Noah S. Philip

Nicotinic acetylcholine receptors and depression: a review of the preclinical and clinical literature

Many patients with depression fail to derive sufficient benefit from available treatment options, with up to a third never reaching remission despite multiple trials of appropriate treatment. Novel antidepressant agents are needed, and drugs targeting nicotinic acetylcholine receptors (nAChRs) appear to hold promise in this regard. nAChRs are involved in a variety of neurobiological systems implicated in the pathophysiology of depression. In addition to their role in cholinergic neurotransmission, they modulate dopamine function and influence inflammation and hypothalamic–pituitary–adrenal axis activity. Preclinical studies have suggested antidepressant-like effects of drugs targeting nAChRs, with the most consistent results observed with α4β2 nAChR modulators such as varenicline and nonspecific nAChR antagonists such as mecamylamine. These agents appear to offer the most potential antidepressant-like efficacy when used in conjunction with other established antidepressant treatments. nAChR modulators also influence neural processes that appear to mediate the behavioral effects of antidepressants, such as hippocampal cell proliferation. Clinical evidence, while limited, shows preliminary efficacy for mecamylamine and varenicline. Taken together, the preclinical and clinical evidence suggests that drugs targeting nAChRs may represent an important new approach to the treatment of depression.

Hyperhomocysteinemia Due to Methionine Synthase Deficiency, cblG: Structure of the MTR Gene, Genotype Diversity, and Recognition of a Common Mutation, P1173L

Mutations in the MTR gene, which encodes methionine synthase on human chromosome 1p43, result in the methylcobalamin deficiency G (cblG) disorder, which is characterized by homocystinuria, hyperhomocysteinemia, and hypomethioninemia. To investigate the molecular basis of the disorder, we have characterized the structure of the MTR gene, thereby identifying exon-intron boundaries. This enabled amplification of each of the 33 exons of the gene, from genomic DNA from a panel of 21 patients with cblG. Thirteen novel mutations were identified. These included five deletions (c.12-13delGC, c.381delA, c.2101delT, c.2669-2670delTG, and c.2796-2800delAAGTC) and two nonsense mutations (R585X and E1204X) that would result in synthesis of truncated proteins that lack portions critical for enzyme function. One mutation was identified that resulted in conversion of A to C of the invariant A of the 3 splice site of intron 9. Five missense mutations (A410P, S437Y, S450H, H595P, and I804T) were identified. The latter mutations, as well as the splice-site mutation, were not detected in a panel of 50 anonymous DNA samples, suggesting that these sequence changes are not polymorphisms present in the general population. In addition, a previously described missense mutation, P1173L, was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-->T transition in a CpG island, has occurred on at least two separate genetic backgrounds.

Alterations of Mitochondrial DNA Copy Number and Telomere Length With Early Adversity and Psychopathology

BACKGROUNDnTelomere shortening and alterations of mitochondrial biogenesis are involved in cellular aging. Childhood adversity is associated with telomere shortening, and several investigations have shown short telomeres in psychiatric disorders. Recent studies have examined whether mitochondria might be involved in neuropsychiatric conditions; findings are limited and no prior work has examined this in relation to stress exposure.nnnMETHODSnTwo-hundred ninety healthy adults provided information on childhood parental loss and maltreatment and completed diagnostic interviews. Participants were categorized into four groups based upon the presence or absence of childhood adversity and the presence or absence of lifetime psychopathology (depressive, anxiety, and substance use disorders). Telomere length and mitochondrial DNA (mtDNA) copy number were measured from leukocyte DNA by quantitative polymerase chain reaction.nnnRESULTSnChildhood adversity and lifetime psychopathology were each associated with shorter telomeres (p < .01) and higher mtDNA copy numbers (p < .001). Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment. A history of substance disorders was also associated with significantly higher mtDNA copy numbers.nnnCONCLUSIONSnThis study provides the first evidence of an alteration of mitochondrial biogenesis with early life stress and with anxiety and substance use disorders. We replicate prior work on telomere length and psychopathology and show that this effect is not secondary to medication use or comorbid medical illness. Finally, we show that early life stress and psychopathology are each associated with these markers of cellular aging.

Augmentation of antidepressants with atypical antipsychotics: a review of the current literature.

Studies have found that a large percentage of depressed patients may have limited response and remission rates when treated with traditional antidepressants. Options for augmenting antidepressant treatment include buspirone, lithium, and triiodothyronine. There are also increasing data concerning the use of atypical antipsychotics as augmenting agents in the treatment of unipolar, nonpsychotic, treatment-resistant depression. Aripiprazole has recently received an indication from the U.S. Food and Drug Administration (FDA) for adjunctive treatment in unipolar, nonpsychotic depression, the first indication of its kind, after two double-blind trials; doses were slightly lower than those recommended for monotherapy in schizophrenia or bipolar disorder. Olanzapine and risperidone have several controlled clinical trials indicating the efficacy of both of these agents, generally at low doses. One trial of quetiapine suggested that it may not be effective in the treatment of unipolar, nonpsychotic depression. One open-label trial of ziprasidone indicated some efficacy. According to these results, aripiprazole, olanzapine, and risperidone are reasonable choices as augmentation agents, with only aripiprazole currently having an FDA indication for this use. Given the preliminary results, double-blind, placebo-controlled trials with quetiapine and ziprasidone are needed, as well as studies comparing atypical antipsychotic agents with traditional augmentation agents in the treatment of depression.

The neurobiological correlates of childhood adversity and implications for treatment.

This article provides an overview of research on the neurobiological correlates of childhood adversity and a selective review of treatment implications.

Patterns of Quetiapine Use in Psychiatric Inpatients: An Examination of Off-Label Use

BACKGROUNDnDespite emerging recognition that off-label use of atypical antipsychotics is widespread, there is little data concerning patterns of such use. To investigate such usage of quetiapine, we evaluated prescribing practices of this drug at our acute-care psychiatric hospital.nnnMETHODSnInpatient orders for quetiapine were obtained from October 2004 to March 2006 and divided into standing or prn (as needed) dose regimens. For patients receiving standing dose regimens, diagnosis, total daily dose, and dosing adequacy were ascertained. For patients receiving prn dosing, diagnosis, behavioral indication, dose, and frequency were determined.nnnRESULTSnThe most common diagnoses in patients receiving standing dose quetiapine were depressive disorders, followed by substance-related, bipolar, and psychotic disorders. Mean dose was 169 +/- 154 mg/day (median = 200 mg/day), with 29.8% of patients receiving > or = 300 mg/day. Only 28.5% of patients had one of the diagnoses for which quetiapine is approved; in these patients, 46.4% received > or = 300 mg/day. Patients receiving prn dosing had a similar distribution of diagnoses. The most common prn dose was 50 mg, given for agitation or insomnia.nnnCONCLUSIONnWe found extensive off-label use of quetiapine. Further research is needed on the safety and efficacy of quetiapine in non-approved doses and diagnoses.

Decreased default network connectivity is associated with early life stress in medication-free healthy adults.

Early life stress (ELS) is a significant risk factor for psychopathology, although there are few functional imaging studies investigating its effects. Previous literature suggests that ELS is associated with changes in structure and function in the medial prefrontal cortex (MPFC), which forms the main anterior node of the default network (DN). This study investigated the impact of ELS history on resting state DN connectivity, using seed-based correlation analyses (SCA) involving the posterior cingulate cortex (PCC). Data were analyzed from 22 adult subjects without psychiatric or medical illness (13 with and 9 without ELS); none were taking psychotropic medication. Relative to controls, the ELS group had significant decreases in DN connectivity, observed between the PCC seed and the MPFC and inferior temporal cortex. Further analyses revealed a trend-level increase in connectivity between the amygdala and MPFC associated with ELS history. In conclusion, this study found that subjects with ELS, in the absence of psychiatric illness and medication exposure, demonstrated decreased DN connectivity, and trend-level increases in connectivity between the amygdala and MPFC. These findings suggest that altered resting state connectivity is a correlate of stress exposure, rather than a product of medication or psychiatric morbidity.

Association of telomere length and mitochondrial DNA copy number in a community sample of healthy adults.

Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The present study examined the association between mitochondrial DNA (mtDNA) copy number and telomere length in a sample of medically healthy adults. Participants (total n=392) were divided into 4 groups based on the presence or absence of early life adversity and lifetime psychopathology: No Adversity/No Disorder, n=136; Adversity/No Disorder, n=91; No Adversity/Disorder, n=46; Adversity/Disorder, n=119. Telomere length and mtDNA copy number were measured using quantitative polymerase chain reaction. There was a positive correlation between mtDNA and telomere length in the entire sample (r=0.120, p<0.001) and in each of the four groups of participants (No Adversity/No Disorder, r=0.291, p=0.001; Adversity/No Disorder r=0.279, p=0.007; No Adversity/Disorder r=0.449, p=0.002; Adversity/Disorder, r=0.558, p<0.001). These correlations remained significant when controlling for age, smoking, and body mass index and establish an association between mtDNA and telomere length in a large group of women and men both with and without early adversity and psychopathology, suggesting co-regulation of telomeres and mitochondrial function. The mechanisms underlying this association may be important in the pathophysiology of age-related medical conditions, such as heart disease and cancer, as well as for stress-associated psychiatric disorders.

Pharmacologic approaches to treatment resistant depression: a re-examination for the modern era

Importance of the field: Treatment-resistant depression (TRD) is common and debilitating. Initial treatment is often insufficient to achieve full remission in a given depressive episode, resulting in more frequent episodes, worsened severity, and major disability. Areas covered in this review: This review surveys literature on the diagnosis and pharmacological management of TRD in light of recent developments. Evidence regarding commonly used treatment options is critically examined and key recommendations are offered. The review ends by considering drugs acting on the melatonin, acetylcholine, and glutamate systems that hold promise as future options for TRD. What the reader will gain: Recent trends and research findings have impacted how the evidence supporting different approaches to TRD should be evaluated. For example, many earlier TRD studies employed tricyclics as the primary antidepressant, but tricyclics have now been superseded by selective serotonin reuptake inhibitors (SSRIs) in routine clinical practice. This deficiency has been addressed by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest effectiveness study of TRD ever conducted. However, design characteristics of the STAR*D study preclude simple comparisons with earlier studies. Take home message: A shortcoming of most treatment recommendations for TRD is their reliance on older studies that do not reflect the current preeminence of SSRIs in clinical practice. This has distorted the prioritization of pharmacological strategies for TRD. Efforts to correct this distortion with effectiveness research, designed to better reflect current practice trends, require critical consideration of the strengths and limitations of this approach.

Efficacy and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major Depression.

BACKGROUNDnTranscranial Magnetic Stimulation (TMS) customarily uses high-field electromagnets to achieve therapeutic efficacy in Major Depressive Disorder (MDD). Low-field magnetic stimulation also may be useful for treatment of MDD, with fewer treatment-emergent adverse events.nnnOBJECTIVE/HYPOTHESISnTo examine efficacy, safety, and tolerability of low-field magnetic stimulation synchronized to an individuals alpha frequency (IAF) (synchronized TMS, or sTMS) for treatment of MDD.nnnMETHODSnSix-week double-blind sham-controlled treatment trial of a novel device that used three rotating neodymium magnets to deliver sTMS treatment. IAF was determined from a single-channel EEG prior to first treatment. Subjects had baseline 17-item Hamilton Depression Rating Scale (HamD17)xa0≥xa017.nnnRESULTSn202 subjects comprised the intent-to-treat (ITT) sample, and 120 subjects completed treatment per-protocol (PP). There was no difference in efficacy between active and sham in the ITT sample. Subjects in the PP sample (Nxa0=xa059), however, had significantly greater mean decrease in HamD17 than sham (Nxa0=xa060) (-9.00 vs.xa0-6.56, Pxa0=xa00.033). PP subjects with a history of poor response or intolerance to medication showed greater improvement with sTMS than did treatment-naïve subjects (-8.58 vs.xa0-4.25, Pxa0=xa00.017). Efficacy in the PP sample reflects exclusion of subjects who received fewer than 80% of scheduled treatments or were inadvertently treated at the incorrect IAF; these subgroups failed to separate from sham. There was no difference in adverse events between sTMS and sham, and no serious adverse events attributable to sTMS.nnnCONCLUSIONSnResults suggest that sTMS may be effective, safe, and well tolerated for treating MDD when administered as intended.