New perspectives on techniques for the clinical psychiatrist: Brain stimulation, chronobiology and psychiatric brain imaging
*Raffaella Zanardi, MD, Department of Psychiatry, Vita-Salute University San Raffaele Hospital, Via Stamira d'Ancona, 20 Milan 20127, Italy. Email: firstname.lastname@example.org
This review summarizes a scientific dialogue between representatives in non-pharmacological treatment options of affective disorders. Among the recently introduced somatic treatments for depression those with most evidenced efficacy will be discussed. The first part of this article presents current opinions about the clinical applications of transcranial magnetic stimulation in the treatment of depression. The second part explains the most relevant uses of chronobiology in mood disorders, while the last part deals with the main perspectives on brain imaging techniques in psychiatry. The aim was to bridge gaps between the research evidence and clinical decisions, and reach an agreement on several key points of chronobiological and brain stimulation techniques, as well as on relevant objectives for future research.
DEPRESSION IS A debilitating and prevalent disease; 4–10% of the general population experiences an episode of major depression within a year, while approximately 30% of men and 40% of women suffer from at least one episode during their lifetime.1
Different antidepressants are available to treat a depressive episode. Nevertheless, the therapeutic latency, the non-response rate and the side-effects of antidepressants are important reasons to search for new non-pharmacological techniques to treat depressive episodes. Among non-pharmacological techniques we focused on transcranial brain stimulation and chronobiologic treatments and we chose not to include such invasive therapies as electroconvulsive therapy (ECT), magnetic seizure therapy and vagus nerve stimulation. Moreover, we describe functional brain imaging, as a tool to investigate neuronal function in vivo, to evaluate the correlation between neural function and treatment response and, eventually, the neural predictors of clinical outcome.
TRANSCRANIAL BRAIN STIMULATION: TREATMENT OF DEPRESSION, OBSESSIVE–COMPULSIVE DISORDER AND TOURETTE SYNDROME WITH TRANSCRANIAL MAGNETIC STIMULATION
Repetitive transcranial magnetic stimulation (rTMS) has become a major research tool in experimental clinical neurophysiology2,3 and cognitive neuroscience4,5 due to its potential to non-invasively and focally stimulate cortical brain regions. Given that the prefrontal cortex plays a significant role in the control of mood and emotional behavior, rTMS has been investigated as an experimental tool in healthy volunteers and as a therapeutic intervention in patients with affective disorders. Preclinical and clinical findings of functional neuroimaging studies demonstrate that rTMS of the dorsolateral prefrontal cortex (DLPFC) modulates regional brain activity in key regions of fronto-limbic circuits, for example anterior cingulate and mesolimbic areas.6 Moreover, there is robust mainly preclinical evidence that rTMS acts on various neuroendocrine and neurotransmitter systems involved in the pathophysiology of depression, that is, it exerts effects on the hypothalamic–pituitary–thyroid and the hypothalamic–pituitary–adrenal axes, on serotonin receptor levels, and induces glutamate release at the stimulation site and dopamine release in mesostriatal and mesolimbic regions.7 Recently, it has been shown that rTMS can also induce striatal dopamine release in patients suffering from major depression,8 as well as in those affected by Parkinson's disease.9–11
An important issue before introducing rTMS into clinical practice is the safety of this therapeutic approach. Several rTMS clinical trials have been conducted, not only in depression, but also in other neuropsychiatric disorders such as schizophrenia, obsessive–compulsive disorder, Parkinson's disease, stroke, epilepsy, tinnitus and chronic pain. These studies show that rTMS is a safe treatment and is associated with few, mild and rapidly reversible side-effects, such as headache and neck pain.12 Although there is a concern that rTMS – especially high-frequency rTMS – can induce seizures, this side-effect can normally be avoided if published safety guidelines are adhered to.13,14 In single cases, however, where comorbidity and co-medication reduce seizure thresholds the benefit versus risk ratio needs to be carefully considered. Moreover, past trials have showed that rTMS treatment induces no long-term changes in the electroencephalography (EEG) and in the cognitive performance; on the contrary, there is evidence that rTMS induces an enhancement in some aspects of the cognition that seems mood independent.
Their is multifold evidence that prefrontal rTMS has considerable antidepressant efficacy,15 but currently published as well as ongoing multicenter trials will provide more robust data on the issues of antidepressant efficacy and effectiveness. The first large, multicenter, randomized controlled trial, involving 301 medication-free patients with major depression who had not benefited from prior treatment, has largely confirmed the safety and efficacy of rTMS, particularly when administered for at least 4 weeks.16 Compared to other brain stimulation approaches, such as ECT, rTMS might have a similar efficacy in non-psychotic depression, thereby providing a less invasive alternative treatment for patients with refractory and severe major depression. In addition, rTMS treatment might be beneficial for a broad spectrum of depressive patients. A recent study showed that rTMS therapy in younger and less treatment-resistant patients is associated with a better outcome, which leads to the question of whether rTMS treatment might be considered also as the first-line treatment for depression along with antidepressant.17 Moreover, rTMS has been shown to be a useful and safe adjunctive treatment for drug-resistant depressed patients when compared to sham stimulation.16,18 Two recent trials have also shown that the response to selective serotonin re-uptake inhibitors (SSRI) and tricyclic antidepressants can be accelerated by concomitant rTMS treatment.19,20
The role of two polymorphisms that influence the response to antidepressants has also been analyzed: the polymorphisms of the serotonin transporter promoter region (SERTPR) and of the 5-HT1A serotonergic receptor promoter region (−1019 C/G). In particular, C/C patients had a better response to rTMS.21
Although several studies on major depression and rTMS have been published, the optimum parameters of stimulation have not been defined as yet. The main reasons for this are: (i) previous studies have mainly used fixed stimulation parameters; and (ii) potential new alternatives of stimulation have not been fully explored yet. An up-to-date review, however, has shown that recent trials, which are likely to have benefited from the insights gained in the earlier trials, have shown larger effect sizes.22 Moreover, different methods such as priming 1-Hz rTMS treatment with 6-Hz rTMS,23 preconditioning rTMS treatment with transcranial direct current stimulation (tDCS),24 theta burst stimulation (TBS)25 and the combination of rTMS with other antidepressants treatments such as antidepressant pharmacotherapy and cognitive behavior therapy (CBT) might further enhance the magnitude and impact of rTMS treatment. In particular, when given after cathodal polarity tDCS (cathode placed over M1), 5-Hz rTMS resulted in a marked facilitation of cortico-spinal excitability.24 TBS, with a burst of three stimuli at 50 Hz (i.e. 20 ms between each stimulus repeated at intervals of 200 ms, i.e. 5 Hz), if administered for 190 s (600 pulses) at 80% of the motor threshold, produced a marked increase in cortical excitability.25 Further studies should evaluate the tolerability and the effects on cortical excitability of TBS with an increased number of pulses and a higher motor threshold. Clinical trials are needed to test if this increase in cortical excitability is correlated with a better clinical response. Finally, it is critical to investigate whether a dose-adjustment strategy with individualized stimulation parameters might maximize its clinical benefits. Therefore development of methods of monitoring brain activity during rTMS treatment such as online EEG might provide valuable information regarding the status of brain cortical excitability. This information can be used to adjust the parameters of rTMS treatment.
Limited data are available about the role of TMS as long-term maintenance therapy for mood disorders. Recent case series suggested that rTMS might be used as an adjunctive maintenance treatment for patients with bipolar depression26 or with refractory depression.27 These data are in agreement with those of the O'Reardon et al. study, which followed 10 unipolar patients for a period ranging from 6 months to 6 years.28 Clearly, these are preliminary data and further trials are necessary to better evaluate the role of rTMS as maintenance therapy in depression.
Several rTMS trials have shown that rTMS is a safe and well-tolerated treatment if administered following the published safety guidelines.13,14
The bulk of studies published on rTMS in the treatment of depression and the most comprehensive and recently updated meta-analysis29,30 show that active rTMS is significantly more effective than sham treatment, but the optimum set of stimulation parameters is still to be determined. Given the large amount of patients who do not achieve response or full remission with antidepressant drugs, the combination with rTMS should be more widely available in clinical practice to treat drug-resistant patients as an initial step until further studies determine whether other strategies of rTMS treatment, such as using rTMS as a first-line therapy, are clinically effective when compared to standard treatments. When using rTMS in clinical practice, age should be taken into account, given that younger patients respond better than elderly patients.17 Another issue that should be considered is the presence of psychotic features, because the possible increase of dopamine induced by rTMS8 may worsen these symptoms. Because evidence for the effectiveness of rTMS in long-term treatment of depression is still scarce, TMS should be used as a treatment in the acute phase.26–28 Moreover, it is important to consider the relationship between clinical benefit and the amount of time needed to regularly undergo rTMS.
CHRONOTHERAPEUTICS OF MOOD DISORDERS
A disruption of circadian rhythms has been hypothesized to be involved in the pathogenesis of mood disorders. This disruption is manifested not only in well-known rhythms such those of cortisol secretion, body temperature or the sleep–wake cycle, but also in other functions such as heart rate.
Circadian rhythms are regulated by a biological clock located in the suprachiasmatic nuclei and are synchronized not only by the external light–dark cycle, but also by other zeitgebers. The genetic components of the master clock follow a circadian pattern of transcriptional–translational feedback loops in order to produce a circadian rhythm. Clock genes are found in all cells, and some zeitgebers (light) act only on the central clock, others (e.g. food) only on peripheral clocks.31
Recent observations about clock genes and their role in the regulation of mammalian circadian rhythmicity have raised interest about the possible role of such genetic mechanisms in the circadian rhythm abnormalities that characterize major depressive episodes.32 A first study in healthy human subjects provides evidence to support this hypothesis: CLOCKgene polymorphism plays a role in the regulation of long-term cyclicity in affective illness.33
The sleep–wake cycle is the most studied rhythmic phenomenon in affective disorders and research on this topic began prior to the general interest on biological rhythms. Approximately 90% of depressed patients complain of bad sleep quality and this clinical observation during a depressive episode is not only a subjective impression but is also reflected in objective sleep EEG measures, for example in Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep changes.34
Because a dysregulation of the sleep–wake cycle can induce a manic or a depressive episode, and remission from depression is often accompanied by a regularization of circadian abnormalities, manipulations of the sleep–wake cycle have been used for the treatment of depression for the last 30 years.35
The consensus arrived at for clinical acute management of a depressive episode using chronotherapeutic methods was: wake therapy, dark therapy and bright light therapy.
Wake therapy (total or partial sleep deprivation) is useful in the treatment of major depression: a single night without sleep can restore euthymia in approximately 60% of treated depressed patients.36 A better effect has been observed in bipolar than in unipolar depressed patients.37 Because approximately 80% of responders relapse shortly after recovery sleep, recent studies have focused on the possibility of sustaining these rapid but transient effects of wake therapy over time. A high proportion (50–70%) of sustained response to total sleep deprivation (TSD) has been attained by combining TSD with other antidepressant or mood stabilizing treatments: both serotonergic, noradrenergic, mixed noradrenergic/serotonergic drugs, lithium salts and light therapy could successfully maintain the acute antidepressant effect of sleep deprivation.38 In particular, ongoing long-term treatment with lithium salts was shown to sustain the effects of repeated TSD, leading to sustained symptomatological remission in approximately 60% of patients.39 Regimens using repeated sleep deprivation (three times a week) seem to sustain the antidepressive effect as well. Recent data suggest that the combination of TSD and light therapy is useful in the treatment of an acute depressive episode in treatment-resistant patients.40
Based on the phase advance hypothesis of depression,41 some European studies indicated that prolonged manipulations of the sleep–wake cycle, such as sleep phase advance, are also able to sustain the effects of TSD both with or without a combined antidepressant drug treatment.42
Consistent data have linked sleep–wake and light–dark rhythms with psychopathological status in patients affected by bipolar disorder, with sleep loss and light exposure elevating mood. These observations led to the hypothesis that sleep disruption due to multiple types of environmental stimuli could act as triggering factors for mood episodes in bipolar patients, and that a strict control of the sleep–wake and light–dark rhythms could act as a mood stabilizer.43 Following this perspective, in a recent study 16 bipolar inpatients affected by a manic episode were exposed to a regimen of 14 h of enforced darkness ('dark therapy', DT) for 3 consecutive days; patients with a manic episode lasting <2 weeks had an amelioration of mood.44 This observation confirms previous findings45 but does not help to clarify whether the therapeutic effects of treatment are due to the dark environment or to improved sleep.
As described here, circadian rhythms are regulated by a biological clock that is principally synchronized by the external light–dark cycle. Bright-light therapy (LT) has been established over the last 20 years as the treatment of choice for seasonal affective disorder.46,47 Morning bright light is more effective than evening administration, and the duration of administration varies from 0.5 to 2 h. Timed light therapy shifts circadian phase and thereby modifies the phase relationship between the internal clock, sleep, and the external light–dark cycle.48 Morning light is scheduled relative to the individual's patients chronotype (later for evening types than for morning types) in order to optimize circadian rhythm phase advances.47,49,50 Many studies have been conducted with the aim of defining the parameters of light administration. Most commonly used is broad-spectrum white light; the question of whether there is any improved efficacy of blue light as opposed to putative harmful retinal side-effects is under intensive discussion.
Light therapy has been also used more and more in non-seasonal major depression. Light therapy is recommended as an add-on to conventional antidepressants in unipolar patients,40 or lithium in bipolar patients. This method provides a viable alternative for patients who refuse, resist or cannot tolerate medication, or for those in whom drugs may be contraindicated, as in antepartum depression.
In clinical practice wake therapy is quite more effective in bipolar than in unipolar patients,37 while light therapy has a better documented effectiveness on seasonal disorders.46 Nevertheless, recent studies showed a good efficacy of LT in other depressive syndromes as well.51 In the last few years the combination of antidepressant drugs and lithium salts with sleep–wake rhythm manipulation and light therapy, have provided clinicians with new ways to achieve rapid and sustained antidepressant responses. Given the urgent need for new strategies to treat patients with residual depressive symptoms, further clinical trials of wake therapy and/or adjuvant light therapy, coupled with follow-up studies of long-term recurrence, are a high priority.
NEW TECHNOLOGIES: PSYCHIATRIC BRAIN IMAGING
Psychiatric disorders have a very complex etiology, with known interactions among genetic, psychological, and environmental factors. Despite their clinical impact, the specific neurophysiologic basis of psychiatric disorders are still unknown. Considerable progress, however, has been made in identifying the brain regions and neural circuits that underlie normal and abnormal emotion processing, cognitive functioning, perceptions and mood regulation. In the past years neuroimaging research has emerged as a valuable tool in enlarging our knowledge and understanding of mental diseases. Of the several neuroimaging modalities, including positron emission tomography, functional magnetic resonance imaging (fMRI), and single-photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS) provides unique information on the tissue concentration in vivo of some 25–30 biochemical constituents in anatomically distinct areas of the brain. Importantly, MRS is non-invasive, has high spatial resolution, and requires neither radioactive tracers nor ionizing radiation. Although MRS has been used primarily as a research tool, the recent improvements in technology make MRS a valuable tool for both researchers and clinicians. In fact, MRS has demonstrated utility for both diagnosis and treatment assessment in numerous central nervous system disorders.52,53
Because neurochemical information of the brain can be obtained in vivo, MRS holds considerable promise to illuminate brain mechanisms involved in depression.54,55 In psychiatry, investigators are primarily using proton (1H) MRS. 1H spectroscopy can distinguish N-aspartate (NAA), creatine and phosphocreatine, and phosphatidylcholine. Signals can be obtained from glutamate, glutamine, γ-aminobutyric acid, lactate and inositol phosphates. NAA is found in neurons and is absent in most glial cell lines. Decreases in NAA may reflect a diminished number or density of neurons. Creatine and phosphocreatine are important energy substrates, and phosphatidylcholine is an important component of cell membranes. Comparisons have been made of the concentrations of substances between healthy brains and brains with neuropsychiatric abnormalities.56,57 With respect to treatment strategies for depression, MRS may prove ideal for longitudinal studies aimed at defining the neurochemical correlates of different therapeutic strategies, the contribution of the different neurotransmitters to the functioning of brain areas putatively involved in the pathogenesis of the disease, or the differences between mood pathology and euthymic state.58,59
fMRI research, with its superior resolution compared to other imaging techniques, has provided unprecedented opportunities for elucidating the anatomical correlates of major depression. Indeed, functional neuroimaging studies have proved to be a useful method for investigating the neural correlates of some of the core features of major depression, such as sustained negative emotion processing, specific mood congruent bias to negative information, rumination, and cognitive impairment.60
The acute tryptophan depletion (ATD) technique has been used to probe 5-HT function in several populations, most commonly in patients recovered from depression. A consistent finding is that ATD causes a partial return of symptoms in some patients recovered from depression, particularly those stabilized on SSRI. Several studies have investigated the effect of ATD on regional blood oxygen-level dependent (BOLD) responses during cognitive paradigms using fMRI in healthy volunteers.61 Roiser et al.62 performed a double-blind, placebo-controlled crossover-design study. Participants attended two testing days during which their only dietary intake consisted of a 33-g amino acid mixture that either contained or lacked tryptophan. Five hours following amino acid ingestion (T5), participants performed the Affective Go/No-Go test during fMRI. Patients and controls differed in terms of the effect of ATD on BOLD responses to emotional stimuli, as shown by treatment × diagnosis interactions in several regions previously implicated in depression. These included the right frontal polar cortex, left anterior insula, left ventrolateral prefrontal cortex, left posterior orbital cortex, anterior cingulate cortex (ACC), posterior cingulate cortex, right parahippocampal gyrus and left caudate.
Models of emotion perception in depression do not always entirely accord to findings because there is conflicting evidence of increased or decreased indices of brain activation in depression, such as metabolic changes, regional cerebral blood flow (rCBF), and BOLD contrast.63,64 These inconsistencies are partly due to variations in sample size, sample characteristics (e.g. age and gender), medication status (treatment-naive, unmedicated, or medicated), chronicity of illness, and the imaging techniques and parameters used. The definition of a phenotype, however, which is homogenous with respect to imaging abnormalities, still represents the major limit in comparing the results available in the literature. Clinical neuroscientific investigations into the biology of mood disorders struggle with the limitation that psychiatric nosology remains at a syndromic level, in which non-specific behavioral and neurovegetative signs, rather than pathophysiology, are used to define major depression. There are regions, however, that have been consistently identified to have metabolic changes in sadness and depression.65,66 Mayberg et al. found that sadness in healthy subjects was associated with both increases and decreases in rCBF, compared with rest: increases were seen in ventral limbic and paralimbic sites (subgenual cingulate [Brodmann area 25] and ventral, mid-, and posterior insula); decreases were predominantly in dorsal cortical regions (right dorsal prefrontal [Brodmann area 46/9], inferior parietal [Brodmann area 40], dorsal anterior cingulate [Brodmann area 24b], and posterior cingulate [Brodmann area 23/31]).67 Moreover, some of the most interesting findings of neuroimaging studies are the correlates of response to treatment in depression. In a subset of patients given pharmacological treatment for depression, post-treatment metabolism relative to pretreatment metabolism was associated with both increases and decreases in specific limbic-paralimbic and neocortical sites, but in a pattern inverse to that seen with provoked sadness. Remission of depression was characterized by metabolic increases in dorsal cortical regions (right dorsolateral prefrontal [Brodmann area 46/9], inferior parietal [Brodmann area 40], dorsal anterior cingulate [Brodmann area 24b], and posterior cingulate [Brodmann area 23/31]) and concomitant decreases in ventral limbic and paralimbic sites (subgenual cingulate [Brodmann area 25] and ventral, mid-, and posterior insula).67 Mayberg et al. reported that metabolic activity in ventral anterior cingulate was elevated before treatment and reduced after clinical improvement in responders to antidepressant medications.68
Davidson et al. found that neural responses to blocks of negative and positive affective stimuli in ACC and insula were associated with response to venlafaxine antidepressant treatment.69 Changes in fMRI activation in the amygdala with ongoing bupropion extended release (XL) medication correlated with improvements on the Hamilton Rating Scale for Depression.70
A fundamental neuropsychological impairment in depression is a mood-congruent processing bias such that ambiguous or positive events tend to be perceived as negative. In particular, depressed patients show a diminished ability to discern affective facial expressions. In a study by Fu et al., depressed subjects had reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex over time, and a negatively correlated increase of differential response to variable affective intensity (dynamic range) in the prefrontal cortex.71 Symptomatic improvement after treatment with fluoxetine was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. Chen et al. evaluated fMRI and structural MRI (sMRI) data as predictors of symptom change in people with depression.72 Faster improvement was predicted by greater functional activation of ACC. Faster rates of symptom improvement were strongly associated with greater gray matter volume in ACC, insula, and right temporo-parietal cortex. Because MRI is a less expensive and complex technique, these results could facilitate study of antidepressant predictors of response on a larger scale.
The effect on brain activation of non-pharmacological intervention for the treatment of depression, such as CBT, has also been tested through an emotional words task.73 Improved response to CBT was associated with lower pretreatment reactivity in the subgenual cingulate cortex and higher pretreatment reactivity in the amygdala.
Also studies on sleep deprivation have found that patients who underwent this treatment had consistent cerebral metabolic changes. Ebert et al. first reported in a SPECT study that one of the markers that differentiates depressed responders from depressed non-responders at baseline is higher cingulate activity in the responders, which is decreased with sleep deprivation response.74 Further, three different groups reported that responders had increased relative localized metabolic activity in the general location of the ventral ACC compared with non-responders or normal controls at baseline.75–77 All the studies in which patients, both before and after sleep deprivation, were compared, reported that clinical improvement was associated with normalization of the increased metabolic activity in the area of the ventral anterior cingulate/medial prefrontal regions.74–77
SPECT has been used also to study predictors and correlates of the response to TMS in depression. Langguth et al. have shown that high pretreatment anterior cingulated cortex activity was a positive predictor of treatment response to 2 weeks of 10-Hz rTMS over left DLPFC.78 Shinsuke et al. have found that a successful rTMS treatment was associated with a significant increase in rCBF in the left DLPFC in the stimulated region.79 Moreover, there was a relationship between the improvement in symptoms of depression and the increase in rCBF in the left DLPFC, the left subgenual cingulate, the anterior cingulated cortex, the ventrolateral prefrontal cortex, the orbitofrontal cortex, the anterior insula, and the right putamen/pallidum.
The recent mapping of the human genome has prompted a new series of questions that include the function of individual genes at the level of brain physiology, the contribution of genetic factors to susceptibility to psychiatric disorders, and their related neurobiology. Within the framework of these questions, recent studies are beginning to explain the relationship between genes, neurons, brain networks, and behavior, as well as to shed light on the basis of the individual variability with regard to this relationship.80,81 Current brain imaging techniques provide novel tools to study more specifically the relationship between behavior, pathophysiology, genetics, and treatment.82 The major contribution of these techniques is that they permit the creation and analysis of statistical maps of brain activity in single subjects as well as in groups of individuals. Thus, functional brain imaging allows statistical exploration of the main effect of genes at the brain systems level during specific behaviors. Furthermore, once the physiological effect of genetic variants is known, the effect of the same genetic variants can be measured in brain disorders.
Brain-derived neurotrophic factor (BDNF) and serotonin transporter (SERT) genes, both of which have been associated with psychopathological states, are important in brain development and in functions related to memory and emotion. Genetic variations of the BDNF (val66met) and SERT gene (5-HTTLPR) affect the function of these proteins in neurons and predict variation in human memory and in fear behavior. In a previous work Pezawas et al. showed that the S allele of 5-HTTLPR affects the integrity, function and connectivity, and presumably development of a neural circuit linking amygdala and rostral anterior cingulate circuitry, a circuitry related to anxious temperament and depression in the presence of environmental adversity.83 Additionally, they could show that val66met BDNF affects the development and function of brain circuitries (hippocampus, DLPFC) prominently implicated in aspects of cognitive functioning (e.g. working memory).84 Convergent evidence links BDNF to depression, such as data showing an association of the functional val66met BDNF polymorphism with increased risk for mood disorders, for temperamental traits related to mood disorders, and associated increases of BDNF expression after ECT and antidepressive SSRI treatment.85 These data implicating a biological interaction of BDNF with 5-HTTLPR-dependent signaling suggest a molecular mechanism that could support an epistatic interaction between the functional variants in these genes in risk for depression. Recently, Benedetti et al. focused on the interaction between genotype, antidepressant response and a BOLD fMRI moral valence task.86 The search for genetic factors predisposing to antidepressant response in affective disorders showed that a polymorphism in SERTPR predicted efficacy for a range of treatments,87 including TSD alone or in combination with LT in patients affected by bipolar depression. The same SERTPR has been shown to influence core features of affective illness, such as age at onset and recurrence of mood episodes, and, in healthy subjects, the neural response of limbic structures to emotional stimuli88 and the functional coupling of ACC and medial prefrontal cortex with amygdala.83 The effect of TSD combined with light therapy on event-related neural responses to a go/no-go task with emotional words in a homogeneous sample of patients affected by bipolar depression was assessed. Significant interactions of treatment, response to treatment, and moral valence of the stimuli were found in ACC, DLPFC, insula, and parietal cortex. In these areas responders changed their BOLD responses to emotional stimuli in a pattern opposite to that of non-responders. Genotype of the promoter for the serotonin transporter predicted response to treatment: at end-point, but not at baseline, homozygotes for the short allele had significantly worse Hamilton rating scale for depression (HDRS) scores. Genotype of the promoter for the serotonin transporter also influenced baseline neural responses in anterior cingulated cortex and DLPFC.86
Brain volume was investigated for regions that had a significant interaction of SERTPR polymorphism (l/l, l/s, and s/s) and moral valence of the stimuli (positive–negative) at baseline in order to see if the predictive value of SERTPR genotype could be correlated to a baseline influence on neural responses to the task. Two of these voxels were located in the a priori regions of interest: right ACC (Brodmann area 24) and right DLPFC (Brodmann area 46).
Furthermore, in both ACC and DLPFC baseline activations for negative and for positive stimuli varied according to SERTPR genotype, with l/l subjects having minimal activations for negative, and maximal for positive stimuli; s/s subjects having the opposite pattern; and heterozygotes l/s having intermediate values.86
Nowadays, agreement about the future key role of neuroimaging techniques, especially those that are non-invasive such as fMRI, has been reached. The ability of fMRI to investigate the function of integrated neural networks within the human brain makes it the optimal tool to elucidate individual differences in behavior, psychopathology and personality.
TMS and chronotherapeutics are non-pharmacological techniques to treat depressive episodes that could be used to enhance or to replace antidepressants. Neuroimaging techniques show that the antidepressant response to these treatments may share common biological substrates. The optimal target for chronotherapeutics seems to be the classical depressive syndrome; moreover, consistent findings showed that diagnosis is a predictor of response, with bipolar depressed patients receiving higher benefit than unipolar depressed patients from sleep deprivation.37 In contrast, TMS has been longer evaluated as a treatment for patients with refractory and severe major depression but recent trials have also shown that the response to antidepressants can be accelerated by concomitant rTMS treatment.16,18,20
Nevertheless, available evidence does not allow the creation of a treatment algorithm to unmistakably select and combine these treatments in different types of depression. All these therapies can be combined with traditional antidepressants when drugs do not produce a satisfying clinical effect, giving a wide application in clinical practice.
Future perspective is to better analyze these treatments, to search for optimum parameters and to develop a treatment algorithm for the choice of the best non-pharmacological antidepressant therapy for each patient.
Brain imaging techniques examine the relationship between behavior, pathophysiology, genetics, and treatment, and the development of this area would help to optimize the application both of rTMS and of chronotherapeutics.