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Mechanisms of action for potentially novel antidepressants
s4
Symposia
lithium had had a higher frequency of psychotic features in the index episode than those on lithium. These data demonstrate that ‘information, support and supervision‘ are not sufficient to counteract the tendency of bipolar patients on long-term lithium treatment to drop out. Adjunctive psychoeducational and psychotherapeutic interventions may improve patients’ acceptance of lithium prophylaxis, but their ability to reduce the impact of factors such as perceived inefficacy of treatment or trouble related to side effects (which accounted for about two thirds of interruptions in our sample) remains to be documented. In patients who keep on taking lithium for several years, a drastic reduction of the mean annual time spent in hospital is almost the rule. However, bipolar patients who remain on lithium for several years represent a self-selected population in which some groups at high risk of poor outcome may be underrepresented.
References Maj, M., Pirozzi, R., Magliano, L. and Bartoli, L. (1998) Long-term outcome of lithium prophylaxis in bipolar disorder: a five-year prospective study on 402 patients attending a lithium clinic. Am. J. Psychiatry, in press.
S.1.5 Suicide and psychopharmacology 0 E.C. Dimitriou, B’ University Department of Psychiatv, Aristotelian University qf Thessaloniki Medical School, Psychiatric Hospital of Thessaloniki, 36 Konstantinoupoleos Ave, Stavroupolis, 56429 Thessaloniki, Greece Suicidal behaviour can be regarded as an aggressive act directed towards the self. It is closely related to depression, schizophrenia and drug misuse and it is estimated that more than 15% of these patients will die by committing suicide. Psychotropic drugs are mostly used in the treatment of all psychiatric conditions that have a high suicide risk. Also, doctors prescribe higher doses of psychotropic drugs to those patients who have a high suicide risk, and suicide patients obtain 15 times more prescription drugs. Because of it, psychotropic medications are readily available and account for 80% of all drug overdoses involving prescription medications. Antidepressants seem to be the most available psychotropic drugs for an overdose. Data collected mainly in the eighties showed that tricyclics accounted for the majority of deaths by antidepressants, but new data collected in the nineties show that newer antidepressants have taken the lead. Antipsychotics are rarely used for an overdose, possibly because patients, whom these drugs are prescribed for (mainly schizophrenics) prefer more violent methods. Benzodiazepines are frequently used in combination with other drugs. Their lethality is significantly low, although there are studies reporting that 11 to 15% of suicide victims used exclusively benzodiazepines. Women are using benzodiazepines four times more frequently than men. Barbiturates are nowadays very seldom used and they are detected more frequently in suicides than in attempted suicides. One third of suicide victims ingest alcohol before committing suicide, men being twofold than women. There is a controversy whether antidepressants facilitate or diminish suicide thoughts. Fluoxetine thought to facilitate suicidality, but newer observations do nat support this hypothesis. It is argued that most SSRIs exercise some protective effects on the emergence of suicide thoughts, while from the older antidepressants maprotiline seems to increase suicide thoughts in comparison to placebo. Reversible MAOIs are also regarded as safer to older antidepressants. With regard to antipsychotics, flupenthixol and trifluoperazine seem to reduce suicidal behjtviour. The toxicity of psychotropic drugs differs greatly and their lethality is positively related to the dosage taken. Tricyclic antidepressants seem to be the most toxic psychotropic drugs because of their increased cardiotoxicity in comparison to other psychotropics. Side-effects of psychotropics, such as sleep disturbances, anxiety, nervousness and akathisia may facilitate suicide thoughts. It is of paramount importance specialists and general practitioners to be well acquainted with the pharmacological and clinical profile of psychotropics and to use them properly. Nowadays, office practice and drug management have become more complicated and require strong therapeutic
alliance to ensure good compliance and to avoid undertreatment. It must also become clear that severity of depression is not a reliable predictor of suicide behaviour.
Mechanisms of action for potentially novel antidepressants
S.1.6 n
J. Perezh, M. Popoli‘ and N. Bnmello”. ‘Center of Neuropharmacology, Institute of Pharmacological Sciences, Via Balzaretti 9, Milan, Italy. bDepartment of Neuropsychiatric Sciences HRS, University of Milan, Milan, Italy. “I.R.C.C.S. Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy. dDepartment of Pharmaceutical Sciences, University of Modena, Italy
G. Racagni”,
The role of monoamines (serotonin, 5-HT; norepinephrine, NE; dopamine, DA) in the mechanism of action of antidepressants and in the pathophysiology of depression has been examined widely in the last three decades. Despite the tremendous research efforts, these studies have failed to identify a common action of antidepressant treatments and to advance our knowledge on the biology of affective disorders. The characterization of the biochemistry of synapse, through the years ’50s and ‘7Os, has lead to the synthesis of antidepressants which have as target either the monoamine transporters (tricyclics, SSRI, NE and DA reuptake blockers) and monoamine oxidase. The fact that these drugs cause a short-term increase in synaptic levels of monoamines supported the hypothesis that reduced availability of monoamine neurotransmitters could play a role in the pathogenesis of depression. However, it remains unclear why the time for the therapeutic action of antidepressant treatments requires several weeks, even though levels of monoamines are increased rapidly after drug administration. In the years ‘SOS, the theory of monoamine receptor adaptations took place. The persistent activation of these receptors, as a consequence of antidepressant induced elevation of 5-HT and NE levels, would lead to receptor down regulation that would than explain the delayed therapeutic action of different classes of antidepressants. However, there are many question marks with this hypothesis, since not all the antidepressants down-regulate the levels of beta or 5-HT receptor subtypes and monoamine receptor antagonists have not been proved to possess antidepressive activity. Recent advances in molecular and cellular biology have put forward a role for intracellular signal transduction pathways and the regulation of specific target genes in the action of antidepressants. This presentation will review the role of intracellular messengers in depression and will present evidence that the signal transduction pathways could represent novel targets in the action of novel antidepressant drugs.
S.2 Drug and alcohol addiction S 2 El
1
Brain mechanisms in addiction
C. Spyraki. Laboratory of Pharmacology, Department of Basic Sciences, School qf Medicine, University of Crete The study of brain reward substrate and mechanisms is pivotal in both psychiatry and psychopharmacology, This derives from the facts that a) a number of addictive i.e. repetitive, compulsive, nonsensical, unhealthy nonbeneficial, attitudes are included in the symptomatology of psychoses and may reflect pathological brain reward and learning substrates and b) drug abuse, itself an addictive behavior, is now considered as a brain disease mainly due to a dysregulated hedonic homeostatic brain mechanism, The common brain effects of addictive substances suggest common brain mechanisms underlying all addictions, Common neurobiological mechanisms involved, such as the mesolimbic dopamine (DA) system, opioid peptidergic systems, hormone and stress systems are beginning to be characterized. For a number of years we have focused on the role of the pallidal substrate in learning, reward and addiction. This brain area is abundant in enkephalins and it bears reciprocal connections with the dopaminergic systems, Initially, we have shown that globus pallidum (GP) is important in spontaneous and drug-induced locomotor behaviors, In addition we reported that GP lesionned animals exhibit normal aquisition in behavioral tests but appear reluctant to approach or to avoid appetitive and aversive stimuli correspondingly in learned tasks. The results of this first
Symposia
lithium had had a higher frequency of psychotic features in the index episode than those on lithium. These data demonstrate that ‘information, support and supervision‘ are not sufficient to counteract the tendency of bipolar patients on long-term lithium treatment to drop out. Adjunctive psychoeducational and psychotherapeutic interventions may improve patients’ acceptance of lithium prophylaxis, but their ability to reduce the impact of factors such as perceived inefficacy of treatment or trouble related to side effects (which accounted for about two thirds of interruptions in our sample) remains to be documented. In patients who keep on taking lithium for several years, a drastic reduction of the mean annual time spent in hospital is almost the rule. However, bipolar patients who remain on lithium for several years represent a self-selected population in which some groups at high risk of poor outcome may be underrepresented.
References Maj, M., Pirozzi, R., Magliano, L. and Bartoli, L. (1998) Long-term outcome of lithium prophylaxis in bipolar disorder: a five-year prospective study on 402 patients attending a lithium clinic. Am. J. Psychiatry, in press.
S.1.5 Suicide and psychopharmacology 0 E.C. Dimitriou, B’ University Department of Psychiatv, Aristotelian University qf Thessaloniki Medical School, Psychiatric Hospital of Thessaloniki, 36 Konstantinoupoleos Ave, Stavroupolis, 56429 Thessaloniki, Greece Suicidal behaviour can be regarded as an aggressive act directed towards the self. It is closely related to depression, schizophrenia and drug misuse and it is estimated that more than 15% of these patients will die by committing suicide. Psychotropic drugs are mostly used in the treatment of all psychiatric conditions that have a high suicide risk. Also, doctors prescribe higher doses of psychotropic drugs to those patients who have a high suicide risk, and suicide patients obtain 15 times more prescription drugs. Because of it, psychotropic medications are readily available and account for 80% of all drug overdoses involving prescription medications. Antidepressants seem to be the most available psychotropic drugs for an overdose. Data collected mainly in the eighties showed that tricyclics accounted for the majority of deaths by antidepressants, but new data collected in the nineties show that newer antidepressants have taken the lead. Antipsychotics are rarely used for an overdose, possibly because patients, whom these drugs are prescribed for (mainly schizophrenics) prefer more violent methods. Benzodiazepines are frequently used in combination with other drugs. Their lethality is significantly low, although there are studies reporting that 11 to 15% of suicide victims used exclusively benzodiazepines. Women are using benzodiazepines four times more frequently than men. Barbiturates are nowadays very seldom used and they are detected more frequently in suicides than in attempted suicides. One third of suicide victims ingest alcohol before committing suicide, men being twofold than women. There is a controversy whether antidepressants facilitate or diminish suicide thoughts. Fluoxetine thought to facilitate suicidality, but newer observations do nat support this hypothesis. It is argued that most SSRIs exercise some protective effects on the emergence of suicide thoughts, while from the older antidepressants maprotiline seems to increase suicide thoughts in comparison to placebo. Reversible MAOIs are also regarded as safer to older antidepressants. With regard to antipsychotics, flupenthixol and trifluoperazine seem to reduce suicidal behjtviour. The toxicity of psychotropic drugs differs greatly and their lethality is positively related to the dosage taken. Tricyclic antidepressants seem to be the most toxic psychotropic drugs because of their increased cardiotoxicity in comparison to other psychotropics. Side-effects of psychotropics, such as sleep disturbances, anxiety, nervousness and akathisia may facilitate suicide thoughts. It is of paramount importance specialists and general practitioners to be well acquainted with the pharmacological and clinical profile of psychotropics and to use them properly. Nowadays, office practice and drug management have become more complicated and require strong therapeutic
alliance to ensure good compliance and to avoid undertreatment. It must also become clear that severity of depression is not a reliable predictor of suicide behaviour.
Mechanisms of action for potentially novel antidepressants
S.1.6 n
J. Perezh, M. Popoli‘ and N. Bnmello”. ‘Center of Neuropharmacology, Institute of Pharmacological Sciences, Via Balzaretti 9, Milan, Italy. bDepartment of Neuropsychiatric Sciences HRS, University of Milan, Milan, Italy. “I.R.C.C.S. Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy. dDepartment of Pharmaceutical Sciences, University of Modena, Italy
G. Racagni”,
The role of monoamines (serotonin, 5-HT; norepinephrine, NE; dopamine, DA) in the mechanism of action of antidepressants and in the pathophysiology of depression has been examined widely in the last three decades. Despite the tremendous research efforts, these studies have failed to identify a common action of antidepressant treatments and to advance our knowledge on the biology of affective disorders. The characterization of the biochemistry of synapse, through the years ’50s and ‘7Os, has lead to the synthesis of antidepressants which have as target either the monoamine transporters (tricyclics, SSRI, NE and DA reuptake blockers) and monoamine oxidase. The fact that these drugs cause a short-term increase in synaptic levels of monoamines supported the hypothesis that reduced availability of monoamine neurotransmitters could play a role in the pathogenesis of depression. However, it remains unclear why the time for the therapeutic action of antidepressant treatments requires several weeks, even though levels of monoamines are increased rapidly after drug administration. In the years ‘SOS, the theory of monoamine receptor adaptations took place. The persistent activation of these receptors, as a consequence of antidepressant induced elevation of 5-HT and NE levels, would lead to receptor down regulation that would than explain the delayed therapeutic action of different classes of antidepressants. However, there are many question marks with this hypothesis, since not all the antidepressants down-regulate the levels of beta or 5-HT receptor subtypes and monoamine receptor antagonists have not been proved to possess antidepressive activity. Recent advances in molecular and cellular biology have put forward a role for intracellular signal transduction pathways and the regulation of specific target genes in the action of antidepressants. This presentation will review the role of intracellular messengers in depression and will present evidence that the signal transduction pathways could represent novel targets in the action of novel antidepressant drugs.
S.2 Drug and alcohol addiction S 2 El
1
Brain mechanisms in addiction
C. Spyraki. Laboratory of Pharmacology, Department of Basic Sciences, School qf Medicine, University of Crete The study of brain reward substrate and mechanisms is pivotal in both psychiatry and psychopharmacology, This derives from the facts that a) a number of addictive i.e. repetitive, compulsive, nonsensical, unhealthy nonbeneficial, attitudes are included in the symptomatology of psychoses and may reflect pathological brain reward and learning substrates and b) drug abuse, itself an addictive behavior, is now considered as a brain disease mainly due to a dysregulated hedonic homeostatic brain mechanism, The common brain effects of addictive substances suggest common brain mechanisms underlying all addictions, Common neurobiological mechanisms involved, such as the mesolimbic dopamine (DA) system, opioid peptidergic systems, hormone and stress systems are beginning to be characterized. For a number of years we have focused on the role of the pallidal substrate in learning, reward and addiction. This brain area is abundant in enkephalins and it bears reciprocal connections with the dopaminergic systems, Initially, we have shown that globus pallidum (GP) is important in spontaneous and drug-induced locomotor behaviors, In addition we reported that GP lesionned animals exhibit normal aquisition in behavioral tests but appear reluctant to approach or to avoid appetitive and aversive stimuli correspondingly in learned tasks. The results of this first