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.

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.

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.

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.

Update on the efficacy of pharmacotherapy for social anxiety disorder: a meta-analysis.

INTRODUCTION: Social anxiety disorder (SAD) is a common mental health problem that tends to be chronic in nature; fortunately, effective pharmacotherapy options exist. The current study provides an updated meta-analytic review of their efficacy and potential guidelines for their application in SAD. METHODS: A comprehensive search of the current literature yielded 39 randomized, pill placebo-controlled trials of pharmacotherapy for adults diagnosed with SAD. Data on potential moderators of treatment outcome were collected, as well as data necessary to calculate effect sizes using Hedges's g. RESULTS: The overall effect size of pharmacotherapy for SAD is small to medium (Hedges's g = 0.39). The most effective pharmacotherapy type was phenelzine (Hedges's g = 1.14), followed by paroxetine (Hedges's g = 0.49), venlafaxine ER (Hedges's g = 0.45) and moclobemide (Hedges's g = 0.23). CONCLUSION: Effect sizes were not moderated by age, sex, length of treatment, diagnostic subtype initial severity, maximum potential dose, or publication year. It is concluded that pharmacotherapy is effective for treating SAD, but there is considerable variation and room for further improvement. Future directions may include pharmacological enhancement of psychological processes, such as d-cycloserine augmentation of exposure procedures.

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.

[Phenelzine: legacy or current psychiatric practice?]. / Fenelzina: retaggio o attualità nella pratica psichiatrica?

Monoamine oxidase inhibitors (MAO-I) are the first drugs of antidepressant classes discovered. Phenelzine is a worldwide prescribed MAO-I, studied in a variety of mood and anxiety disorders. Purpose of the present paper is to critically review the results reported in the scientific international literature focusing on efficacy and safety of phenelzine in clinical psychiatric practice, in order to achieve a better understanding of the relationship between pharmacological data, therapeutic approach and side or adverse effects. We performed a careful PubMed (1980-2012) search on clinical pharmacology and clinical use of phenelzine in various psychiatric disorders. We reported our findings discussing separately clinical pharmacology data and systematic controlled, randomised and not randomised, clinical studies.

The MAO inhibitor phenelzine can improve functional outcomes in mice with established clinical signs in experimental autoimmune encephalomyelitis (EAE).

Many symptoms in multiple sclerosis (MS) can be related to changes in the levels of key neurotransmitters. These neurotransmitters have a direct role in the maintenance of neurons and also have immunomodulatory properties. Previously we have shown that when treatment began prior to the onset of clinical signs, daily treatment with the monoamine oxidase (MAO) inhibitor phenelzine (PLZ), which also elevates CNS levels of GABA, lead to substantial behavioral improvements in the experimental autoimmune encephalomyelitis (EAE), the animal model for MS. To determine whether PLZ could have beneficial effects in an already established disease state, we conducted experiments in which PLZ treatment only began when mice with EAE exhibited the first clinical signs of the disease. Using this more clinically relevant treatment approach, we find that PLZ treatment can reduce the severity of clinical signs and improve exploratory behaviors for the duration of the experiment in mice with EAE. Treatment with PLZ did not affect the infiltration of CD4+ T-cells into the spinal cord nor did it reduce the degree of reactive gliosis as measured by Iba1 immunostaining. Beginning PLZ treatment after the start of clinical signs did however lead to significantly better 5-HT innervation density in the ventral horn of the spinal cord and also resulted in higher levels of GABA, dopamine and norepinephrine in the brain and spinal cord. These results indicate that even in an established EAE disease state, PLZ can have clinical benefits. These benefits likely derive from PLZ's ability to normalize the innervation to ventral horn motor neuron pools as well as the elevations in GABA and biogenic amines that have been shown to have anti-inflammatory properties.

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.

A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder.

CONTEXT: Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment. OBJECTIVE: To determine whether combined medication and cognitive behavioral treatment is superior to either monotherapy or pill placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Research clinics at Columbia University and Temple University. PARTICIPANTS: One hundred twenty-eight individuals with a primary DSM-IV diagnosis of social anxiety disorder. INTERVENTIONS: Cognitive behavioral group therapy (CBGT), phenelzine sulfate, pill placebo, and combined CBGT plus phenelzine. MAIN OUTCOME MEASURES: Liebowitz Social Anxiety Scale and Clinical Global Impression (CGI) scale scores at weeks 12 and 24. RESULTS: Linear mixed-effects models showed a specific order of effects, with steepest reductions in Liebowitz Social Anxiety Scale scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test = 4.97, P < .01). The CGI response rates in the intention-to-treat sample at week 12 were 9 of 27 (33.3%) (placebo), 16 of 34 (47.1%) (CBGT), 19 of 35 (54.3%) (phenelzine), and 23 of 32 (71.9%) (combined treatment) (chi(2)(1) = 8.76, P < .01). Corresponding remission rates (CGI = 1) were 2 of 27 (7.4%), 3 of 34 (8.8%), 8 of 35 (22.9%), and 15 of 32 (46.9%) (chi(2)(1) = 15.92, P < .01). At week 24, response rates were 9 of 27 (33.3%), 18 of 34 (52.9%), 17 of 35 (48.6%), and 25 of 32 (78.1%) (chi(2)(1) = 12.02, P = .001). Remission rates were 4 of 27 (14.8%), 8 of 34 (23.5%), 9 of 35 (25.7%), and 17 of 32 (53.1%) (chi(2)(1) = 10.72, P = .001). CONCLUSION: Combined phenelzine and CBGT treatment is superior to either treatment alone and to placebo on dimensional measures and on rates of response and remission.