imipramine was found to improve mood while being used in a protocol to search for an antipsychotic : ' iproniazid , a drug used in the treatment of tuberculosis , was likewise found to have beneficial effects on mood .
the former , a tricyclic antidepressant ( tca ) , and the latter , a monoamine oxidase inhibitor ( maoi ) , belong to two classes of drugs still in use today .
depressive mood appears to be attributable to diminished activity of the dopaminergic , noradrenergic , and serotonergic neurotransmitter systems .
antidepressants restore the activity of these transmitters by inhibiting reuptake in the presynaptic neurons . additionally , the classic antidepressants have effects on other neurons ( eg , histamine , acetylcholine ) , resulting in major side effects limiting their broader use .
depressive symptoms have been described in as many as 40 different disorders , which would imply that they could be used in all of them . 
 
although the efficacy of tcas has been well established , the high incidence of side effects and the high number of nonresponders or treatment - resistant patients represent drawbacks that have made it necessary to search for new drugs .
the development of selective serotonin reuptake inhibitors ( ssris ) was the first attempt based on a pathophysiological approach .
these drugs , which have similar efficacy , but less side effects than the tcas , have become the preferred pharmacological treatment for depression . however , the high number of nonresponders and the delay in onset of response have limited their value .
today , up to seven different classes of antidepressants are available , which mainly differ in their selectivity for the respective monoamines and their receptors . 
 
these discoveries have intensively stimulated biochemical - pharmacological research into the mechanism of action of antidepressants .
findings from these investigations suggest that enhanced activity of the central noradrenergic and/or serotonergic transmitter system is essential for the clinical antidepressant action .
such enhancement could be achieved either presynaptically by blocking 2-adrenergic receptors , or in the synaptic cleft by inhibiting the transmitter reuptake or the main metabolic enzyme monoamine oxidase ( mao ) . the increased transmitter concentration in the synaptic cleft after chronic treatment leads to a downregulation of postsynaptic -receptors , sometimes modulated by interaction with neuropeptides and hormones . 
 
in addition , depending on the antidepressant used , the sensitivity of 5-ht2a , somatodendritic 5-ht1a , or noradrenergic 1 receptors may be reduced , leading to an overall increase in serotonin transmission .
such receptor alterations appear to provide the best explanation for the delay in clinical antidepressant response .
the introduction of new classes of antidepressants has led to renewed thinking about their mechanism of action .
recent investigations of second messenger systems such as the adenylate cyclase system and the phosphatidylinositol system are very promising .
antidepressant drugs , including the mood stabilizers lithium and carbamazepine , modulate both of these second messenger systems , which in turn modulate the phosphorylation status of neuronal proteins via protein kinase .
the outcome is a positive alteration of the gene expression of the relevant biochemical structures ( enzymes , transporters , receptors ) , thus restoring the normal function of the respective neuronal systems .
thanks to clearer understanding of the function of this complex serotonergic system we now know that a great number of normal and abnormal behaviors can be attributed to dysfunction of the serotonergic neurons , in addition to their role in depression .
the limited number of serotonin neurons in the brain ( approximately 300 000 ) suggests that their role is mainly a modulating one .
this implies that they act to either dampen or accelerate a given type of behavior .
drugs targeting the serotonergic system are therefore able to influence many kinds of behavior abnormalities ( figure 1 ) . 
  concerning the norepinephrine system
as already mentioned , some forms of depression are assumed to be accompanied by reduced noradrenergic activity .
however , this is a matter for discussion , and some forms of depression may even be accompanied by increased noradrenergic function .
it is hypothesized that noradrenergic neurons in the locus ceruleus are activated or increased in anxiety and panic disorders .
conversely , a norepinephrine deficit is invoked to explain disturbances of attention , psychomotor retardation , and impaired vigilance .
some antidepressants also increase dopaminergic neuron activity , either directly or indirectly , by acting on serotonergic and noradrenergic pathways .
dopamine , a major transmitter of the reward system also plays a role in depressive states .
dopaminergic antidepressants could be of interest in some subgroups of depression , but so far no such drugs are available in europe
. however , in some patients with refractory depression , dopaminergic drugs like amphetamine have some beneficial effects . 
 
neuronal circuits establish functional relationships between serotonergic , noradrenergic , and dopaminergic systems , which explains why deficiency in one system impairs the other systems as well , and why even specific drugs like the ssris arc also able to modulate the other systems .
the variety of the clinical uses for the newer antidepressants may necessitate a reexamination of traditional diagnostic categories and of theories on the way antidepressants work .
antidepressant drugs are used in a wide range of psychiatric disorders . empirical evidence in the 70s suggested that the nonselective serotonin antidepressant clomipramine improved symptoms of ocd .
newer generations of antidepressants with fewer side effects have proved to be even more active in ocd . furthermore , 5-ht1a serotonin agonists are being investigated in general anxiety disorders .
other potential indications for ssris and the new generation of antidepressants are panic disorders , premenstrual dysphoric disorder , eating disorders , substance abuse disorder , chronic pain , dementia , and personality disorders with aggression or impulse disturbances , and general anxiety disorders . 
 
depressive symptoms arc frequently diagnosed in patients with schizophrenia and have been described in schizoaffective disorders .
. this may be the reason why such patients are frequently ( 50% of cases ) treated simultaneously with antipsychotics and antidepressants . 
 
antidepressants are also useful in the treatment of a group of 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 etiology of depression ( as a symptom ) in these disorders is similar to that of major depression as an entity , and therefore would explain the efficacy of ssris .
although not impossible , it would be contrary to expectation if the mechanism of antidepressant effect was independent of the mechanism of depression in migraine , premenstrual dysphoric disorder , and other conditions . and it would be even more difficult to believe that different , chemically unrelated antidepressant drugs , share the same pharmacological properties while having different mechanisms of action . 

disturbances in neurodevelopment and/or abnormal immune function may be responsible for schizophrenic symptoms . additionally , abnormal
dopamine , norepinephrine , and serotonin transmitter activities in some areas of the brain may be pathophysiological relevant to some schizophrenic syndromes . other theories put forward disturbances in the glutamatergic and gabaergic circuits .
because of this heterogeneity and the impossibility of characterizing clinical subgroups of schizophrenic patients , none of these theories has been conclusively proved so far . 
 
the discovery of chlorpromazine for the treatment of schizophrenia opened new perspectives for the care of psychiatric patients .
unfortunately , chlorpromazine and the other classic neuroleptics produce side effects that limit their widespread use . for many years
, the dopamine hypothesis , based on the assumed mechanism of action of these compounds , was the predominant theory . 
 
the introduction of new atypical neuroleptics such as clozapine , which was the first one , paved the way for revisiting the dopamine hypothesis of schizophrenia and related theories on the mechanism of action of neuroleptics . to explain the unique features of clozapine , new theories have been put forward , partly in relation to interference with dopamine receptor subtypes and partly in relation to interference with other neurotransmitters such as norepinephrine and serotonin .
the nonspecificity of second - generation atypical neuroleptics for the dopaminergic system , the therapeutic ineffectiveness of some selective dopaminergic drugs , the lack of success of genetic studies targeted to the dopaminergic system , and the disappointing biochemical findings in schizophrenic patients have resulted in alternative theories of pathogenic causes of schizophrenia being proposed , opening up new perspectives for the development of future drugs . based on neuropath ological and neuroanatomical findings and in concordance with the revised dopamine hypothesis ,
new models have been postulated focusing attention on the excitatory amino acid y - aminobutyric acid ( gaba ) and the most ubiquitous amino acid transmitter in the brain , glutamate . 
 
psychotic symptoms of schizophrenia have been divided into negative symptoms ( blunted affect , anhedonia , asociality , 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 dopaminergic activity and positive symptoms ( hallucinations , delusions , and thought disorders ) .
they also appear in disorders other than schizophrenia as well as many nonpsychotic disorders , and are related to increased activity of the subcortical striatal dopaminergic neurons .
was considered as the standard treatment for bipolar depressive and manic patients , the pharmacological strategies for bipolar disorder included neuroleptics and antidepressants .
they are now mainly used to treat the psychotic symptoms present during one of the poles of the disorder , or as an adjunctive treatment 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 .
preliminary reports suggest that the newer atypical antipsychotics olanzapine and sertindole may also be effective in stabilizing mood or in the management of affective symptoms .
the occurrence of psychotic symptoms is frequent during the evolution of idiopathic parkinson 's disease and other parkinsonian syndromes .
they seem to be related to interactions between the underlying neuropathologies manifestations of the syndromes and the adverse effects associated with chronic antiparkinsonian drug administration . in patients with advanced parkinson 's disease
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 an exacerbation of motor disability . 

as mentioned above , since no solid alternatives have emerged from biological research to replace the current hypothesis regarding the pathogenesis of psychiatric disorders , the development of new psychotropic drugs remains based on the restoration of the imbalance in the monoamincrgic system .
this is exemplified by the development of the new antidepressants . the postulate that depression results from a dysfunction in the noradrenergic , serotonergic , and dopaminergic systems leads logically to the attempt to design antidepressants that act mainly on one of the neurotransmitter systems .
the idea is to increase selectivity without compromising efficacy , while at the same time reducing the side effects that result of interactions with these and other neurotransmitter systems .
thus , blockade of serotonin reuptake gave rise to the now well - known ssris . a new class of drugs , which selectively inhibit the reuptake of norepinephrine , was recently introduced onto the market
however , experience with psychotropic drugs acting on either the noradrenergic or the serotonergic systems suggest how important it is ( at least in certain situations ) to act on both systems at once .
research was therefore undertaken to develop new antidepressants with a dual action on these systems .
although drug development tries to focus on specific mechanisms involved in depression and its symptoms , clinical research is not nosologically but transnosologically oriented .
the tools used to monitor therapeutic response in clinical trials are usually rating scales that evaluate the depressive or psychotic state rather than treatment efficacy on a specific entity .
efficacy , nosology , and duration of treatment are based on the antidepressant effect , and , therefore , in many of the specific entities where they are presently used , these variables have not been confirmed .
similarly , in most trials focusing on therapeutic outcome , there are no differences between different drugs belonging to the same therapeutic group .
the current situation is therefore characterized by disharmony prevailing between psychotropic drug development , nosological classification of diseases , clinical research , and therapeutic uses of psychotropic drugs .
 the current clinical use of psychotropic drugs is transnosologically oriented . 
 this is facilitated by the current classification of mental disorders ( international classification of diseases , 10th revision [ icd-10 ] ) and is perhaps justified if depression and psychosis ( taken here as examples ) are considered as being complex syndromes with heterogeneous etiologies , but common pathogenesis , more than specific entities . 
 however , this approach does not identify possible differences between specific psychiatric entities , which could in turn mask differences in therapeutic responses and , therefore , therapeutic outcome . 
 this is compounded by the current disharmony between the nosological classification of diseases , drug development , clinical research , and therapeutic uses of psychotropic drugs . 
 functional pharmacology targeting abnormal behavioral traits could represent an avenue for future research and treatment . 
Clinical treatment with antidepressants
Treatment of schizophrenia and other psychiatric disorders with antipsychotics
Transnosological use of psychotropics: drug development and clinical research
Conclusion