Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice.

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.

Augmentation of phenelzine with aripiprazole and quetiapine in a treatment-resistant patient with psychotic unipolar depression: case report and literature review.

Irreversible monoamine oxidase inhibitor (MAOI) antidepressants have significant efficacy in treatment-resistant unipolar depression, but in some instances patients may not achieve remission. Among the adjunctive and augmentation strategies, certain second-generation antipsychotics (SGAs) have approval for inadequate responders to antidepressant therapy, including aripiprazole, brexpiprazole, and quetiapine, with lurasidone and the olanzapine/fluoxetine combination indicated for bipolar depression. Clinicians may eschew SGA options in part due to the limited literature on SGA-MAOI combinations, with only one published case involving aripiprazole, and none for olanzapine, lurasidone, or brexpiprazole. In addition to the limited publication history on SGA-MAOI treatment, clinicians may also be deterred by uncertainty regarding SGA mechanisms and the risk of serotonin syndrome or other adverse outcomes. This paper describes the case of a 54-year-old male with a history of psychotic unipolar depression treated with a combination of phenelzine, aripiprazole, and quetiapine, and reviews the 12 published cases of SGA-MAOI combination therapy with a focus on the pharmacological basis for serotonin syndrome, and the SGA mechanisms that should not be associated with a risk for this syndrome.

Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis.

BACKGROUND: Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS. METHODS: We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs. RESULTS: Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs. CONCLUSIONS: These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.

MAOIs - does the evidence warrant their resurrection?

OBJECTIVE: The place of monoamine oxidase inhibitors (MAOIs) in psychiatry is reviewed, and the question posed as to whether they are now justifiably disregarded by prescribers. METHOD: Multiple databases (PubMed, Medline, Embase, Cochrane) were interrogated to provide an overview regarding the use, efficacy and toxicity of MAOIs. Data regarding funded use of these agents in New Zealand were obtained from PHARMAC. RESULTS: Evidence supports the use of MAOIs in major depressive disorder, certain anxiety disorders and, to lesser extent, bipolar depression. Older non-selective agents, such as phenelzine and tranylcypromine, have distinctive efficacy in 'atypical' and treatment-resistant depression, but at the cost of serious tolerability problems. Their relegation and perception by clinicians as 'last resort' medications - if considered at all - has occurred in the context of various concerns, notably dietary restrictions, potential adverse drug interactions and the usual requirement for divided doses. CONCLUSIONS: Sufficient evidence supports consideration of MAOIs in treatment-refractory and atypical depressive disorders, and in social anxiety disorder. Psychiatrists in training need to gain experience in using these agents.

The comprehensive management of pregnant women with major mood disorders: a case study involving phenelzine, lithium, and quetiapine.

Pregnancy in women with severe mental illness (SMI) often bring added dimensions of complexity; considering that this group of women are choosing to have children at increasing rates, more highly complex cases will require management. A 31-year-old primigravida with a diagnosis of bipolar affective disorder was treated with an antidepressant, mood stabiliser and antipsychotic. This case discusses preconception counselling, pregnancy and labour management that resulted in the delivery of a 4,200 g baby at 39 weeks by emergency caesarian section. This case highlights the collaborative approach to care that is needed in this group of women and the need for increasing awareness and knowledge in health professionals. It follows the management from preconception through to the postpartum period.

Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine.

The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the antidepressant. In the years and decades that followed, MAOIs have been used in the treatment of several pathologies including Parkinson's disease, Alzheimer's disease, and various cancers and as anti-inflammatory agents. Despite once enjoying widespread use, MAOIs have dwindled in popularity due to side effects, food-drug interactions, and the introduction of other antidepressant drug classes such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The recently published prescriber's guide for the use of MAOIs in treating depression has kindled a resurgence of their use in the clinical space. It is therefore timely to review key aspects of the four "classic" MAOIs: high-dose selegiline, isocarboxazid, phenelzine, and tranylcypromine. This review discusses their chemical synthesis, metabolism, pharmacology, adverse effects, and the history and importance of these drugs within the broader field of chemical neuroscience.

The MAO inhibitor phenelzine improves functional outcomes in mice with experimental autoimmune encephalomyelitis (EAE).

Multiple sclerosis (MS) and the animal model, experimental autoimmune encephalomyelitis (EAE), are both accompanied by motor and non-motor symptoms. Pathological changes in the activities of key neurotransmitters likely underlie many of these symptoms. We have previously described disturbances in the levels of 5-hydroxytryptamine (5-HT/serotonin), noradrenaline (NE) and γ-aminobutyric acid (GABA) in a mouse model of EAE. The potential therapeutic effect of a drug that targets these three neurotransmitters, the antidepressant and anti-panic drug phenelzine (PLZ), was assessed in mice with MOG(35-55) induced EAE. The neurotransmitter content of EAE and control tissue after PLZ administration was first evaluated by HPLC. The ability of PLZ treatment to modulate EAE disease course and clinical signs was then assessed. Daily PLZ treatment, starting seven days after disease induction, delayed EAE onset, reduced disease severity in the chronic phase and was associated with substantial improvements in exploratory behavior and a novel measure of sickness and/or depression. Upon completion of the experiment, PLZ's effects on histopathological markers of the disease were examined. No differences were observed in T cell infiltration, microglia/macrophage reactivity, demyelination or axonal injury in PLZ-treated spinal cords. However, EAE mice treated with PLZ showed a normalization of 5-HT levels in the ventral horn of the spinal cord that might account for the improvements in behavioral outcomes. These results demonstrate the therapeutic potential of MAO inhibitors such as PLZ in MS. Additionally, the behavioral changes observed in EAE mice indicate that alterations in non-motor or 'affective' measures may be valuable to consider in addition to traditional measures of gross locomotor function.

Phenelzine, a small organic compound mimicking the functions of cell adhesion molecule L1, promotes functional recovery after mouse spinal cord injury.

BACKGROUND: Neural cell adhesion molecule L1 contributes to nervous system development and maintenance by promoting neuronal survival, neuritogenesis, axonal regrowth/sprouting, myelination, and synapse formation and plasticity. L1 also enhances recovery after spinal cord injury and ameliorates neurodegenerative processes in experimental rodent models. Aiming for clinical translation of L1 into therapy we screened for and functionally characterized in vitro the small organic molecule phenelzine, which mimics characteristic L1 functions. OBJECTIVE: The present study was designed to evaluate the potential of this compound in vivo in a mouse model of spinal cord injury. METHODS AND RESULTS: In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice. Phenelzine application upregulated L1 expression in the spinal cord and stimulated the cognate L1-mediated intracellular signaling cascades in the spinal cord tissue. Phenelzine-treated mice showed decreased levels of pro-inflammatory cytokines, such as interleukin-1ß, interleukin-6, and tumor necrosis factor-α in the injured spinal cord during the acute phase of inflammation. CONCLUSIONS: This study provides new insights into the role of phenelzine in L1-mediated neural functions and modulation of inflammation. The combined results raise hopes that phenelzine may develop into a therapeutic agent for nervous system injuries.

Phenelzine, a cell adhesion molecule L1 mimetic small organic compound, promotes functional recovery and axonal regrowth in spinal cord-injured zebrafish.

Injury to the spinal cord initiates a cascade of cellular and molecular events that contribute to the tissue environment that is non-permissive for cell survival and axonal regrowth/sprouting in the adult mammalian central nervous system. The endogenous repair response is impaired in this generally inhibitory environment. Previous studies indicate that homophilic interactions of the neural cell adhesion molecule L1 (L1CAM) promote recovery after spinal cord injury and ameliorate neurodegenerative processes in experimental rodent and zebrafish models. In light of reports that phenelzine, a small organic compound that mimics L1, stimulates neuronal survival, neuronal migration, neurite outgrowth, and Schwann cell proliferation in vitro in a L1-dependent manner, we examined the restorative potential of phenelzine in a zebrafish model of spinal cord injury. Addition of phenelzine into the aquarium water immediately after spinal cord injury accelerated locomotor recovery and promoted axonal regrowth and remyelination in larval and adult zebrafish. Phenelzine treatment up-regulated the expression and proteolysis of L1.1 (a homolog of the mammalian recognition molecule L1) and phosphorylation of Erk in the spinal cord caudal to lesion site. By combining the results of the present study with those of other studies, we propose that phenelzine bears hopes for therapy of nervous system injuries.

Efficacy and safety of antidepressant monotherapy in the treatment of bipolar-II depression.

Sparse data exist regarding the risks and benefits of treating bipolar-II depression with antidepressants alone. On the basis of studies of bipolar-I patients, treatment guidelines suggest antidepressants should be augmented with mood stabilizers. Whether these recommendations apply to bipolar-II is unclear. A post-hoc analysis of a double-blind study, which compared the relative efficacy of placebo, imipramine and phenelzine in depressed outpatients. Patients rated 1 ('very much improved') or 2 ('much improved') on the Clinical Global Inventory Scale were considered responders. In an intent to treat analysis, no significant differences between bipolar patients (N=62) and unipolar patients (N=248) in response rates to placebo, imipramine and phenelzine were seen. No patient developed manic symptoms that required medication discontinuation or mood stabilizer augmentation. Antidepressant monotherapy was found to be a safe and effective treatment for bipolar-II depression.

Treatment of depression with atypical features: a meta-analytic approach.

The present meta-analysis addressed the empirical evidence regarding the treatment of major depression with atypical features. The superiority of monoamine oxidase inhibitors (MAOIs) compared with other antidepressants in the treatment of major depression with atypical features has been frequently reported. According to the CONSORT Statement, studies included in our meta-analysis had to meet several criteria, especially a double-blind, controlled condition and an operational diagnosis according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-III or DSM-IV criteria, respectively. Four databases for research-based evidence were used in a systematic review: Medline, Embase, Psyndex and PsycInfo. Only eight publications met inclusion/exclusion criteria, resulting in 11 comparisons. Our results contrast an effect size of 0.45 (95% confidence interval) for a comparison of MAOIs vs. placebo with an effect size of 0.02 (95% confidence interval: - 0.10-0.14) for a comparison of MAOIs vs. selective serotonin reuptake inhibitors. The effect size for MAOIs vs. tricyclic antidepressants was 0.27 (95% confidence interval: 0.16-0.42). MAOIs may be more effective for atypical major depressive disorder than tricyclic antidepressants. Most clinical research has been conducted on irreversible MAOIs. Additional studies testing more recently developed antidepressants (including reversible MAOIs) with an improved safety profile would be warranted. The available data are insufficient for a direct comparison between MAOIs and selective serotonin reuptake inhibitors.

Transdermal selegiline: the new generation of monoamine oxidase inhibitors.

The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions. To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the "cheese-reaction"). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.

Use of pattern analysis to identify true drug response. A replication.

In any antidepressant study, placebo response in patients assigned active drug is a troubling source of variance. There have been few attempts to identify the patients whose conditions improve as a result of true drug effect, in contrast with improvement that is a result of nonspecific effects. In a previous report we demonstrated that true drug effect seemed to be characterized by a two-week delay in onset and persistence. We described a method of pattern analysis to identify such patients. In this report, we describe the use of pattern analysis to replicate our initial findings. Data from a new sample of 150 nonmelancholic patients support the hypothesis that true drug effect is characterized by a two-week delay in onset and persistence of improvement, once achieved. There was little evidence of the onset of antidepressant effect before two weeks. The theoretical and clinical implications of this work are discussed.

Phenelzine vs atenolol in social phobia. A placebo-controlled comparison.

Seventy-four patients who met DSM-III criteria for social phobia completed 8 weeks of double-blind, randomly assigned treatment with the monoamine oxidase inhibitor phenelzine sulfate, the cardioselective beta-adrenergic blocker atenolol, or placebo. The overall response rates were 64% for phenelzine, 30% for atenolol, and 23% for placebo. Phenelzine was widely superior to both atenolol and placebo on independent rater analyses and, to a lesser extent, on self-report, with no significant differences between atenolol and placebo. At the end of 16 weeks, phenelzine was still significantly superior to placebo, while atenolol showed an intermediate response that did not differ significantly from either of the other treatments. Patients with generalized social phobia constituted 76% of the sample, and they were preferentially responsive to phenelzine. The small size of the discrete social phobic sample precluded separate outcome analyses for this subtype. Overall, the findings support the responsivity of social phobia to monoamine oxidase inhibitors.

How effective and safe is continuation therapy in elderly depressed patients? Factors affecting relapse rate.

Sixty elderly depressed patients who had responded to either nortriptyline hydrochloride or phenelzine sulfate were followed up under double-blind conditions during four to eight months of continuation treatment. Over 70% of patients (43) remained well during this period, while 11 (18.3%) had relapses, three (5.0%) dropped out because of side effects, and three (5.0%) prematurely terminated in good clinical condition. There was no significant difference in the relapse rate between patients receiving nortriptyline (five [16.7%]) and those receiving phenelzine (six [20.0%]). Patients receiving phenelzine were more likely to require dose reductions, and all three patients who dropped out because of side effects were receiving phenelzine. Patients with chronic depression (greater than two years' duration) accounted for all of the relapses.

A placebo-controlled comparison of nortriptyline and phenelzine in maintenance therapy of elderly depressed patients.

Fifty-one elderly depressed outpatients who had responded to antidepressants and completed continuation therapy were observed under double-blind conditions for 1 year. Twenty-three had been switched to placebo, while 13 and 15 took nortriptyline hydrochloride and phenelzine sulfate, respectively. Patients administered phenelzine did significantly better with 13.3% recurrences than patients administered either nortriptyline (53.8% recurrences) or placebo (65.2% recurrences). In addition, patients who had higher Hamilton scores and who had an earlier age of onset of the first depressive episode were significantly more likely to have recurrences.

A multiple-dose, controlled study of phenelzine in depression-anxiety states.

In a double-blind, controlled experiment, 62 outpatients with symptoms of depression with anxiety were selected for treatment with phenelzine sulfate, 60 mg daily, phenelzine sulfate, 30 mg daily, or placebo for six weeks. Forty-nine patients (79%) completed the experiment. Phenelzine sulfate, 60 mg daily, was significantly more effective than placebo in relieving symptoms of both depression and anxiety. Phenelzine sulfate, 30 mg daily, did not differ from the placebo. Only phenelzine sulfate, 60 mg daily, resulted in a median inhibition of platelet monoamine oxidase that exceded 80%. The results confirm a previous study that found phenelzine to be effective in the treatment of outpatients with depressive-anxiety states. Drug dosage is an important variable influencing clinical outcome in this patient group.

Cognitive-behavioral and pharmacological treatments of social phobia. A controlled study.

Sixty-five patients with social phobia were treated in a study that compared a cognitive-behavioral group treatment program with pharmacotherapy with alprazolam, phenelzine sulfate, or pill-placebo plus instructions for self-directed exposure to phobic stimuli. Statistically significant repeated-measures effects were shown on all measures, indicating that the treatments studied were associated with substantial improvements in patients with severe and chronic social phobia. Patients who were treated with phenelzine were rated by clinicians as more improved on a measure of work and social disability than patients who were treated with alprazolam or placebo (patients in the cognitive-behavior therapy group were not rated on this measure). Subjects showed positive cognitive changes from before to after treatment, and there were no differences between treatment groups on the cognitive measure. We discuss the implications of these findings within the context of demographic and clinical predictors of response.