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Professor of Psychiatry and Pharmacology
Head of Department of Neurochemistry
Serendipity is a phenomenon first describd by the English writer Horace Walpole (1717–97) after a Persian fairytale: while wandering in their search for happiness, the three princes of Serendip made unexpected discoveries of objects they had not been actively seeking, by accident and sagacity. The first discoveries of psychotropic drugs, such as chlorpromazine and haloperidol for schizophrenia and imipramine for depression, were serendipitous, arising from careful clinical observations in small numbers of patients. Based on these early discoveries, many “me too” drugs with similar mechanisms of action came onto the market.
Exploration of the mechanisms of action of these drugs contributed to our knowledge of the way the brain functions. The functioning brain consists of multiple systems and many neurones operating in concert. These neurones use biogenic amines, such as noradrenaline, serotonin (5-HT) and dopamine as transmitters; they are synthesised presynaptically in the neurones, stored in vesicles and released into the synaptic cleft, where they react with postsynaptic G-coupled receptors. These receptors activate ion channels indirectly through G-proteins. In a further step, levels of secondary messengers such as cAMP, cGMP and isonitol triphosphate are altered. These complex intracellular events lead to the activation of protein kinases and phosphatases, which change receptor sensitivities and neuronal activities. The released transmitters are deactivated via reuptake mechanisms through an active process using transporter proteins.
Psychotropic drugs, antidepressants as well as antipsychotics, modulate neuronal activity by either blocking receptors or inhibiting the deactivation of transmitters. In general, antidepressants stimulate the activity of neurones and antipsychotics reduce their activity.
Depressive mood seems to be the result of diminished activity in the noradrenergic, serotoninergic and dopaminergic neurotransmitter systems. Antidepressants restore activity by inhibiting transmitter reuptake by the presynaptic neurones. They also affect other types of neurones (eg, histamine and acetylcholine), causing major side-effects that limit the broader use of antidepressants.
Although the efficacy of the older, tricyclic antidepressants is well established, the high incidence of side-effects and the high numbers of nonresponders and treatment-resistant patients represent a drawback that has led to the development of new drugs.
The development of selective serotonin reuptake inhibitors (SSRIs) was the first attempt at using a pathophysiological approach to management. With similar efficacy but fewer side-effects, these drugs have become the preferred pharmacological treatment for depression. Again, the great number of nonresponders and the delay in the onset of response limit their value. Meta-analytical studies have shown that they are less effective than tricyclic antidepressants in severe depression, so antidepressants with dual mechanisms of action have been developed. Today up to eight different classes of antidepressants are available. They principally differ in their selectivity for the monoamines and their respective receptors.(1)
Understanding the function of the serotonin system has allowed the specific development of drugs for psychiatric disorders other than depression. A great number of normal and abnormal behaviours are attributable to the serotoninergic neurones. However, the limited number of serotonin neurones in the brain (around 300,000) suggests that they mainly have a modulating function – either dampening or accelerating a behaviour. Drugs targeting serotonin functions influence many kinds of behaviour (see Figure 1).
There have been attempts to link noradrenergic dysfunction to subgroups of depression. It is assumed that some forms of depression are accompanied by reduced noradrenergic activity. However, this is a matter of discussion, and some forms of depression may even be accompanied by higher levels of noradrenergic function.Theories about anxiety and panic disorders assume that the noradrenergic neurones in the locus ceruleus are activated or increased in these conditions. A noradrenaline deficit explains disturbances of attention, psychomotor retardation and impaired attention.
Some antidepressants elevate the activity of dopamine neurones, either directly or indirectly via serotonin and noradrenaline neurones. Dopaminergic drugs, such as amineptine or nomifensin, have been shown to be effective in subgroups of depression, but their use is limited because of the risk of abuse. As a result, they are no longer on the market. In selective refractory depressive patients, dopaminergic drugs like amphetamine have some beneficial effects.(2)
It is difficult to link the three different monaminergic systems to specific psychiatric symptoms as they do not work independently of each other. The functional relationship that exists between the serotoninergic, noradrenergic and dopaminergic systems explains why a deficit in one system also impairs the other systems, and why even specific drugs such as SSRIs modulate the other systems as well. The variety of clinical uses for newer antidepressants may compel a re-examination of traditional diagnostic categories and theories on the way antidepressants work.
Antidepressant drugs are used in a wide range of psychiatric disorders. Empirical evidence in the 1970s suggested that the nonselective serotonin antidepressant clomipramine improved symptoms of obsessive- compulsive disorder (OCD). Newer generations of antidepressants with fewer side-effects have shown to be even more active in OCD. Furthermore, 5-HT(1A) agonists are being investigated in general anxiety disorders. 5-HT(2) receptor antagonists are tested for schizophrenic symptoms, anxiety or dysthymia. Other potential indications for SSRIs and the new generation of antidepressants include: panic disorders, premenstrual dysphoric disorder, eating disorders, substance abuse disorder, chronic pain, dementia, personality disorders with aggression or impulse disturbances, and general anxiety disorders.
Depressive symptoms are frequently diagnosed in patients with schizophrenia and have been described in schizoaffective disorders. They can also occur after the acute phase of schizophrenia or following neuroleptic treatment. SSRIs seem to be useful in combination with antipsychotics to treat this condition, and such patients are frequently (50%) treated simultaneously with antipsychotics and antidepressants.
Antidepressants are also useful in the treatment of a group of psychosomatic disorders that may be phenomenologically and genetically related to major depression, such as fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, atypical facial pain, and premenstrual dysphoric disorder. It is likely that the aetiology of depression (as a symptom) in these disorders is similar to that of major depression as an entity.
Genetic and biological studies show that schizophrenia is a heterogeneous disease. Disturbances in neurological development and/or abnormal immune function may be responsible for schizophrenic symptoms. Additionally, abnormal dopamine, noradrenaline and serotonin transmitter activities in some areas of the brain may be pathophysiologically relevant for some schizophrenic syndromes. Other theories assume disturbances in the glutamatergic and GABA-ergic circuits. Because of this heterogeneity and the impossibility of characterising clinical subgroups of schizophrenic patients, none of these theories has been proved as yet.
The discovery of chlorpromazine for the treatment of schizophrenia opened new perspectives for the care of psychiatric patients. Unfortunately, chlorpromazine and the other classical neuroleptics produce side-effects that limit their widespread use. For many years, the dopamine hypothesis, which is closely related to the assumed mechanism of action of these compounds, was the predominant theory of action. The introduction of new atypical neuroleptics, such as clozapine, opened the way for revision of the dopamine hypothesis. To explain the unique features of clozapine, new theories propose interference with dopamine receptor subtypes and other neurotransmitters, such as noradrenaline and serotonin. The nonspecificity of secondgeneration atypical neuroleptics for the dopamine system, the failure of some selective dopaminergic drugs in therapy, the unsuccessful genetic studies targeting the dopaminergic system, and the disappointing biochemical findings in schizophrenic patients have led to alternative theories of the pathogenic causes of schizophrenia, which have opened new perspectives for the future development of new drugs. Based on neuropathological and neuroanatomical findings, and in concordance with the revised dopamine hypothesis, new models draw attention to the role of the excitatory amino acid γ-aminobutyric acid (GABA) and to the most ubiquitous amino acid transmitter in the brain – glutamate.
The psychotic symptoms of schizophrenia have been divided into negative symptoms (blunted affect, anhedonia, asociality and inability to initiate and carry out complex tasks to completion), which seem to be related to cortical hypofunction, and which in turn may be associated with decreased mesocortical dopamine activity, and positive symptoms (hallucinations, delusions and thought disorder). They also appear in disorders other than schizophrenia as well as many nonpsychotic disorders related to increased activity of the subcortical, striatal dopamine neurones.
Antipsychotic drugs are used to treat many other psychiatric disorders. Before lithium was considered the drug of choice for bipolar depressive and manic patients, the pharmacological strategies for bipolar disorder included neuroleptics and antidepressants. They have been principally used to treat the psychotic symptoms present during one of the poles of the disorder or in adjunct when other alternatives have failed. There have been several reports that clozapine may be more effective in patients with mania and schizoaffective disorder than in patients with schizophrenia. Refractory rapid-cycling and dysphoric mania also seem to improve with clozapine. Both psychotic and mood symptoms respond well to clozapine monotherapy.
Preliminary reports suggest that the newer atypical antipsychotics olanzapine and sertindole may also be effective in stabilising mood or in the management of affective symptoms. Refractory psychotic depressions have also been successfully treated with clozapine or amisulpride therapy.
Psychotic symptoms frequently occur during the evolution of idiopathic Parkinson’s disease and other parkinsonian syndromes. They seem to be related to interactions between the underlying neuropathologies of the syndromes and the adverse effects associated with chronic antiparkinsonian drug administration. In patients with advanced Parkinson’s disease, there is also a high prevalence of affective co-morbidity. Classical neuroleptics may improve the symptoms but usually worsen parkinsonism. Clozapine has been used successfully since 1985 with few extrapyramidal effects. Olanzapine has been reported to be effective in the suppression of psychotic symptoms in these patients, but the currently available dose increments may result in the exacerbation of motor disability.
The problem with co-medication
Due to therapy nonresponse, co-morbidity and disorders such as bipolar disorder, many patients are treated simultaneously with more than one medication, most frequently with three, or, especially in the case of elderly patients, sometimes more than 10 medicines. This co-medication can have synergistic additive or antagonistic effects.
On the level of pharmacokinetics the inhibition or promotion of metabolising cytochromes is one of the reasons for abnormal plasma levels. If co-medication is unavoidable, the dosage must be adjusted and, if possible, therapeutic drug monitoring must be considered. On the pharmacodynamic level, the combination of two or more antipsychotics can lead to additive blockade of the dopamine receptor, which can cause more extrapyramidal side-effects. Blockade of α-receptors can produce cardiovascular sideeffects.
Such effects are unpredictable if more than one drug with such properties is given.
Co-medications can sometimes have additive beneficial effects. If, for instance, a patient does not respond to an SSRI antidepressant, a specific noradrenaline reuptake inhibitor such as reboxetine may be useful. If a symptom such as sleep disturbance or feeling suicidal is predominant, then therapy with an additional sedative drug such as mirtazapine in antidepressant therapy may be helpful. Newer results show that patients with suicidal thoughts can be treated with clozapine or with olanzapine.
Augmentation strategies such as the combination of an antidepressant with the mood stabiliser lithium or with thyroid hormones and oestrogens can be helpful in some patients.
In the second article of this two-part series we will examine the diagnostic issues that impact on psychiatric care and look in greater detail at the pharmacokinetic and pharmacodynamic aspects of psychopharmacology.
College of Neuropsychopharma cology (ECNP) Congress
20-24 September 2003
Prague, Czech Republic
Association of European Psychiatrists (AEP)
Spring Symposium Regional Meeting
24-26 April 2003
12th AEP Congress
14-18 April 2004