“The European Medicines Agency has recommended restricting the use of modafinil-containing medicines. The medicine should only be used to treat sleepiness associated with narcolepsy. Doctors and patients should no longer use the medicine for the treatment of idiopathic hypersomnia, excessive sleepiness associated with obstructive sleep apnoea and chronic shift work sleep disorder.”

Click here to download the full press release.

This article will focus on the classification of serotonin receptors, as well as drug classes that act on serotonergic transmission. This includes 5-HT agonists, antagonists and medications that modulate 5-HT at the presynaptic level, all of them of very high clinical relevance. Overdose of a combitation of serotonergic agents can lead to serotonin syndrome.

Outline:

• Serotonin receptors
• Drugs acting on serotonergic transmission: MAO inhibitors, SNRIs, SSRIs
• Serotonin agonists
• Serotonin antagonists

Serotonin receptors

Based on biochemical and pharmacological criteria, serotonin receptors are classified into seven main receptor subtypes, 5-HT1–7. Of major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated ion channel.

5-HT1 receptors are subdivided into 5-HT1A, 5-HT1B, and 5-HT1D receptors; while 5-HT2 subtypes include 5-HT2A, 5-HT2B, and 5-HT2C.

Drugs acting on serotonergic neurotransmission

The figure above depicts how serotonin neurotransmission may be modified at the presynaptic level by inhibiting degradation, storage or reuptake.

MAO inhibitors

Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinson’s disease (selegiline). Dietary restrictions (because of tyramine toxicity) limit their widespread use.

Inhibitors of serotonin storage

They interfere withe the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil.

SNRI

SNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentration-dependent manner. Agents in this class include venlafaxine and duloxetine, they may be effective for the treatment of depression in patients in whom SSRIs are ineffective.

SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity.

TCAs

Tricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby causing enhancement of postsynaptic response.

Serotonin agonists

Serotonin receptors agonists have wide clinical applications, from treatment of depression to abortive medications for migraine headache. According to the receptor they activate, they can be divided into:

5-HT1A agonists

Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression.

5-HT1B and 5-HT1D agonists

The “triptans” are a drug class useful as abortive medication for the treatment of  acute migraine headaches. They are very effective medications that bind to 5-HT1B and 5-HT1D receptors in cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved in “sterile inflammation”.

5-HT2C agonist

Trazodone was previously believed to be a 5-HT2C receptor antagonist. However,  recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific.

5-HT4 agonists

Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity.

Non-selective agonists

Ergotamine activates a more than one subtype of 5-HT receptor, it binds to  5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks.

LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties.

5-HT2 antagonists

Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its antihypertensive effect.

Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors.  It represents a class of atypical antipsychotic drugs, one key advantage of this group is its reduced incidence of extrapyramidal side effects compared to the classical antipsychotics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia.

Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor.

5-HT3 antagonists

This class includes drugs such as ondansetron, palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV).

References and further reading

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.

Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Brunton, L.B., Lazo, J.S., & Parker, K.L. (Eds.). “Goodman & Gilman’s the pharmacological basis of therapeutics“,  11th edition. New York: McGraw-Hill:2005.

Watch animation

They approach the following topics related to the neurobiology of drug addiction.

• Methamphetamine actions on dopamine vesicles.
• LSD action on serotonin receptors.
• Heroin effects on opioid receptors .
• How marijuana interacts with the cannabinoid system and its receptors.
• Activation of the GABA-A ionotropic receptor by alcohol.
• Cocaine action on dopamine reuptake.

This blog has a related post that explains nicotine addiction mechanism through a 3-D video animation.

Antipsychotics Review in Primary care. A PPT By Shomir Banerjee, M.D.

Dr. Banerjee discusses the topic from a Family Medicine specialist point of view. Some other resources related to Family Medicine by the same author can be found at Shomir.org.

Presentation outline:

• Differences between first and second generation antipsychotics.
• How do typical and atypical Antipsychotics work? Mechanisms of action.
• Classification by potency.
• Acute extrapyramidal symptoms with high potency agents ( Akathisia, Dystonia, Parkinsonism).
• Neuroleptic Malignant Syndrome.
• Tardive Dyskinesia.
• Atypical vs Typical Antipsychotics.
• Are atypicals “better?”
• Monitoring
• Analysis of agents: clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify).

Download PPT file

Conventional Antipsychotics: Concise Review for  Non-Psychiatrists Treating Developmentally Disabled Population. A PPT by S. Christopher Shim, M.D.

Dr. Shim is an American Psychiatric Association Distinguished Fellow who shares his practical approach on conventional antipsychotics with non-psychiatrists.

Presentation outline:

• Equivalence between high potency agents: Haloperidol, fluphenazine, thiothixine, trifluoperazine, pimozide.
• Equivalence between low potency agents: thioridazine, chlorpromazine, mesoridazine.
• Benefits & risks of high and low potency agents.
• Safety and Tolerability –side effects profile-.
• EPS (Extra Pyramidal Symptoms): features and treatment.
• Cardiovascular effects: Malignant Arrhythmias (torsade de pointes), Sudden Cardiac Death
• Cautions: Reduction or Discontinuation of Conventional Antipsychotic Medications

Download PPT file

Treatment of Schizophrenia (and Related Psychotic Disorders). A PPT by Scott Stroup, MD, MPH.

This presentation explores some of the most relevant clinical features of schizophrenia as well as other psychoses. It also reviews in chronological order of approval some of the most important neuroleptics (both first and second generation). As the presentations shown above, it highlights the most important side effects related to the use of antipsychotic medications. It also focuses on non-pharmacological therapies and other type of interventions .

Download PPT file

It is oriented to a general audience. However, it’s useful to review the brain reward system and some important dopamine pathways.

You may also be interested in other posts such as:

• EMEA’s recommendations on Methylphenidate.
• Methadone for chronic pain.

Further reading

Addiction, Dopamine, and the Molecular Mechanisms of Memory. Neuron, Vol. 25, 515–532, March, 2000. Free Full Text – PDF -

Is there a common molecular pathway for addiction? EJ Nestler – Nature neuroscience, 2005.  Free Full Text – PDF -

According to the SMC, the manufacturer did not present a sufficiently robust economic analysis to gain acceptance.

Psychiatrist Daniel Carlat from “The Carlat Psychiatry  Blog” refers to aripiprazole as “ the antipsychotic most likely to cause akathisia”.

The video below is the US TV ad for Abilify. As you can see, there is an aggressive marketing campaign to promote aripiprazole as a medication in bipolar disorder, targeted both to prescribers and patients.

As related information,  SMC previously reviewed aripiprazole for agitation control in patients with schizophrenia and accepted the IM formulation use only if oral therapy is not appropriate.

Mechanism of action

Agomelatine acts as an agonist on melatonin MT1 and MT2 receptors. Additionally, it blocks serotonin 2C (5-HT2C) receptors.

Efficacy and place in therapy

On November 2008, EMEA issued a positive opinion for granting a Marketing Authorization to Valdoxan, after a resubmission by the applicant.  Agomelatine was launched in the UK in June 2009 for the treatment of major depressive episodes in adults.

Few trials have compared agomelatine with  ‘established’ antidepressants like venlafaxine and sertraline. Most clinical trials compared agomelatine to placebo. As with most new drugs, time and experience from experts will tell which place it has on the therapeutic options for the treatment of depression.

The following document is a drug specific review for agomelatine by the London New Drugs Group.

Download review (PDF file)

References and further reading

Agomelatine for depression – horizon scanning review. Centre for Reviews and Dissemination. 2003.

J Pierre Olié, S Kasper.  Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder (abstract). The International Journal of Neuropsychopharmacology, 2007. Cambridge Univ Press.

S.H. Kennedy , R. Emsley. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. (PDF Free Full text). European Neuropsychopharmacology, 2006.

Essential Evidence Plus

In this podcast Dr. Ebell and Dr. Wilkes (National Public Radio) discuss the POEM titled:

“Antidepressants only modestly effective for adolescent depression”

Listen to the podcast on antidepressants for adolescent depression.

Summary:

• Desvenlafaxine is the active metabolite of venlafaxine.
• There is no evidence that desvenlafaxine is more effective, safer or better tolerated than venlafaxine or other antidepressants.
• Doses above 50 mg/day are unlikely to provide further clinical benefit and are associated with a higher incidence of adverse effects.
• Common adverse effects include nausea, headache, dizziness, dry mouth and diarrhoea.
• Desvenlafaxine should not be used in children and adolescents.
• Reduce the dose slowly to avoid discontinuation symptoms.

In an article published in Annals of Pharmacotherapy.  Desvenlafaxine: Another "Me Too" Drug?, the authors conclude:

“With the overall similarity between these 2 drugs and the potential lack of cost savings, the need for desvenlafaxine and its ultimate utility in treating major depressive disorder appears to be insignificant.”

Advice for healthcare professionals:
• At normal doses, atomoxetine can be associated with treatment-emergent psychotic or manic symptoms (eg, hallucinations, delusional thinking, mania, or agitation) in children and adolescents without a history of psychotic illness or mania.
• If such symptoms occur , consideration should be given to a possible causal role of atomoxetine and discontinuation of treatment.
• It remains possible that atomoxetine might exacerbate pre-existing psychotic or manic symptoms.

The Midlands Therapeutics Review and Advisory Committee stated in a May 2006 verdict and summary of atomoxetine:

“Initiation of atomoxetine treatment and stabilisation of the dose should be the responsibility of a specialist. It is then appropiate to prescribe atomoxetine in primary care with the guidance of an ESCA”.

Recently (January 2009), the FDA reminded about the risk of serious hepatic damage with atomoxetine.