). Research letter: Psychotherapy increases brain serotonin 5-HT1A receptors in patients with major depressive disorder. Psychol. Med. 40, 523–528.10.1017/S0033291709991607Search in Google Scholar PubMed
Karlsson, H., Hirvonen, J., Salminen, J.K., and Hietala, J. (2011). No association between serotonin 5-HT 1A receptors and spirituality among patients with major depressive disorders or healthy volunteers. Mol. Psychiatry 16, 282–285.10.1038/mp.2009.126Search in Google Scholar PubMed
Kim, J.H., Son, Y.D., Kim, J.H., Choi, E.J., Lee, S.Y., Lee, J.E., Cho, Z.H. and Kim, Y.B. (2015). Serotonin transporter availability in thalamic subregions in schizophrenia: a study using 7.0-T MRI with [(11)C]DASB high-resolution PET. Psychiatry Res. 231, 50–57.10.1016/j.pscychresns.2014.10.022Search in Google Scholar PubMed
Konradi, C. and Heckers, S. (2003). Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol. Ther. 97, 153–179.10.1016/S0163-7258(02)00328-5Search in Google Scholar
Kraus, C., Baldinger, P., Rami-Mark, C., Gryglewsky, G., Kranz, G.S., Haeusler, D., Hahn, A., Wadsak, W., Mitterhauser, M., Rujescu, D., Kasper, S., and Lanzenberger, R. (2014). Exploring the impact of BDNF Val66Met genotype on serotonin transporter and serotonin-1A receptor binding. PLoS One 9, e106810.10.1371/journal.pone.0106810Search in Google Scholar
Lan, M.J., Hesselgrave, N., Ciarleglio, A., Ogden, R.T., Sullivan, G.M., Mann, J.J., and Parsey, R.V. (2013). Higher pretreatment 5-HT1A receptor binding potential in bipolar disorder depression is associated with treatment remission: a naturalistic treatment pilot PET study. Synapse 6, 73–78.Search in Google Scholar
Lanzenberger, R.R., Mitterhauser, M., Spindelegger, C., Wadsak, W., Klein, N., Mien, L.K., Holik, A., Attarbaschi, T., Mossaheb, N., Sacher, J., Geiss-Granadia, T., Kletter, K., Kasper, S., and Tauscher, J. (2007). Reduced serotonin-1A receptor binding in social anxiety disorder. Biol. Psychiatry 61, 1081–1089.10.1016/j.biopsych.2006.05.022Search in Google Scholar
Laruelle, M., Abi-Dargham, A., van Dyck, C., Gil, R., D’Souza, D.C., Krystal, J., Seibyl, J., Baldwin, R., and Innis, R. (2000). Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [(123)I]β-CIT. Biol. Psychiatry 47, 371–379.10.1016/S0006-3223(99)00257-7Search in Google Scholar
Lehto, S., Tolmunen, T., Joensuu, M., Saarinen, P.I., Vanninen, R., Ahola, P., Tiihonen, J., Kuikka, J., and Lehtonen, J. (2006). Midbrain binding of [123I]nor-β-CIT in atypical depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1251–1255.Search in Google Scholar
Lehto, S.M., Tolmunen, T., Kuikka, J., Valkonen-Korhonen, M., Joensuu, M., Saarinen, P.I., Vanninen, R., Ahola, P., Tiihonen, J., and Lehtonen, J. (2008). Midbrain serotonin and striatum dopamine transporter binding in double depression: a one-year follow-up study. Neurosci. Lett. 441, 291–295.10.1016/j.neulet.2008.06.042Search in Google Scholar PubMed
Lerond, J., Lothe, A., Ryvlin, P., Bouvard, S., d’Amato, T., Ciumas, C., Daléry, J., Poulet, E., and Saoud, M. (2013). Effects of aripiprazole, risperidone, and olanzapine on 5-HT1A receptors in patients with schizophrenia. J. Clin. Psychopharmacol. 33, 84–89.10.1097/JCP.0b013e31827b97a6Search in Google Scholar PubMed
Lewis, R., Kapur, S., Jones, C., DaSilva, J., DaSilva, J., Brown, G.M., Wilson, A.A., Houle, S., and Zipursky, R.B. (1999). Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. Am. J. Psychiatry 156, 72–78.10.1176/ajp.156.1.72Search in Google Scholar PubMed
Liik, M., Paris, M., Vahter, L., Gross-Paju, K., and Haldre, S. (2013). 123I-ADAM SPET imaging of serotonin transporter in patients with epilepsy and comorbid depression. BMC Neurol. 13, 204.10.1186/1471-2377-13-204Search in Google Scholar PubMed PubMed Central
Lothe, A., Saoud, M., Bouvard, S., Redouté, J., Lerond, J., and Ryvlin, P. (2012). 5-HT(1A) receptor binding changes in patients with major depressive disorder before and after antidepressant treatment: a pilot [18F]MPPF positron emission tomography study. Psychiatry Res. 203, 103–104.10.1016/j.pscychresns.2011.09.001Search in Google Scholar PubMed
Lowry, C.A., Johnson, P.L., Hay-Schmidt, A., Mikkelsen, J., and Shekhar, A. (2005). Modulation of anxiety circuits by serotonergic systems. Stress 8, 233–246.10.1080/10253890500492787Search in Google Scholar PubMed
Lundgren, J.D., Amsterdam, J., Newberg, A., Allison, K.C., Wintering, N., and Stunkard, A.J. (2009). Differences in serotonin transporter binding affinity in patients with major depressive disorder and night eating syndrome. Eat Weight Disord. 14, 45–50.10.1007/BF03327794Search in Google Scholar
Luparini, M.R., Garrone, B., Pazzagli, M., Pinza, M., and Pepeu, G. (2004). A cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone. Prog. Neuropsychopharmacol. Biol. Psychiatry 28, 1117–1127.Search in Google Scholar
Malison, R.T., Price, L.H., Berman, R., van Dyck, C.H., Pelton, G.H., Carpenter, L., Sanacora, G., Owens, M.J., Nemeroff, C.B., Rajeevan, N., Baldwin, R.M., Seibyl, J.P., Innis, R.B., and Charney, D.S. (1998). Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 β-carbomethoxy-3 β-(4-iodophenyl)tropane and single photon emission computed tomography. Biol. Psychiatry 44, 1090–1098.10.1016/S0006-3223(98)00272-8Search in Google Scholar
Mamo, D, Graff, A., Mizrahi, R., Shammi, C.M., Romeyer, F., and Kapur, S. (2007). Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am. J. Psychiatry 164, 1411–1417.10.1176/appi.ajp.2007.06091479Search in Google Scholar PubMed
Marchi, M., Fontana, G., Paudice, P., and Raiteri, M. (1988). The activation of phosphatidylinositol turnover is not directly involved in the modulation of neurotransmitter release mediated by presynaptic muscarinic receptors. Neurochem. Res. 13, 903–907.10.1007/BF00970760Search in Google Scholar PubMed
Marksteiner, J., Walch, T., Bodner, T., Gurka, P., and Donnemiller, E. (2003). Fluoxetine in Alzheimer’s disease with severe obsessive compulsive symptoms and a low density of serotonin transporter sites. Pharmacopsychiatry 36, 207–209.10.1055/s-2003-43051Search in Google Scholar PubMed
Maron, E., Kuikka, J.T., Shlik, J., Vasar, V., Vanninen, E., and Tiihonen, J. (2004a). Reduced brain serotonin transporter binding in patients with panic disorder. Psychiatry Res. 132, 173–181.10.1016/j.pscychresns.2003.10.004Search in Google Scholar PubMed
Maron, E., Kuikka, J.T., Ulst, K., Tiihonen, J., Vasar, V., and Shlik, J. (2004b). SPECT imaging of serotonin transporter binding in patients with generalized anxiety disorder. Eur. Arch. Psychiatry Clin. Neurosci. 254, 392–396.10.1007/s00406-004-0520-3Search in Google Scholar PubMed
Maron, E., Tõru, I., Hirvonen, J., Tuominen, L., Lumme, V., Vasar, V., Shlik, J., Nutt, D.J., Helin, S., Någren, K., Tiihonen, J., and Hietala, J. (2011). Gender differences in brain serotonin transporter availability in panic disorder. J. Psychopharmacol. 25, 952–959.10.1177/0269881110389207Search in Google Scholar PubMed
Matsumoto, R., Ichise, M., Ito, H., Ando, T., Takahashi, H., Ikoma, Y., Kosaka, J., Arakawa, R., Fujimura, Y., Ota, M., Takano, A., Fukui, K., Nakayama, K., and Suhara, T. (2010). Reduced serotonin transporter binding in the insular cortex in patients with obsessive-compulsive disorder: a [11C]DASB PET study. Neuroimage 49, 121–126.10.1016/j.neuroimage.2009.07.069Search in Google Scholar PubMed
Meltzer, C.C., Price, J.C., Mathis, C.A., Greer, P.J., Cantwell, M.N., Houck, P.R., Mulsant, B.H., Ben-Eliezer, D., Lopresti, B., DeKosky, S.T., and Reynolds, C.F. (1999). PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders. Am. J. Psychiatry 156, 1871–1878.10.1176/ajp.156.12.1871Search in Google Scholar
Messa, C., Colombo, C., Moresco, R.M., Gobbo, C., Galli, L., Lucignani, G., Gilardi, M.C., Rizzo, G., Smeraldi, E., Zanardi, R., Artigas, F., and Fazio, F. (2003). 5-HT(2A) receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET study. Psychopharmacology (Berl.) 167, 72–78.10.1007/s00213-002-1379-5Search in Google Scholar PubMed
Meyer, J.H., Kapur, S., Houle, S., DaSilva, J., Owczarek, B., Brown, G.M., Wilson, A.A., Kennedy, S.H. (1999). Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study. Am. J. Psychiatry 156, 1029–1034.10.1176/ajp.156.7.1029Search in Google Scholar
Meyer, J.H., Kapur, S., Eisfeld, B., Brown, G.M., Houle, S., DaSilva, J., Wilson, A.A., Rafi-Tari, S., Mayberg, H.S., and Kennedy, S.H. (2001). The effect of paroxetine on 5-HT(2A) receptors in depression: an [18F]setoperone PET imaging study. Am. J. Psychiatry 158, 78–85.10.1176/appi.ajp.158.1.78Search in Google Scholar PubMed
Meyer, J.H., McMain, S., Kennedy, S.H., Korman, L., Brown, G.M., DaSilva, J.N., Wilson, A.A., Blak, T., Eynan-Harvey, R., Goulding, V.S., Houle, S., and Links, P. (2003). Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am. J. Psychiatry 160, 90–99.10.1176/appi.ajp.160.1.90Search in Google Scholar PubMed
Meyer, J.H., Houle, S., Sagrati, S., Carella, A., Hussey, D.F., Ginovart, N., Goulding, V., Kennedy, J., and Wilson, A.A. (2004a). Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61, 1271–1279.10.1001/archpsyc.61.12.1271Search in Google Scholar PubMed
Meyer, J.H., Wilson, A.A., Sagrati, S., Hussey, D., Carella, A., Potter, W.Z., Ginovart, N., Spencer, E.P., Cheok, A., and Houle, S. (2004b). Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am. J. Psychiatry 161, 826–835.10.1176/appi.ajp.161.5.826Search in Google Scholar PubMed
Miller, J.M., Oquendo, M.A., Ogden, R.T., Mann, J.J., and Parsey, R.V. (2008). Serotonin transporter binding as a possible predictor of one-year remission in major depressive disorder. J. Psychiatr. Res. 42, 1137–1144.10.1016/j.jpsychires.2008.01.012Search in Google Scholar PubMed PubMed Central
Miller, J.M., Brennan, K.G., Ogden, T.R., Oquendo, M.A., Sullivan, G.M., Mann, J.J., and Parsey, R.V. (2009a). Elevated serotonin 1A binding in remitted major depressive disorder: evidence for a trait biological abnormality. Neuropsychopharmacology 34, 2275–2284.10.1038/npp.2009.54Search in Google Scholar PubMed PubMed Central
Miller, J.M., Kinnally, E.L., Ogden, R.T., Oquendo, M.A., Mann, J.J., and Parsey, R.V. (2009b). Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder. Synapse 63, 565–573.10.1002/syn.20637Search in Google Scholar PubMed PubMed Central
Miller, J.M., Hesselgrave, N., Ogden, R.T., Sullivan, G.M., Oquendo, M.A., Mann, J.J., and Parsey, R.V. (2013a). Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol Psychiatry 74, 287–295.10.1016/j.biopsych.2013.01.024Search in Google Scholar PubMed PubMed Central
Miller, J.M., Hesselgrave, N., Ogden, R.T., Zanderigo, F., Oquendo, M.A., Mann, J.J., Parsey, R.V. (2013b). Brain serotonin 1A receptor binding as a predictor of treatment outcome in major depressive disorder. Biol Psychiatry. 74, 760–767.10.1016/j.biopsych.2013.03.021Search in Google Scholar PubMed PubMed Central
Mineur, Y.S. and Picciotto, M.R. (2010). Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends Pharmacol. Sci. 31, 580–586.10.1016/j.tips.2010.09.004Search in Google Scholar PubMed PubMed Central
Mintun, M.A., Sheline, Y.I., Moerlein, S.M., Vlassenko, A.G., Huang, Y., Snyder, A.Z. (2004). Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biol. Psychiatry 55, 217–224.10.1016/j.biopsych.2003.08.015Search in Google Scholar PubMed
Mitchell, N.D. and Baker, G.B. (2010). An update on the role of glutamate in the pathophysiology of depression. Acta Psychiatr. Scand. 122, 192–210.10.1111/j.1600-0447.2009.01529.xSearch in Google Scholar PubMed
Moses-Kolko, E.L., Wisner, K.L., Price, J.C., Berga, S.L., Drevets, W.C., Hanusa, B.H., Loucks, T.L., and Meltzer, C.C. (2008). Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study. Fertil. Steril. 89, 685–692.10.1016/j.fertnstert.2007.03.059Search in Google Scholar PubMed PubMed Central
Müller-Vahl, K.R., Meyer, G.J., Knapp, W.H., Emrich, H.M., Gielow, P., Brücke, T., and Berding, G. (2005). Serotonin transporter binding in Tourette syndrome. Neurosci. Lett. 385, 120–125.10.1016/j.neulet.2005.05.031Search in Google Scholar PubMed
Murrough, J.W., Henry, S., Hu, J., Gallezot, J.D., Planeta-Wilson, B., Neumaier, J.F., and Neumeister, A. (2011). Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder. Psychopharmacology (Berl.) 213, 547–553.10.1007/s00213-010-1881-0Search in Google Scholar PubMed PubMed Central
Nash, J.R., Sargent, P.A., Rabiner, E.A., Hood, S.D., Argyropoulos, S.V., Potokar, J.P., Grasby, P.M., and Nutt, D.J. (2008). Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br. J. Psychiatry 193, 229–234.10.1192/bjp.bp.107.041186Search in Google Scholar PubMed
Neumeister, A., Bain, E., Nugent, A.C., Carson, R.E., Bonne, O., Luckenbaugh, D.A., Eckelman, W., Herscovitch, P., Charney, D.S., and Drevets, W.C. (2004). Reduced serotonin type 1A receptor binding in panic disorder. J. Neurosci. 24, 589–591.10.1523/JNEUROSCI.4921-03.2004Search in Google Scholar PubMed PubMed Central
Newberg, A.B., Amsterdam, J.D., and Wintering, N. (2005). 123I-ADAM binding to serotonin transporters in patients with major depression and healthy controls: a preliminary study. J. Nucl. Med. 46, 973–977.Search in Google Scholar
Newberg, A.B., Amsterdam, J.D., Wintering, N., and Shults, J. (2012). Low brain serotonin transporter binding in major depressive disorder. Psychiatry Res. 202, 161–167.10.1016/j.pscychresns.2011.12.015Search in Google Scholar PubMed PubMed Central
Ngan, E.T., Yatham, L.N., Ruth, T.J., and Liddle, P.F. (2000). Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: a PET study using [18F]setoperone. Am. J. Psychiatry 157, 1016–1018.10.1176/appi.ajp.157.6.1016Search in Google Scholar PubMed
Nikolaus, S., Antke, C., and Müller, H.W. (2009). In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders. Behav. Brain Res. 204, 32–66.10.1016/j.bbr.2009.06.009Search in Google Scholar PubMed
Nikolaus, S., Beu, M., Antke, C., and Müller, H.W. (2010). Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders – results from in vivo imaging studies. Rev. Neurosci. 21, 119–139.10.1515/REVNEURO.2010.21.2.119Search in Google Scholar
Nikolaus, S., Hautzel, H., Heinzel, A., and Müller, H.W. (2012). Key players in major and bipolar depression – a retrospective analysis of in vivo imaging studies. Behav. Brain Res. 232, 358–390.10.1016/j.bbr.2012.03.021Search in Google Scholar
Nikolaus, S., de Souza Silva, M.A., Hautzel, H., Huston, J.P., and Müller, H.W. (2013). The neurotachykinin NK1 receptor – a novel target for diagnostics and therapy. Curr. Mol. Imaging 2, 130–147.10.2174/2211555211302020004Search in Google Scholar
Nikolaus, S., Hautzel, H., Heinzel, A., and Müller, H.W. (2014a). Neurochemical dysfunction in treated and nontreated schizophrenia – a retrospective analysis of in vivo imaging studies. Rev. Neurosci. 25, 25–96.10.1515/revneuro-2013-0063Search in Google Scholar
Nikolaus, S., Hautzel, H., and Müller, H.W. (2014b). Focus on GABAA receptor function – a comparative analysis of in vivo imaging studies on neuropsychiatric disorders. Nuklearmedizin 53, 227–237.10.3413/Nukmed-0647-14-03Search in Google Scholar
Nugent, A.C., Bain, E.E., Carlson, P.J., Neumeister, A., Bonne, O., Carson, R.E., Eckelman, W., Herscovitch, P., Zarate, C.A. Jr, Charney, D.S., and Drevets, W.C. (2013). Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression. Eur. Neuropsychopharmacol. 23, 822–829.10.1016/j.euroneuro.2012.11.005Search in Google Scholar
Nuss, P. (2015). Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr. Dis. Treat. 11, 165–175.Search in Google Scholar
Nye, J.A., Purselle, D., Plisson, C., Voll, R.J., Stehouwer, J.S., Votaw, J.R., Kilts, C.D., Goodman, M.M., and Nemeroff, C.B. (2013). Decreased brainstem and putamen SERT binding potential in depressed suicide attempters using [11C]-zient PET imaging. Depress. Anxiety 30, 902–907.10.1002/da.22049Search in Google Scholar
Okubo, Y., Suhara, T., Suzuki, K., Kobayashi, K., Inoue, O., Terasaki, O., Someya, Y., Sassa, T., Sudo, Y., Matsushima, E., Iyo, M., Tateno, Y., and Michi, T. (2000). Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography. Life Sci. 66, 2455–2464.10.1016/S0024-3205(00)80005-3Search in Google Scholar
Oquendo, M.A., Hastings, R.S., Huang, Y.Y., Simpson, N., Ogden, R.T., Hu, X.Z., Goldman, D., Arango, V., Van Heertum, R.L., Mann, J.J., and Parsey, R.V. (2007). Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography. Arch. Gen. Psychiatry 64, 201–208.10.1001/archpsyc.64.2.201Search in Google Scholar PubMed PubMed Central
Palacios, J.M., Camps, M., Cortés, R., and Probst, A. (1988). Mapping dopamine receptors in the human brain. J. Neural. Transm. Suppl. 27, 227–235.10.1007/978-3-7091-8954-2_20Search in Google Scholar PubMed
Parsey, R.V., Oquendo, M.A., Ogden, R.T., Olvet, D.M., Simpson, N., Huang, Y.Y., Van Heertum, R.L., Arango, V., and Mann, J.J. (2006a). Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol. Psychiatry 59, 106–113.10.1016/j.biopsych.2005.06.016Search in Google Scholar
Parsey, R.V., Hastings, R.S., Oquendo, M.A., Huang, Y.Y., Simpson, N., Arcement, J., Huang, Y., Ogden, R.T., Van Heertum, R.L., Arango, V., and Mann, J.J. (2006b). Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am. J. Psychiatry 163, 52–58.10.1176/appi.ajp.163.1.52Search in Google Scholar
Parsey, R.V., Olvet, D.M., Oquendo, M.A., Huang, Y.Y., Ogden, R.T., and Mann, J.J. (2006c). Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology 31, 1745–1749.10.1038/sj.npp.1300992Search in Google Scholar
Paul, E.D. and Lowry, C.A. (2013). Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders. J. Psychopharmacol. 27, 1090–1106.10.1177/0269881113490328Search in Google Scholar
Pehrson, A.L. and Sanchez, C. (2015). Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug. Des. Devel. Ther. 19, 603–624.10.2147/DDDT.S62912Search in Google Scholar
Perani, D., Garibotto, V., Gorini, A., Moresco, R.M., Henin, M., Panzacchi, A., Matarrese, M., Carpinelli, A., Bellodi, L., and Fazio, F. (2008). In vivo PET study of 5HT(2A) serotonin and D(2) dopamine dysfunction in drug-naive obsessive-compulsive disorder. Neuroimage. 42, 306–314.10.1016/j.neuroimage.2008.04.233Search in Google Scholar
Pogarell, O., Hamann, C., Pöpperl, G., Uckel, G., Choukèr, M., Zaudig, M., Riedel, M., Möller, H.J., Hegerl, U., and Tatsch, K. (2003). Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder. Biol. Psychiatry 54, 1406–1413.10.1016/S0006-3223(03)00183-5Search in Google Scholar
Politis, M., Wu, K., Loane, C., Kiferle, L., Molloy, S., Brooks, D.J., and Piccini, P. (2010). Staging of serotonergic dysfunction in Parkinson’s disease: an in vivo 11C-DASB PET study. Neurobiol. Dis. 40, 216–221.10.1016/j.nbd.2010.05.028Search in Google Scholar PubMed
Rasmussen, H., Ebdrup, B.H., Erritzoe, D., Aggernaes, B., Oranje, B., Kalbitzer, J., Pinborg, L.H., Baaré, W.F., Svarer, C., Lublin, H., Knudsen, G.M., and Glenthoj, B. (2011). Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine. Psychopharmacology (Berl.) 213, 583–592.10.1007/s00213-010-1941-5Search in Google Scholar PubMed
Reimold, M., Smolka, M.N., Zimmer, A., Batra, A., Knobel, A., Solbach, C., Mundt, A., Smoltczyk, H.U., Goldman, D., Mann, K., Reischl, G., Machulla, H.-J., Bares, R., and Heinz, A. (2007a). Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity – a [11C]DASB PET study. J. Neural. Transm. 114, 1603–1609.10.1007/s00702-007-0785-6Search in Google Scholar PubMed
Reimold, M., Solbach, C., Noda, S., Schaefer, J.E., Bartels, M., Beneke, M., Machulla, H.J., Bares, R., Glaser, T., and Wormstall, H. (2007b). Occupancy of dopamine D(1), D(2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol. Psychopharmacology (Berl.). 190, 241–249.10.1007/s00213-006-0611-0Search in Google Scholar PubMed
Reimold, M., Batra, A., Knobel, A., Smolka, M.N., Zimmer, A., Mann, K., Solbach, C., Reischl, G., Schwärzler, F., Gründer, G., Machulla, H.-J., Bares, R., and Heinz, A. (2008). Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Mol. Psychiatry 13, 606–613.10.1038/sj.mp.4002149Search in Google Scholar PubMed
Reivich, M., Amsterdam, J.D., Brunswick, D.J., and Shiue, C.Y. (2004). PET brain imaging with [11C](+)McN5652 shows increased serotonin transporter availability in major depression. J Affect. Disord. 82, 321–327.10.1016/j.jad.2003.12.014Search in Google Scholar PubMed
Rosa-Neto, P., Diksic, M., Okazawa, H., Leyton, M., Ghadirian, N., Mzengeza, S., Nakai, A., Debonnel, G., Blier, P., and Benkelfat, C. (2004). Measurement of brain regional α-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch. Gen. Psychiatry 61, 556–563.10.1001/archpsyc.61.6.556Search in Google Scholar PubMed
Ruhé, H.G., Booij, J., Reitsma, J.B., and Schene, A.H. (2009). Serotonin transporter binding with [123I]β-CIT SPECT in major depressive disorder versus controls: effect of season and gender. Eur. J. Nucl. Med. Mol. Imaging 36, 841–849.10.1007/s00259-008-1057-xSearch in Google Scholar PubMed
Ryding, E., Ahnlide, J.A., Lindström, M., Rosén, I., and Träskman-Bendz, L. (2006). Regional brain serotonin and dopamine transporter binding capacity in suicide attempters relate to impulsiveness and mental energy. Psychiatry Res. 148, 195–203.10.1016/j.pscychresns.2006.06.001Search in Google Scholar PubMed
Saarinen, P.I., Lehtonen, J., Joensuu, M., Tolmunen, T., Ahola, P., Vanninen, R., Kuikka, J., and Tiihonen, J. (2005). An outcome of psychodynamic psychotherapy: a case study of the change in serotonin transporter binding and the activation of the dream screen. Am. J. Psychother. 59, 61–73.10.1176/appi.psychotherapy.2005.59.1.61Search in Google Scholar PubMed
Sargent, P.A., Kjaer, K.H., Bench, C.J., Rabiner, E.A., Messa, C., Meyer, J., Gunn, R.N., Grasby, P.M., and Cowen, P.J. (2000). Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch. Gen. Psychiatry 57, 174–180.10.1001/archpsyc.57.2.174Search in Google Scholar PubMed
Savitz, J., Lucki, I., and Drevets, W.C. (2009). 5-HT(1A) receptor function in major depressive disorder. Prog. Neurobiol. 88, 17–31.10.1016/j.pneurobio.2009.01.009Search in Google Scholar PubMed PubMed Central
Seeman, P. and Lee, T. (1975). Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219.10.1126/science.1145194Search in Google Scholar PubMed
Serretti, A. and Mandelli, L. (2008). The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions. Mol. Psychiatry 13, 742–771.10.1038/mp.2008.29Search in Google Scholar
Serretti, A., Drago, A., and De Ronchi, D. (2007). HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Curr. Med. Chem. 14, 2053–2069.10.2174/092986707781368450Search in Google Scholar
Sheline, Y.I., Mintun, M.A., Barch, D.M., Wilkins, C., Snyder, A.Z., and Moerlein, S.M. (2004). Decreased hippocampal 5-HT(2A) receptor binding in older depressed patients using [18F]altanserin positron emission tomography. Neuropsychopharmacology 29, 2235–2241.10.1038/sj.npp.1300555Search in Google Scholar
Simpson, H.B., Lombardo, I., Slifstein, M., Huang, H.Y., Hwang, D.R., Abi-Dargham, A., Liebowitz, M.R., and Laruelle, M. (2003). Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [11C]McN 5652. Biol. Psychiatry 54, 1414–1421.10.1016/S0006-3223(03)00544-4Search in Google Scholar
Smith, D.F., Stork, B.S., Wegener, G., Ashkanian, M., Jakobsen, S., Bender, D., Audrain, H., Vase, K.H., Hansen, S.B., Videbech, P., and Rosenberg, R. (2009). [11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging. Psychopharmacology (Berl.) 206, 133–140.10.1007/s00213-009-1587-3Search in Google Scholar PubMed
Spetea, M. (2013). Opioid receptors and their ligands in the musculoskeletal system and relevance for pain control. Curr. Pharm. Des. 213, 7382–7390.Search in Google Scholar
Staley, J.K., Sanacora, G., Tamagnan, G., Maciejewski, P.K., Malison, R.T., Berman, R.M., Vythilingam, M., Kugaya, A., Baldwin, R.M., Seibyl, J.P., Charney, D., and Innis, R.B. (2006). Sex differences in diencephalon serotonin transporter availability in major depression. Biol. Psychiatry 59, 40–47.10.1016/j.biopsych.2005.06.012Search in Google Scholar PubMed
Stein, D.J., Westenberg, H.G., and Liebowitz, M.R. (2002). Social anxiety disorder and generalized anxiety disorder: serotonergic and dopaminergic neurocircuitry. J. Clin. Psychiatry 63(Suppl 6), 12–19.Search in Google Scholar
Stengler-Wenzke, K., Müller, U., Angermeyer, M.C., Sabri, O., and Hesse, S. (2004). Reduced serotonin transporter-availability in obsessive-compulsive disorder (OCD). Eur. Arch. Psychiatry Clin. Neurosci. 254, 252–255.Search in Google Scholar
Stengler-Wenzke, K., Müller, U., Barthel, H., Angermeyer, M.C., Sabri, O., and Hesse, S. (2006). Serotonin transporter imaging with [123I]β-CIT SPECT before and after one year of citalopram treatment of obsessive-compulsive disorder. Neuropsychobiology 53, 40–45.10.1159/000090702Search in Google Scholar PubMed
Sullivan, G.M., Ogden, R.T., Oquendo, M.A., Kumar, J.S., Simpson, N., Huang, Y.Y., Mann, J.J., and Parsey, R.V. (2009). Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Biol. Psychiatry 66, 223–230.10.1016/j.biopsych.2009.01.028Search in Google Scholar PubMed PubMed Central
Sullivan, G.M., Ogden, R.T., Huang, Y.Y., Oquendo, M.A., Mann, J.J., and Parsey, R.V. (2013). Higher in vivo serotonin-1a binding in posttraumatic stress disorder: a PET study with [11C]WAY-100635. Depress. Anxiety 30, 197–206.10.1002/da.22019Search in Google Scholar PubMed PubMed Central
Tauscher, J., Kapur, S., Verhoeff, N.P., Hussey, D.F., Daskalakis, Z.J., Tauscher-Wisniewski, S., Wilson, A.A., Houle, S., Kasper, S., and Zipursky, R.B. (2002). Brain serotonin 5-HT(1A) receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635. Arch. Gen. Psychiatry 59, 514–520.10.1001/archpsyc.59.6.514Search in Google Scholar PubMed
Taylor, S.F. and Tso, I.F. (2014). GABA abnormalities in schizophrenia: a methodological review of in vivo studies. Schizophr. Res. doi: 10.1016/j.schres.2014.10.011. [Epub ahead of print].10.1016/j.schres.2014.10.011Search in Google Scholar
Theodore, W.H., Hasler, G., Giovacchini, G., Kelley, K., Reeves-Tyer, P., Herscovitch, P., and Drevets, W. (2007). Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy. Epilepsia 48, 1526–1530.10.1111/j.1528-1167.2007.01089.xSearch in Google Scholar
Tolmunen, T., Joensuu, M., Saarinen, P.I., Mussalo, H., Ahola, P., Vanninen, R., Kuikka, J., Tiihonen, J., and Lehtonen, J. (2004). Elevated midbrain serotonin transporter availability in mixed mania: a case report. BMC Psychiatry 4, 27.10.1186/1471-244X-4-27Search in Google Scholar
Travis, M.J., Busatto, G.F., Pilowsky, L.S., Mulligan, R., Acton, P.D., Gacinovic, S., Mertens, J., Terrière, D., Costa, D.C., Ell, P.J., and Kerwin, R.W. (1998). 5-HT2A receptor blockade in patients with schizophrenia treated with risperidone or clozapine. A SPET study using the novel 5-HT2A ligand 123I-5-I-R-91150. Br. J. Psychiatry 173, 236–241.10.1192/bjp.173.3.236Search in Google Scholar
Trichard, C., Paillère-Martinot, M.L., Attar-Levy, D., Blin, J., Feline, A., and Martinot, J.L. (1998). No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophr. Res. 31, 13–17.10.1016/S0920-9964(98)00014-0Search in Google Scholar
Uebelhack, R., Franke, L., Herold, N., Plotkin, M., Amthauer, H., and Felix, R. (2006). Brain and platelet serotonin transporter in humans-correlation between [123I]-ADAM SPECT and serotonergic measurements in platelets. Neurosci. Lett. 406, 153–158.10.1016/j.neulet.2006.06.004Search in Google Scholar
Van der Wee, N.J., Stevens, H., Hardeman, J.A., Mandl, R.C., Denys, D.A., van Megen, H.J., Kahn, R.S., and Westenberg, H.M. (2004). Enhanced dopamine transporter density in psychotropic-naive patients with obsessive-compulsive disorder shown by [123I]β-CIT SPECT. Am. J. Psychiatry 161, 2201–2206.10.1176/appi.ajp.161.12.2201Search in Google Scholar
Van der Wee, N.J., van Veen, J.F., Stevens, H., van Vliet, I.M., van Rijk, P.P., and Westenberg, H.G. (2008). Increased serotonin and dopamine transporter binding in psychotropic medication-naive patients with generalized social anxiety disorder shown by 123I-beta-(4-iodophenyl)-tropane SPECT. J. Nucl. Med. 49, 757–763.10.2967/jnumed.107.045518Search in Google Scholar
van Heeringen, C., Audenaert, K., Van Laere, K., Dumont, F., Slegers, G., Mertens, J., and Dierckx, R.A. (2003). Prefrontal 5-HT2a receptor binding index, hopelessness and personality characteristics in attempted suicide. J. Affect Disord. 74, 149–158.10.1016/S0165-0327(01)00482-7Search in Google Scholar
Verhoeff, N.P., Meyer, J.H., Kecojevic, A., Hussey, D., Lewis, R., Tauscher, J., Zipursky, R.B., and Kapur, S. (2000). A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia. Psychiatry Res. 99, 123–135.10.1016/S0165-1781(00)00198-0Search in Google Scholar
Viinamäkki, H., Kuikka, J., Tiihonen, J., and Lehtonen, J. (1998). Change in monoamine transporter density related to clinical recovery: a case-control study. Nord. J. Psychiatry 52, 39–44.10.1080/080394898422553Search in Google Scholar
Willeit, M., Praschak-Rieder, N., Neumeister, A., Pirker, W., Asenbaum, S., Vitouch, O., Tauscher, J., Hilger, E., Stastny, J., Brücke, T., and Kasper, S. (2000). [123I]-β-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biol. Psychiatry 47, 482–489.10.1016/S0006-3223(99)00293-0Search in Google Scholar
Willner, P. (1983). Dopamine and depression: a review of recent evidence: I. Empirical studies. Brain Res. 287, 211–224.Search in Google Scholar
Wittchen, H.U. and Jacobi, F. (2005). Size and burden of mental disorders in Europe – a critical review and appraisal of 27 studies. Eur. Neuropsychopharmacol. 15, 357–376.10.1016/j.euroneuro.2005.04.012Search in Google Scholar PubMed
Wong, D.F., Brasić, J.R., Singer, H.S., Schretlen, D.J., Kuwabara, H., Zhou, Y., Nandi, A., Maris, M.A., Alexander, M., Ye, W., Rousset, O., Kumar, A., Szabo, Z., Gjedde, A., and Grace, A.A. (2008). Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette syndrome: clues from an in vivo neurochemistry study with PET. Neuropsychopharmacology 33, 1239–1251.10.1038/sj.npp.1301528Search in Google Scholar PubMed PubMed Central
Yamamoto, K., Shinba, T., and Yoshii, M. (2014). Psychiatric symptoms of noradrenergic dysfunction: a pathophysiological view. Psychiatry Clin. Neurosci. 68, 1–20.10.1111/pcn.12126Search in Google Scholar PubMed
Yasuno, F., Suhara, T., Okubo, Y., Sudo, Y., Inoue, M., Ichimiya, T., Takano, A., Nakayama, K., Halldin, C., and Farde, L. (2004). Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia. Am. J. Psychiatry 161, 1016–1022.10.1176/appi.ajp.161.6.1016Search in Google Scholar PubMed
Yatham, L.N., Liddle, P.F., Shiah, I.S., Scarrow, G., Lam, R.W., Adam, M.J., Zis, A.P., Ruth, T.J. (2000). Brain serotonin2 receptors in major depression: a positron emission tomography study. Arch Gen Psychiatry 57, 850–858.10.1001/archpsyc.57.9.850Search in Google Scholar PubMed
Yatham, L.N., Liddle, P.F., Erez, J., Kauer-Sant’Anna, M., Lam, R.W., Imperial, M., Sossi, V., and Ruth, T.J. (2010). Brain serotonin-2 receptors in acute mania. Br. J. Psychiatry 196, 47–51.10.1192/bjp.bp.108.057919Search in Google Scholar PubMed
Yeh, Y.W., Ho, P.S., Chen, C.Y., Kuo, S.C., Liang, C.S., Ma, K.H., Shiue, C.Y., Huang, W.S., Cheng, C.Y., Wang, T.Y., Lu, R.B., and Huang, S.Y. (2014). Incongruent reduction of serotonin transporter associated with suicide attempts in patients with major depressive disorder: a positron emission tomography study with 4-[18F]-ADAM. Int. J. Neuropsychopharmacol. 18, 1–9.Search in Google Scholar
Zitterl, W., Aigner, M., Stompe, T., Zitterl-Eglseer, K., Gutierrez-Lobos, K., Schmidl-Mohl, B., Wenzel, T., Demal, U., Zettinig, G., Hornik, K., and Thau, K. (2007). [123I]-β-CIT SPECT imaging shows reduced thalamus- hypothalamus serotonin transporter availability in 24 drug-free obsessive-compulsive checkers. Neuropsychopharmacology 32, 1661–1668.10.1038/sj.npp.1301290Search in Google Scholar PubMed
©2016 by De Gruyter
