Fig. 12.1
The production pathways of the monoamines dopamine, noradrenaline and serotonin in the brain. The precursors tyrosine, phenylalanine and tryptophan enter the brain through the blood–brain barrier (BBB) after competing for places on the large neutral amino acid transporters (LAT). If sufficient oxygen is available, phenylalanine converts to tyrosine which then converts to l-dopa and dopamine. On oxygenation dopamine converts to noradrenaline and finally adrenaline. With available oxygen, tryptophan converts to 5-hydroxytryptophan (5-HT) which converts to serotonin. Monoamine production has to be maintained to counter metabolic attrition and other causes of depletion, such as leakage through a defective blood–brain barrier. Medications such as serotonin reuptake inhibitors (SSRIs), for example, counter synaptic serotonin reuptake. Other medications are l-dopa and tricyclic antidepressants (TCA) which can be used to supplement deficiencies
In psychiatric disorders such as major depression (MD), potential monoamine deficiencies may benefit from pharmaceutical monoamine supplementation. Supplementation should be considered additional to internally generated monoamines, which depend on adequate precursor supplies, oxygen, cellular and synaptic integrity.
While the monoamine hypothesis explains aspects of biochemical pathology in depression, it does not explain the antidepressant lag time which is the time it takes from first antidepressant application to antidepressant response, often several weeks. Such lag times may be due to receptor up- or downregulation or binding in adapting neuronal networks and circuits (Malberg and Blendy 2005).
Diurnal neurotransmitter variation may also play a role. For example, noradrenaline and serotonin availability are influenced by sleep when levels transiently decrease in areas such as the pons and amygdala (Shouse et al. 2000).
In a study of mood disorder, six unipolar depressed patients and eight healthy subjects underwent separate (18)F-FDG PET scans during waking and in their first REM sleep period. Compared to healthy controls, the depressed patients showed increased uptake in their tectal regions and in the left sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala and subiculum complex during REM sleep (Nofzinger et al. 1999). In a study on sleep deprivation in 14 medicated patients, technetium-99m hexamethylpropyleneamineoxime (99mTc HMPAO) SPECT scans revealed hypoperfusion in the left prefrontal cortex which was reversible upon remission. Before sleep deprivation therapy, the responding patients had a significantly higher anterior cingulate perfusion than nonresponding patients, which normalised after sleep deprivation (Holthoff et al. 1999).
While it is well known that sleep deprivation can temporarily counter depression, it is equally known that repeated REM sleep withdrawal will result in “REM rebound”. This “rebound” is associated with symptoms of depression and bipolar disorder. The severity of the rebound is related to the severity of “REM suppression” countered by subsequent increases in REM sleep (Suchecki et al. 2012; Greene and Siegel 2004). In recent drug developments, efforts have been made to explore the effect of sleep influencing medication in depression, for example, by using the melatonergic agonist agomelatine (Kasper et al. 2009).
Hypothyroidism is a well-known cause of depression that can occur due to insufficient thyroid hormone availability in the blood. A prospective cross-sectional study involving 254 patients showed that hypothyroidism increases the risk for critical mood deterioration by sevenfold (Larisch et al. 2004). In a 99mTc HMPAO SPECT study of 24 patients with hypothyroidism, 16 presented with a decreased uptake mostly in the posterior parietal lobes bilaterally and in the occipital lobes, including the cuneus. These areas extended to the bilateral prefrontal cortices when deterioration became more profound. After thyroxine replacement, regional cerebral blood flow improved in 9 of the 16 patients (Nagamachi et al. 2004).
Potential causes of depression are multifaceted with biological, psychological and social factors all playing a role. Its clinical manifestation is often assumed concurrent with anomalies in the monoamine homeostasis of the brain. The term “antidepressant drug” for the purpose of this review encompasses a wide range of substances which relieve aspects of the depressive state.
12.2 SPECT and PET Imaging in Psychiatric Disorders
SPECT and PET imaging of the brain in psychiatric disorders and depression typically comprises two aspects of brain function, namely, brain metabolism and brain neuroreceptor availability.
Brain metabolism can be measured directly by positron emission tomography (PET) using the positron emitting glucose analog [(18)F]-fluorodeoxyglucose ((18)F-FDG) or, indirectly, using the lipophilic cerebral perfusion agent technetium-99m hexamethylpropyleneamineoxime (99mTc HMPAO) that concentrates in neurons and partially in glia (Zerarka et al. 2001). Other tracers include 99mTc ethylcysteinate dimer (99mTc ECD), N-isopropyl-p-[123I]-iodoamphetamine (123I IMP), 133Xe and 195Au (Nikolaus et al. 2000). (18)F-FDG follows the path of glucose into the brain and neuronal tissue where it labels metabolic pathways that reflect the glucose metabolism of the brain (Chételat et al. 2005). The lipophilic amines 99mTc HMPAO, 99mTc ECD and 123I IMP pass through the blood–brain barrier in a blood flow-dependent manner and are trapped within the grey matter of the brain (Colamussi et al. 1999; O’Brien et al. 1999; Weder et al. 1990). (18)F-FDG hence reflects brain metabolism and 99mTc HMPAO, 99mTc ECD and 123I IMP mostly cerebral blood flow.
Neuroreceptor availability can be measured by markers of monoamine receptors. Measurable receptors include D1, D2 and 5-HT receptors and dopamine (DaT) and serotonin transporters (SERT). Multiple tracers can be used for imaging these and other aspects of the antidepressant response. These include amongst others 123 I IBZM, [11C]-raclopride, [123I]beta-CIT, 123 ioflupane (DaT Scan), [(11)C]WAY-100635, alpha-[(11)C]methyl-l-tryptophan, [(123)I]-ADAM, [(11)C]DASB, 123I-FP-CIT, [(18)F]FESP, [11C]verapamil, [(18)F]fluoro-l-dopa, [(11)C]-harmine and [(18)F] MPPF.
12.3 SPECT and PET Imaging in Depression
Early studies investigating depression often made use of brain perfusion tracers to gauge brain metabolism. A finding in these early studies was that of a global cerebral hypoperfusion in depression (Fountoulakis et al. 2004; Kanaya and Yonekawa 1990). This was often more pronounced in temporal, inferior frontal and parietal areas of the brain (Austin et al. 1992; Maes et al. 1993).
In a meta-analysis looking at metabolism and cerebral perfusion in major depression in 337 patients and 321 controls, Nikolaus et al. observed a decreased activity bilaterally in the frontal, parietal and occipital lobes; basal ganglia; and thalamus regions of the brain and right temporally, while the limbic region had a decreased uptake left and an increased uptake right (Nikolaus et al. 2000). In an analysis of major studies looking at the monoamine receptor function in depression until 2012, the same group observed that a complex pattern of dysregulation may exist within and between neurotransmitter systems, possibly linked to the subtype and duration of disease, the predominance of individual symptoms and pharmacological interventions (Nikolaus et al. 2012). Their main observations were that in acute depressive disease:
Dopamine synthesis increases frontally and pre-frontally, decreasing in remission.
5-HT1A binding decreases frontally, pre-frontally and occipitally, expanding to the parietal, temporal and cingulate regions upon remission, while 5-HT2A binding decreases in the cingulate regions, shifting to the parietal regions upon remission.
SERT binding increases in the insula and decreases in the thalamus and midbrain region, remaining decreased in the midbrain upon remission.
The above studies and others show that anomalies in cerebral blood flow and metabolism occur globally in depressive patients as do anomalies in receptor function. Although regional suppression of fronto-cortical and limbic circuits has been historically considered characteristic of depression, the evidence to date indicates otherwise, namely, that diffuse, rather than regional, abnormalities tend to occur.
12.3.1 SPECT and PET Imaging of Dopamine Receptors
Four major dopaminergic pathways have been identified in the mammalian brain, namely, the nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular pathways. Dopaminergic receptors are metabotropic G protein-coupled receptors classified to two major groups, the D1 (D1, D5) and the D2 group (D2, D3, D4). The D1 type are exclusively postsynaptic, located mostly in the striatum, nucleus accumbens, substantia nigra, olfactory bulb, amygdala, frontal cortex and to a lesser extent in the hippocampus, cerebellum, thalamus and hypothalamus. The D2 type are expressed pre- and postsynaptically mostly in the striatum, nucleus accumbens, olfactory tubercle and to a lesser extent in the substantia nigra, ventral tegmental brain region, hypothalamus, cortical areas, septum, amygdala and hippocampus (for a comprehensive review, see Beaulieu and Gainetdinov 2011). Tracers that can be used to measure D2 density are 123 I IBZM, a SPECT tracer that marks the postsynaptic D2 receptors, and [11C]-raclopride, a PET tracer that measures the D2 receptor binding in the striatum (Laruelle 2000) (Hierholzer et al. 1992). Both IBZM and [11C]-raclopride show increased binding in the striatum when extracellular dopamine is low (Shah et al. 1997) (Laruelle 2000). Results of preclinical and clinical studies implicate that, in addition to serotonin and norepinephrine, dopaminergic mechanisms may play a role in the pathogenesis and treatment of depression (Lemke 2007).
12.3.2 SPECT and PET Imaging of Dopamine Transporters
Dopamine transporters (DaT) are situated in the presynaptic region of the striatal synapses where they pump dopamine from the synaptic cleft into the presynaptic neuronal space. Commonly used tracers to investigate presynaptic dopamine transporter function are the cocaine derivatives [123I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane ([123I]beta-CIT) and 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123) I]FP-CIT, Ioflupane, DaT Scan) (Brücke et al. 1993; Booij et al. 1998). [123I] beta-CIT imaging can also be used for SERT imaging as it partially binds to these receptors as well (Reneman et al. 2002). Responses to neuroactive drugs can be measured by DaT binding in regions of interest in the brain (Warwick et al. 2012). Decreased DaT availability may occur in affective disorders such as those associated with Parkinson’s disease (Weintraub et al. 2005).
12.3.3 SPECT and PET Imaging of Serotonin Receptors
Serotonin receptors are also known as 5-HT receptors, mostly G protein-coupled receptors, of which the 5-HT1A receptors appear to play a key role in depressive disorders (Savitz et al. 2009) and to a lesser extent 5-HT2 receptors (van Heeringen et al. 2003). 5-HT1A receptors have been localised by the piperazine PET tracer [(11)C]WAY-100635 mostly to the cerebral cortices, hippocampus and raphe nucleus (Ito et al. 1999).
In an analysis of eight studies investigating the 5-HT1A receptor in the brains of patients with major depressive disorder, four reported a decreased 5-HT1A receptor density, two no change and two an increased density. These discrepant results were thought to be due to possible methodological research factors, but other options have to be considered. The disparate findings do not reliably answer the question of whether 5-HT1A receptors are altered in major depression or in subgroups of these patients (Shrestha et al. 2012).
12.3.4 SPECT and PET Imaging of Serotonin Transporters
The serotonin transporter (SERT) is a monoamine transporter that transports serotonin from the synaptic space to the presynaptic neuron. It is responsible for the removal of extracellular 5-HT. Increased SERT action will result in decreased 5-HT concentrations. Selective serotonin re-uptake inhibitors (SSRIs) and antidepressants which block serotonin transporters lead to increased synaptic and extracellular 5-HT (Bel and Artigas 1992; Blier and De Montigny 1983). In a study to determine whether patients with major depression have diminished serotonin transporter (SERT) availability in the brainstem, [123I] beta-CIT SPECT showed a statistically significant reduction in brainstem uptake in depressed subjects (Malison et al. 1998).
12.4 SPECT and PET Imaging of the Antidepressant Drug Response
Clinical trials using PET and SPECT imaging have been completed for several antidepressant pharmaceuticals including the selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), noradrenaline-dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOs) and tricyclic antidepressants (TCAs). For the purpose of this review, references have been sourced through PubMed until October 2012, including keywords such as clinical trial, PET, SPECT and antidepressant.
Some of the more common medications that have been investigated by SPECT and PET in depression are described below. They include the dopamine agonists levodopa and carbidopa; moclobemide and St. John’s wort; selegiline; the SSRIs citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline; the NDRI bupropion; the SNRI venlafaxine; and the TCAs amitriptyline, nortriptyline and desipramine.
12.4.1 Levodopa and Selegiline
One of the most investigated diseases involving dopaminergic synapses of the striatum is Parkinson’s disease (PD). Depression occurs in around 35 % of PD patients, and antidepressants that have dual serotonergic and noradrenergic effects are the drugs of choice for this disease (Aarsland et al. 2011). In an ioflupane study that correlated striatal DaT uptake with anxiety and depression in PD, affected patients had a lower DaT availability than healthy volunteers (Weintraub et al. 2005). A 99TcHMPAO SPECT study that examined regional cerebral blood flow in 52 PD patients showed a significant decrease in regional cerebral blood flow in PD patients with concurrent major depression. The decrease was less severe on treatment, particularly on a levodopa-selegiline combination therapy, less so with levodopa only therapy (Imamura et al. 2011).
12.4.2 Moclobemide and St. John’s Wort
Monoamine oxidase A (MAO-A) inhibitor antidepressants raise the levels of multiple monoamines. MAO-A can be measured using the MAO-A marker [(11)C]-harmine. Brain MAO-A occupancy was measured in 13 depressed patients with a clinically effective dose of the selective MAO-A inhibitor moclobemide and after repeated administrations of St. John’s wort, a herb purported to have MAO-A inhibitor properties. [(11)C]-harmine binding decreased significantly throughout all measured regions after moclobemide, but St. John’s wort did not significantly alter MAO-A density (Sacher et al. 2011).
12.4.3 The SSRIs
It is generally believed that an 80 % serotonin transporter (SERT) occupancy is the therapeutically useful threshold for SSRI antidepressant therapy (Zipursly et al. 2007).
12.4.3.1 Citalopram
99mTc HMPAO SPECT was used to investigate the response of the brain to the SSRI citalopram in 93 patients with MD. The responder group had a regional cerebral blood flow improvement predominantly in the prefrontal and temporal cortices and in the subgenual cingulate cortex after treatment (Brockmann et al. 2009). In another study, 16 depressed older adults and 13 controls underwent 2 resting (18)F-FDG PET studies after placebo and citalopram infusions. Metabolism decreased in the left superior and middle frontal gyri, while an increase was observed in the left inferior parietal lobule, cuneus and thalamus, and in the right putamen (Smith et al. 2009).
The 5-HT1A receptor antagonist pindolol has been used previously to accelerate the clinical effects of antidepressant therapy by preventing negative feedback. Using alpha-[(11)C]methyl-l-tryptophan PET, a double-blind, randomised study compared the changes in its trapping in patients with unipolar depression treated with citalopram plus placebo versus citalopram plus pindol. The combination citalopram plus pindol achieved a more rapid and greater increase of 5-HT synthesis in prefrontal cortex (Berney et al. 2008).
In a study examining midbrain SERT availability in patients with major depression, the relation of SERT occupancy by citalopram to treatment response was assessed in 21 non-medicated depressed patients by the SERT marker [(123)I]-ADAM SPECT. There was a rapid clinical improvement after citalopram in 54 % of the investigated patients, but only a variable SERT uptake (Herold et al. 2006). In another study, 12 patients with major depression had a SERT marker [(11)C]DASB PET scan after a minimum of 4 weeks high-dose SNRI venlafaxine treatment or sertraline or citalopram. At high therapeutic dose rates, the mean striatal SERT occupancy for each antidepressant was approximately 85 % (Voineskos et al. 2007).
In another study in patients with MD, interregional balance between SERT binding in the raphe nuclei and key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex before treatment was investigated using [(11)C]DASB PET. Measurements were performed before and after a single oral dose, as well as after 3 weeks (mean 24.73 ± 3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Treatment response could be predicted by comparing pretreatment SERT binding in the above regions versus median raphe nucleus binding (Lanzenberger et al. 2012).
12.4.3.2 Escitalopram
Escitalopram is a SSRI approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, responsible for serotonin reuptake activity. It has been hypothesised that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at low-affinity allosteric SERT sites, reducing the effectiveness of the S-enantiomer at the high-affinity sites. SERT occupancy in citalopram- and escitalopram-treated healthy volunteers was measured after single and multiple doses of these drugs. The single-dose study showed no attenuating effect of R-citalopram, but after multiple dosing, SERT occupancy was significantly reduced in the presence of R-citalopram. A pooled analysis suggests that the R-enantiomer build up after repeated citalopram dosing may lead to increased inhibition of the S-enantiomer occupancy of SERT (Kasper et al. 2009). In another study, 25 healthy subjects received a single dose of escitalopram or citalopram. Midbrain binding was measured with the SERT marker [(123)I]-ADAM on 2 study days, once without dosing and once 6 h after a single dose of escitalopram or citalopram. The midbrain-cerebellum/cerebellum ratio was the outcome measure for specific SERT binding in the midbrain. The SERT occupancies of escitalopram and citalopram give indirect evidence of a fractional blockade of SERT by the inactive R-citalopram enantiomer (Klein et al. 2006).
12.4.3.3 Fluoxetine
In a study using 123 I IBZM, the cerebral dopamine-D2 receptors were characterised in 13 patients with major depression. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D2 receptor binding during serotonin reuptake inhibition was found in the striatum and anterior cingulate gyrus in treatment responders, but not in non-responders (Larisch et al. 1997).
In a study that looked at fluoxetine treatment and psychotherapy, it was found that fluoxetine increased [11C]-raclopride binding in the lateral thalamus but that this increase did not correlate with clinical improvement (Hirvonen et al. 2011). In a study to determine the response of SERT to fluoxetine treatment, 23 patients with major depression underwent SPECT scanning using [123I]beta-CIT. Higher pretreatment SERT availability correlated with a positive treatment response (Kugaya et al. 2004).
In a study in unipolar depressed men, common and unique response effects to administration of placebo or fluoxetine were assessed after a 6-week, double-blind trial. Placebo response was associated with regional metabolic increases involving the prefrontal, anterior cingulate, premotor, parietal, posterior insula, and posterior cingulate and metabolic decreases involving the subgenual cingulate, parahippocampus and thalamus. Regions of change overlapped those seen in responders administered active fluoxetine. Fluoxetine response, however, was associated with additional subcortical and limbic changes in the brainstem, striatum, anterior insula, and hippocampus, sources of efferent input to the response-specific regions identified with both agents (Mayberg et al. 2002).
12.4.3.4 Paroxetine
In 12 medication-free depressed patients who completed a 6-week trial of either paroxetine or citalopram, striatal binding was measured with the SERT marker [(11)C]DASB. PET scans were completed before and after 4 weeks of treatment. A significant decrease in striatal SERT binding potential was found after either treatment. An 80 % occupancy of receptors in multiple regions was reported (Meyer et al. 2001a, b). In a study of drug-free depressed outpatients, SERT occupancy was quantified by 123I-FP-CIT SPECT imaging at baseline and after 6 weeks paroxetine. A significant positive relationship between SERT occupancy and clinical improvement existed only in patients who had certain SERT promoter genotypes, namely, the L(A)/L(A) genotype (Ruhé et al. 2009).
In a study of unipolar MD, 24 subjects underwent resting (18)F-FDG scanning before and after 12 weeks either paroxetine or interpersonal psychotherapy. Subjects with MD had regional brain metabolic abnormalities at baseline compared to controls that tended to normalise with treatment. Regional metabolic changes appeared similar with the two forms of treatment (Brody et al. 2001).
In another study of MD, (18)F-FDG PET scans were performed on 13 male patients before and after 6 weeks of paroxetine therapy. After successful paroxetine therapy, increased glucose metabolism occurred in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate. Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions (Kennedy et al. 2001).
12.4.3.5 Fluvoxamine
The effect of chronic treatment with fluvoxamine, a potent SSRI that attaches to 5-HT2 and D2 receptors, was tested in drug-naive unipolar depressed patients using fluoro-ethyl-spiperone ([(18)F]FESP), a high-affinity 5-HT2 and D2 antagonist receptor marker. Fluvoxamine treatment significantly improved clinical symptoms and increased [(18)F]FESP binding in the frontal and occipital cortex of patients who completed the study. No significant changes were found in the basal ganglia where [(18)F]FESP binds mainly to D2 dopamine receptors (Moresco et al. 2000). In studies looking at receptor occupancy, it was found that in effective antidepressant therapy an approximately 80 % of SERT binding occurs (Suhara et al. 2003).
12.4.4 The NDRIs and SNRIs
12.4.4.1 Bupropion
Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) that appears to have a selective affinity for dopamine transporters. In a study to investigate DaT binding after bupropion in depressive patients, bupropion treatment occupied less than 22 % of DaT sites, which raises the question whether there is another mechanism involved during treatment with bupropion (Meyer et al. 2002). In a study that looked at the effect of bupropion and venlafaxine on brain metabolism, 20 patients with unipolar depression received a baseline (18)F-FDG scan, then at least 6 weeks of bupropion or venlafaxine monotherapy. Pretreatment scans showed a frontal and left temporal hypometabolism in depressed outpatients. Alterations in regional metabolism were linked to positive antidepressant responses on bupropion and venlafaxine monotherapy (Little et al. 2005).
12.4.4.2 Venlafaxine
Venlafaxine is a serotonin norepinephrine reuptake inhibitor (SNRI). In a study of patients with MD, seven subjects underwent a 99mTc HMPAO SPECT scan to assess cerebral blood flow changes after venlafaxine. The subjects showed an increased cerebral blood flow bilaterally in the thalamus and a decreased flow in the temporal cortex bilaterally and in the left occipital lobe and right cerebellum (Davies et al. 2003).
Another study was completed in 24 patients with MD. They received a (18)F-FDG PET scan before randomisation and after 16 weeks of antidepressant treatment with either cognitive behavioural therapy (CBT) or venlafaxine. Response to CBT was associated with a reciprocal modulation of cortical-limbic connectivity, while venlafaxine engaged additional cortical and striatal regions (Kennedy et al. 2007).
In another study involving 28 patients with MD, 13 patients had 1-h weekly sessions of IPT from the same supervised therapist (E.M.). Fifteen patients took 37.5 mg twice daily of venlafaxine hydrochloride. 99mHMPAO brain SPECT scans were completed before and after 6 weeks treatment. Both treatment groups improved substantially, more so with venlafaxine (Martin et al. 2001).
12.4.5 The TCAs
12.4.5.1 Nortriptyline and Sertraline
Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow was assessed by the planar (133)Xenon inhalation technique after medication washout and following 6–9 weeks of antidepressant treatment. At baseline, the depressed patients had a reduced cerebral blood flow in frontal cortical regions when compared with controls. After treatment, responders showed a reduced perfusion in the frontal regions (Nobler et al. 2000).
12.4.5.2 Amitriptyline
Cerebral blood flow was assessed by HMPAO SPECT in 14 depressed patients with primary fibromyalgia before and after amitriptyline treatment. There was an improvement in the visual analog scale and tender point count after treatment, but the Beck Depression Inventory did not change significantly. After treatment, cerebral blood flow increased bilaterally in the hemithalami and basal ganglia, and decreases were seen in the temporal regions bilaterally and in the left tempero-occipital and right occipital regions. Although perfusion deficits improved parallel to clinical recovery, the Beck depression scores did not change significantly (Adigüzel et al. 2004).
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