Lunceon Seminar

  1. Special Lecture
  2. Clinical Research Educational Seminar
  3. Symposiums
  4. Lunceon Seminar
  5. Oral Abstracts
  6. Poster Abstracts

LS1

Clinically relevant drug interactions with newer antidepressants

Edoardo Spina
Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, and
IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy

Different newer antidepressants have been introduced in clinical practice in the past two decades including selective serotonin reuptake inhibitors (SSRI), serotonin and noradrenaline reuptake inhibitors (SNRIs) and other second-line novel compounds with variable mechanism of action. Antidepressants are frequently involved in drug interactions as they are often prescribed in combination with other drugs used to treat comorbid psychiatric or somatic disorders. Based on their mechanisms, drug interactions can be classified as either pharmacokinetic or as pharmacodynamic. By virtue of a more selective mechanism of action, newer antidepressants have a relatively low potential for pharmacodynamic drug interactions. However, the possibility of the serotonin syndrome should be taken into account when drugs affecting serotonergic transmission, such as SSRIs or SNRIs are coadministered with other serotonergic agents. Moreover, an increased risk of gastrointestinal bleeding has been documented when SSRIs are coadministered with nonsteroidal anti-inflammatory drugs, corticosteroids, oral anticoagulants and antiplatelet drugs (including low-dose aspirin). With regard to pharmacokinetic interactions, major concern with newer antidepressants derives from the possibility that SSRIs as well as other recently marketed compounds may cause metabolic interactions through their ability to inhibit one or more CYPs. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine markedly inhibits CYP1A2 and CYP2C19. Fluoxetine and fluvoxamine are also moderate inhibitors of CYP2C9. Therefore, clinically relevant interactions are expected when these agents are coadministered with substrates of these CYP isoenzymes, especially those with a narrow therapeutic index, such as various antipsychotics, cardiovascular drugs and anticancer agents. Duloxetine and bupropion are moderate inhibitors of CYP2D6, while sertraline may cause significant inhibition of this isoform only at high doses. Other new antidepressants including citalopram, escitalopram, venlafaxine, mirtazapine and reboxetine are weak or negligible inhibitors of the different CYP isoforms and are less likely to interact with other medications. Knowledge of the interaction potential of each individual antidepressant is of great value for rational prescribing and may help clinicians to predict and eventually avoid certain drug combinations. Moreover, clinical manifestations of most metabolic drug interactions may be anticipated and minimised by appropriate dosage adjustments based on close evaluation of clinical effects and, possibly, plasma drug concentration monitoring.

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LS2

Drug treatments for cognitive impairment in schizophrenia

Michael F. Green
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA
VA Greater Los Angeles Healthcare System

The cognitive impairments of schizophrenia are largely independent of the clinical symptoms of the illness, such as psychotic symptoms. They are present in unaffected first-degree relatives, as well as people who are at risk for schizophrenia but who are not ill. For these reasons, the cognitive deficits are considered to be "core" features of the illness. In addition, cognitive deficits in schizophrenia are related to the activities of daily living for patients. Many studies have revealed associations between key cognitive constructs and functional outcome. In addition, impaired cognition limits what patients learn in their rehabilitation programs. Because the cognitive deficits are core features and are related to outcome, considerable efforts are underway to find new treatments for cognitive impairment in schizophrenia. These efforts have been stimulated by activities from the US National Institute of Mental Health NIMH, including the MATRICS and TURNS Initiatives. These activities have provided a pathway for approval of cognitionenhancing drugs. This presentation will present an update on new pharmacological interventions that are designed to enhance cognition and improve daily functioning.
The results of the cognitive effects of second-generation antipsychotic medications have been mixed. Meta-analyses suggest some cognitive benefit for second-generation medications compared with first-generation mediations. However, large clinical trials, including the NIMH-sponsored CATIE project, failed to find an advantage for second-generation medications. Aripiprazole was not included in the CATIE trial, and cognitive data from a separate open-label trial are encouraging. The cognitive effects of anti-dementia drugs in schizophrenia have been generally disappointing. This situation has led to active searches for newer types of drugs for cognition enhancement in schizophrenia. Proof of concept trials of drugs that act on novel mechanisms (e.g., GABA receptor, alpha 7 nicotinic receptor, AMPA receptor, neural protective agents, glycinergic agents) are starting to emerge and are showing mixed results as cognitive enhancers.

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LS5

Antidepressant drugs - Pharmacogenetics and drug-drug interactions

Leif Bertilsson
Clinical Pharmacology at Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden

Many of the antidepressants are metabolized by the polymorphic CYP2D6 (1). Potent inhibitors of this enzyme e.g.
paroxetine may have a pronounced effect on other CYP2D6 substrate drugs. In poor metabolizers (PM) there is no enzyme expressed and therefore no drug-drug interaction will occur. On the other hand in patients with multiple copies of CYP2D6 the ultrarapid metabolism of nortriptyline was shown to be normalized by paroxetine (2). Most neuroleptic drugs are metabolized by CYP2D6 and early it was shown that such drugs e.g. perphenazine and antidepressants e.g.
nortriptyline inhibits the metabolism of each other. Drug-drug interactions with these classes of drugs are today very common.
Clozapine is not metabolized by CYP2D6 and we found that plasma levels of clozapine increases when fluvoxamine was added to the treatment with this drug (3). As fluvoxamine is an inhibitor of CYP1A2 (and CYP2C19) we could clearly show that clozapine is metabolized by CYP1A2. Smoking decreases and heavy coffee consumption increases plasma levels of clozapine. We tried to separate the fluvoxamine inhibition of CYP1A2 from CYP2C19 by decreasing the dose of fluvoxamine to 10-20 mg daily, but both enzymes were inhibited by such low doses of fluvoxamine (4).
The SSRI sertraline is metabolized mainly by CYP3A4 and not by CYP2D6. As CYP2D6 is a low capacity - high affinity enzyme, which is inhibited at lower concentrations of inhibitors than CYP3A4 which is a high capacity - low affinity enzyme. CYP3A4 is however inducible by drugs such as carbamazepine and rifampicin (5) and drug-drug interactions may occur with all drugs but of different kind.

1. Bertilsson L. Clin Pharmacol ther 2007;82:606-9.
2. Laine K et al. Clin Pharmacol Ther 2001;70:327-35.
3. Jerling M et al. Ther Drug Monit 1994;16:368-74.
4. Christensen M et al. Clin Pharmacol Ther 2002;71:141-52.
5. Kanebratt KP et al. Clin Pharmacol Ther 2008;84:589-94.

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LS6

Recognition and Treatment of Patients at Clinical High Risk for Developing Schizophrenia

Donald Addington
Department of Psychiatry, Faculty of Medicine, University of Calgary

The theoretical and clinical approaches to assessment and intervention in patients at clinical high risk of developing schizophrenia are based upon epidemiological and phenomenological knowledge that is well established. Retrospective studies of patient with schizophrenia show a gradual onset of negative then positive symptoms prior to clinical intervention. In the last decade clinicians have developed assessment tools and designed interventions designed to reduce symptoms, improve functioning and prevent the transition to psychosis. Four major studies have been reported using antipsychotic pharmacotherapy, cognitive therapy and poly unsaturated fatty acids (PUFA). Only the PUFA study has demonstrated a statistically significant impact on transition to psychosis. Other interventions have demonstrated improvements in symptoms. A number of conclusions can be drawn from these studies. First the majority of patients have significant impairments in function sufficient to justify intervention. Secondly a stepped care approach can be advocated that takes into consideration, the levels of symptoms and disability the risks of intervention and potential outcomes. The approach to early intervention in psychosis can be seen as part of a broader approach to intervention and prevention in youth mental health. The majority of chronic mental disorders have their onset in adolescence and young adulthood and a broad based approach to early intervention and prevention could have major benefits.

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  1. Special Lecture
  2. Clinical Research Educational Seminar
  3. Symposiums
  4. Lunceon Seminar
  5. Oral Abstracts
  6. Poster Abstracts