You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease
Abstract 1:
Cholinergic neuron loss is a cardinal feature of Alzheimer disease . Nerve growth factor ( NGF ) stimulates cholinergic function , improves memory and prevents cholinergic degeneration in animal models of injury , amyloid overexpression and aging . We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease , implanting autologous fibroblasts genetically modified to express human NGF into the forebrain . After mean follow-up of 22 months in six subjects , no long-term adverse effects of NGF occurred . Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline . Serial PET scans showed significant ( P < 0.05 ) increases in cortical 18-fluorodeoxyglucose after treatment . Brain autopsy from one subject suggested robust growth responses to NGF . Additional clinical trials of NGF for Alzheimer disease are warranted


Title 2:
Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): An exploratory analysis
Abstract 2:
The neurotrophic hypothesis of depression states that the major depressive episode is associated with lower neurotrophic factors levels , which increase with amelioration of depressive symptoms . However , this hypothesis has not been extended to investigate neurotrophic factors other than the brain-derived neurotrophic factor ( BDNF ) . We therefore explored whether plasma levels of neurotrophins 3 ( NT-3 ) and 4 ( NT-4 ) , nerve growth factor ( NGF ) and glial cell line derived neurotrophic factor ( GDNF ) changed after antidepressant treatment and correlated with treatment response . Seventy-three patients with moderate-to-severe , antidepressant-free unipolar depression were assigned to a pharmacological ( sertraline ) and a non-pharmacological ( transcranial direct current stimulation , tDCS ) intervention in a r and omized , 2 × 2 , placebo-controlled design . The plasma levels of NT-3 , NT-4 , NGF and GDNF were determined by enzyme-linked immunosorbent assay before and after a 6-week treatment course and analyzed according to clinical response and allocation group . We found that tDCS and sertraline ( separately and combined ) produced significant improvement in depressive symptoms . Plasma levels of all neurotrophic factors were similar across groups at baseline and remained significantly unchanged regardless of the intervention and of clinical response . Also , baseline plasma levels were not associated with clinical response . To conclude , in this 6-week placebo-controlled trial , NT-3 , NT-4 , NGF and GDNF plasma levels did not significantly change with sertraline or tDCS . These data suggest that these neurotrophic factors are not surrogate biomarkers of treatment response or involved in the antidepressant mechanisms of tDCS


Title 3:
Raised plasma nerve growth factor levels associated with early-stage romantic love
Abstract 3:
Our current knowledge of the neurobiology of romantic love remains scanty . In view of the complexity of a sentiment like love , it would not be surprising that a diversity of biochemical mechanisms could be involved in the mood changes of the initial stage of a romance . In the present study , we have examined whether the early romantic phase of a loving relationship could be associated with alterations in circulating levels of neurotrophins ( NTs ) . Plasma levels of NGF , BDNF , NT-3 and NT-4 were measured in a total of 58 subjects who had recently fallen in love and compared with those of  two control groups  , consisting of subjects who were either single or were already engaged in a long-lasting relationship .  NGF level was significantly higher ( p < 0.001 ) in the subjects in love [ mean ( SEM ) : 227 ( 14 ) pg/ml ] than in either the subjects with a long-lasting relationship [ 123 ( 10 ) pg/ml ] or the subjects with no relationship [ 149 ( 12 ) pg/ml ] . Notably , there was also a significant positive correlation between levels of NGF and the intensity of romantic love as assessed with the passionate love scale ( r = 0.34 ; p = 0.007 ) . No differences in the concentrations of other NTs were detected . In 39 subjects in love who-after 12 - 24 months-maintained the same relationship but were no longer in the same mental state to which they had referred during the initial evaluation , plasma NGF levels decreased and became indistinguishable from those of the control groups . Taken together , these findings suggest that some behavioural and /or psychological features associated with falling in love could be related to raised NGF levels in the bloodstream


Title 4:
NGF serum levels variations in major depressed patients receiving duloxetine
Abstract 4:
BACKGROUND S Nerve growth factor ( NGF ) is involved in the modulation of the neuro-endocrine-immune ( NEI ) system , whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder ( MDD ) . Objective of the study was to investigate NGF levels variations in MDD patients during  antidepressant treatment with duloxetine , a relatively newer SNRI . METHODS 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale ( HAM-D ) and monitored for  NGF serum levels at baseline , week 6 and week 12 of duloxetine treatment ( 60 mg/day ) and at baseline , respectively . RESULTS According to early clinical response to duloxetine ( defined at week 6 by reduction > 50 % of baseline HAM-D score ) , MDD patients were distinguished in early responders ( ER ) and early non-responders ( ENR ) , who overall reached clinical response at week 12 . Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls , not significantly in ER and significantly in ENR . During duloxetine treatment NGF levels further decreased in association with clinical response , reaching significantly lower values in ER at W6 compared to controls , and in ENR at W12 compared to baseline . CONCLUSIONS A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system , since stressors , inducing neuronal instability due to neurotrophins activity changes , permits circuitry remodeling as background in the selection of alternative adaptive behaviors . However , the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point , possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders


Title 5:
Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment.
Abstract 5:
INTRODUCTION Stress , glucocorticoids and anti-depressant treatment have been found to modulate the expression of brain-derived neurotrophic factor ( BDNF ) and nerve growth factor ( NGF ) . Recent research suggests that serum BDNF concentration is reduced in depression and that successful antidepressant treatment leads to an increase in serum BDNF concentration . METHODS We studied depressed patients receiving a st and ardized antidepressant treatment with either 150 mg amitriptyline ( n=20 ) or 40 mg paroxetine ( n=20 ) for 36 days in a prospect i ve design . Changes in the concentrations of serum neurotrophins and salivary cortisol in response to antidepressant treatment were assessed . RESULTS Independent of clinical efficacy there was a significant ' treatment ' by ' medication ' interaction effect on BDNF serum concentrations that indicated a decline of BDNF by 12 % in paroxetine-treated patients while there was an increase by 13 % in amitriptyline-treated patients . Neither antidepressant altered NGF concentrations . The changes in cortisol and neurotrophin concentrations were not related . DISCUSSION Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant instead of being a general characteristic of response to antidepressant treatment


Title 6:
Ultradian Variation of Nerve Growth Factor Plasma Levels in Healthy and Schizophrenic Subjects
Abstract 6:
Some studies in animal models showed that several neurotrophins may be implicated in the regulation of light-dependent suprachiasmatic pacemaker and in other functions implicated in long-term memory acquisition during sleep . However , no data are known about the role played by NGF in ultradian regulation in humans . The aim of this study was to investigate whether or not there is a natural diurnal fluctuation during daytime in healthy and schizophrenic subjects with a normal light/dark cycle . In a sample of 33 subjects ( 10 male schizophrenics and 23 healthy subjects ) an ELISA assay was used to study the ultradian NGF cycle in blood sample s at 9.00 , 13.00 and 20.00 hours . The study showed an ultradian rhythm of NGF in healthy subjects with a “ V ” trend : higher at 9:00 and 20:00 and lower at 13:00 . We also show significant differences between male and female controls . No NGF ultradian rhythm among schizophrenic patients compared to healthy subjects was found . The results of this study lead to a rhythmic NGF regulation that appears altered in schizophrenics , where higher levels in the morning and lower levels in the evening were observed , compared to the controls , and support the hypothesis of a role played by NGF in schizophrenia
Our study highlights the significant differences in peripheral NGF levels in patients with MDD .