International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study.

OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.

Clinical correlates of augmentation/combination treatment strategies in major depressive disorder.

OBJECTIVE: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). METHOD: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. RESULTS: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. CONCLUSION: Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities.

Neuronal cell adhesion genes and antidepressant response in three independent samples.

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.

Chromosome 10q harbors a susceptibility locus for bipolar disorder in Ashkenazi Jewish families.

We report the results of a 10 cM density genome-wide scan and further fine mapping of three chromosomal candidate regions in 10 Belgian multigenerational families with bipolar (BP) disorder. This two-stage approach revealed significant evidence for linkage on chromosome 10q21.3-10q22.3, showing a maximum multipoint parametric heterogeneity logarithm of odds (HLOD) score of 3.28 and a nonparametric linkage (NPL) score of 4.00. Most of the chromosome 10q evidence was derived from a single, large Ashkenazi Jewish pedigree. Haplotype analysis in this pedigree shows that the patients share a 14-marker haplotype, defining a chromosomal candidate region of 19.2 cM. This region was reported previously as a candidate region for BP disorder in several independent linkage analysis studies and in one large meta-analysis. It was also implicated in a linkage study on schizophrenia (SZ) in Ashkenazi Jewish families. Additionally, we found suggestive evidence for linkage on chromosome 19q13.2-13.4 (HLOD 2.01, NPL 1.09) and chromosome 7q21-q22 (HLOD 1.45, NPL 2.28). Together, these observations suggest that a gene located on chromosome 10q21.3-10q22.3 is underlying the susceptibility both for SZ and for BP disorder in at least the Ashkenazi Jewish population.

Hemodialysis in schizophrenics. A double-blind study.

The therapeutic effects of hemodialysis were evaluated in 19 schizophrenics with random assignment to active (n = 10) or sham (n = 9) dialysis. Evaluations were done before and after one month of treatment by an investigator blind to the type of dialysis using four rating scales. Five of the ten patients undergoing active dialysis and three of the nine patients undergoing sham dialysis showed clinical improvement on the psychiatric rating scales. There were no significant differences between the two groups in the magnitude of this improvement. For three patients treated by active dialysis after sham dialysis, there were no significant differences. Three other patients whose conditions dramatically improved by active dialysis did not confirm such a beneficial effect with a second period of active dialysis. Transient improvement of some schizophrenic patients cannot thus be explained by blood clearance through dialysis.

Multiple-threshold transmission of affective disorders.

Data on bipolar and unipolar affective disorders were gathered on first-degree relatives of 255 patients with both illness types. As consistent with a model of continuous liability, bipolar probands were found to have more bipolar relatives and more relatives with any affective disorder than unipolar probands. Multiple-threshold models of inheritance were applied to the data using clinical polarity as a threshold determinant. The hypothesis of multifactorial inheritance was ruled out. Autosomal single-major-locus inheritance provided an acceptable fit to the data. It is proposed that separate genetic mechanisms for bipolar and unipolar disorders need not be present. The two illness types are represented in the model at different thresholds on a single continuum of genetic-environmental liability in which bipolar illness is claimed to be more deviant genetically than unipolar illness.

Color blindness linkage to bipolar manic-depressive illness. New evidence.

Linkage between protanopia and deuteranopia and bipolar manic-depressive illness is demonstrated in a sample of eight informative families ascertained in Brussels. Genetic heterogeneity of bipolar affective disorders is also shown in the present study. These results add new evidence to the hypothesis of X-linked dominant genetic transmission of affective liability in a subgroup of patients with bipolar affective disorders.

Accuracy of the family history method in affective illness. Comparison with direct interviews in family studies.

We interviewed available spouses and first-degree relatives of 140 bipolar and unipolar probands for current and past psychopathology, and assessed interrater reliability. Diagnoses based on direct interviews of relatives were compared with those based on reports of the probands and of all other interviewed family members. Probands underestimated the prevalence of affective illness and other psychiatric disorders in their relatives, and overestimated the age of onset of illness in their ill relatives. Probands reported more accurately about illness in their spouses and parents than in their siblings and children, but accuracy reached acceptable levels for spouses only. Diagnoses on relatives derived by combining reports of all other interviewed family members, including the proband, were slightly more accurate than those based on the proband's reports alone. Good accuracy was obtained only for reports about spouses.

Reduced clonidine rapid eye movement sleep suppression in patients with primary major affective illness.

Clonidine hydrochloride, administered intravenously (2 micrograms/kg) during the second non-rapid eye movement period, was significantly less suppressant of rapid eye movement sleep in 10 depressed patients with primary major affective illness, according to Research Diagnostic Criteria, than in three groups of matched subjects (10 normal controls, 10 patients with minor depression, and 10 patients with generalized anxiety). These results suggest that depressed patients with major primary affective illness have down-regulated alpha 2-adrenergic receptors. These findings are consistent with the cholinergic-aminergic balance hypothesis of depression and support the aminergic side of the concept. Finally, the rapid eye movement sleep response to clonidine could provide a new biological marker of affective illness.

The 24-hour profiles of cortisol, prolactin, and growth hormone secretion in mania.

OBJECTIVE: To characterize sleep and the 24-hour profiles of cortisol, prolactin (PRL), and growth hormone (GH) secretion in mania. METHODS: Blood was sampled at 15-minute intervals, and sleep was polygraphically recorded in eight unmedicated male patients with pure mania and the results compared with those from a group of 14 healthy age-matched controls. The circadian, sleep-related, and pulsatile hormonal variations were quantitatively characterized using specifically designed computer algorithms. RESULTS: The manic state was associated with alterations of corticotropic activity and circadian rhythmicity partially overlapping those previously observed in acute endogenous depression, consisting of an elevation of nocturnal cortisol levels and an early timing of the nadir of the circadian variation. Sleep onset was delayed and the sleep period was reduced. A trend for short rapid eye movement latencies was apparent in the adult patients. Both the amount and the temporal organization of PRL and GH secretion were normal. CONCLUSION: The manic state seems to be characterized by similar but less severe neuroendocrine and circadian abnormalities, compared with major depression.

Circadian and sleep-related endocrine rhythms in schizophrenia.

Plasma levels of prolactin, growth hormone, corticotropin, and cortisol were measured at 15-minute intervals for 24 hours in nine unmedicated male schizophrenic patients and in nine age-matched normal male subjects. Each study was preceded by 3 days of habituation to the laboratory environment. Sleep was polygraphically recorded. The circadian and pulsatile variations present in each hormonal profile were quantitatively characterized with the use of computer algorithms specifically designed for analyses of hormonal fluctuations. The major abnormality of neuroendocrine release that was observed in the schizophrenic patients was an almost threefold enhancement of the sleep-related increase in the prolactin level, associated with an intensified frequency of nocturnal prolactin pulses. This increased stimulatory effect of sleep on prolactin secretion was evident immediately after sleep onset. The normal inhibition of cortisol secretion during early sleep was absent in schizophrenic patients. The major sleep abnormalities were a prolonged sleep latency and a reduction in total rapid eye movement stage sleep. During wakefulness, prolactin and cortisol levels were normal. The 24-hour profile of growth hormone was unaltered in schizophrenic patients, and a sleep-onset growth hormone pulse was observed in all patients. No abnormalities were noted in the levels or temporal organization of corticotropin secretion. Both the amplitude and the timing of the cortisol rhythm were normal. We conclude that, in schizophrenic men, pituitary-adrenal function and circadian time-keeping are normal but prolactin secretion is hyperresponsive to the physiologic stimulus of sleep onset. Schizophrenia thus appears to be characterized by a subset of neuroendocrine disturbances distinct from that observed in major endogenous depression.

The 24-hour profile of plasma prolactin in men with major endogenous depressive illness.

Plasma prolactin (PRL) levels were measured at 15-minute intervals for 24 hours in 18 men suffering from major endogenous depressive illness and in 7 age-matched healthy men. Eleven of the 18 depressed patients were restudied during clinical remission following either electroconvulsive therapy or treatment with amitriptyline hydrochloride. During the acute phase of the illness, the unipolar depressed patients had fragmented patterns of PRL secretion with an early timing of the nocturnal secretory phase of PRL, which started, on the average, 2 hours earlier than in healthy subjects. Moreover, the amplitude of the circadian variation of PRL was reduced in these patients, with subnormal PRL levels occurring during the midsleep period. This latter abnormality was also observed in bipolar patients, who had otherwise normal PRL profiles. These lower midsleep PRL concentrations were associated with a significant increase in the amount of time spent awake during the same period. Antidepressant treatment did not consistently correct the abnormalities in the patterns of PRL release observed during the acute phase of the illness. These results indicate that early timing of nocturnal PRL secretion and damping of the nighttime PRL elevation may be found in men with endogenous depressive disorders. In contrast to disturbances of the corticotropic and somatotropic axes, these abnormalities of PRL secretion may still be present during clinical remission following antidepressant treatment.

In search of anticipation in unipolar affective disorder.

Controversial evidence exists regarding the presence of the phenomenon of anticipation in affective disorder. To further evaluate this hypothesis on the unipolar pattern of the disease, we examined 21 two-generation pairs of first and second degree relatives with unipolar recurrent major depression. Biases from index-patient and from unaffected sibs were taken into consideration. A significant difference in the age at onset and episode frequency (as measure of disease severity) between parental and offspring generation was observed. The median age at onset of the parental generation was 37+/-8.2 years compared to 22+/-8.3 years in the offspring generation (p=0.001). The offspring generation also experienced an episode frequency two times greater than the parent generation (p=0.001). Anticipation was demonstrated in 95% of pairs regarding age at onset and in 84% of pairs in episode frequency. However, the observation of a birth cohort effect may possibly explain the differences in age at onset between generations in our sample.

Genetic control of 24-hour growth hormone secretion in man: a twin study.

The aim of this study was to delineate the contributions of genetic and environmental factors in the regulation of the 24-h GH secretion. The 24-h profile of plasma GH was obtained at 15-min intervals in 10 pairs of monozygotic and 9 pairs of dizygotic normal male twins, aged 16-34 yr. Sleep was polygraphically monitored. Significant pulses of GH secretion were identified using a modification of the computer algorithm ULTRA. For each significant pulse, the amount of GH secreted was calculated by deconvolution. A procedure specially developed for twin studies was used to partition the variance of investigated parameters into genetic and environmental contributions. A major genetic effect was evidenced on GH secretion during wakefulness (with a heritability estimate of 0.74) and, to a lesser extent, on the 24-h GH secretion. Significant genetic influences were also identified for slow wave sleep and height. These data demonstrate that human GH secretion in young adulthood is markedly dependent on genetic factors.

Diurnal hypersecretion of growth hormone in depression.

A 24-h profile of plasma GH concentrations was obtained together with polygraphic recordings of sleep in 16 men suffering from a major depressive disorder (8 unipolar and 8 bipolar) and in 8 age- and sex-matched normal men. None of the patients had any physical illness. All were studied after a drug-free period of at least 15 days. Blood was sampled every 15 min. The amount of GH released in every significant secretory spike was estimated using a computer program. Both unipolar and bipolar depressed patients secreted more GH than normal men (mean +/- SD, 441 +/- 189 micrograms/24 h for unipolar depressed men; 357 +/- 143 micrograms/24 h for bipolar depressed men vs. 172 +/- 101 micrograms/24 h for normal men (P less than 0.01). This hypersecretion occurred during waking hours rather than during sleep. The increase in daytime GH release was more marked in unipolar depressed patients. During sleep, depressed patients and normal men secreted similar amounts of GH despite an overall reduction in slow wave stages in depressed patients. An early sleep GH increase was found in all but one of the normal men, but was absent in seven of the eight unipolar depressed patients, who had, instead, a presleep increase in between 2100-0000 h. No consistent disturbance of the temporal association between sleep onset and GH secretion was found in bipolar depressed patients.

24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment.

Plasma ACTH, cortisol, and GH concentrations were measured at 15-min intervals for 24 h in 11 men suffering from major depressive illness during an acute episode of depression and during clinical remission following antidepressant treatment with either electroconvulsive therapy or amitriptyline. Seven age-matched normal men also were studied. During the acute phase of the illness, the patients had abnormally short rapid eye movement sleep latencies, hypercortisolism, early timing of the nadirs of the ACTH-cortisol rhythms, and shorter nocturnal periods of quiescent cortisol secretion. GH was hypersecreted during wakefulness, and a major pulse occurred before, rather than after, sleep onset. After treatment, rapid eye movement sleep latencies were lengthened, and cortisol levels returned to normal due to a decrease in the magnitude of episodic pulses. Moreover, the timing of the circadian rhythms of ACTH and cortisol as well as the duration of the quiescent period of cortisol secretion were normalized. The amount of GH secreted during wakefulness decreased to normal values, with fewer significant GH pulses. The major elevation of GH secretion in the early part of the night occurred later than that during the depressive episode. These results demonstrate that a disorder of circadian rhythmicity characterizes acute episodes of major depressive illness and that this chronobiological abnormality as well as the hypersecretion of ACTH, cortisol, and GH are state rather than trait dependent.

Immediate and delayed alterations of adrenocorticotropin and cortisol nyctohemeral profiles after corticotropin-releasing factor in normal man.

Intravenous injections of 50 micrograms corticotropin-releasing factor (CRF) to four normal men at 0900 and 2300 h were followed by significant plasma ACTH and cortisol elevations, without changes in GH and PRL concentrations. The responses were more easily assessed late in the evening than in the morning, when they were superimposed upon the spontaneous hormonal variations. The initial hormonal response was always followed by a period of decreased hormonal values compared to control patterns. The normal pituitary-adrenal response to CRF was blunted or abolished by prior administration of dexamethasone. These data suggest that exogenous administration or CRF-induced endogenous production of glucocorticoids modulates the sensitivity of corticotropic cells to the action of CRF. Since normal ACTH and cortisol secretory episodes are likely to obscure the effects of CRF, stimulation tests for clinical purposes should be performed during the quiescent period, i.e. late in the evening.