3.   Psychopharmacology


Psychopharmacology is very extensive branch of medicine. This chapter will emphasize basic pharmacological concepts of action of antipsychotics and antidepressants only. The reader should consult standard reference sources for more information from psychopharmacology.


Psychotropic drugs are amphiphilic molecules frequently; i.e. they are soluble both in the water phase and in the lipid bilayer. Amphiphilic drugs rapidly permeate through plasma membrane and/or accumulate in hydrophobic interior of lipid bilayer (Figure 3.1), so, interactions are possible both with membrane macromolecules and with cytoplasmatic or nuclear molecules.


Central nervous system drugs act primary as agonists or antagonists of neurotransmitter receptors, inhibitors of regulatory enzymes or blockers of stimulators of neurotransmitter membrane transporters (Table 3.1). Classification psychotropic drugs according to effects on mental functions are shown in Table 3.2.


Figure 3.1. Interaction of amphiphilic drugs with membrane



Table 3.1. Potential action of psychotropics

1. synthesis and storage of neurotransmitter

2. releasing of neurotransmitter

3. receptor-neurotransmitter interactions (blockade of receptors)

4. catabolism of neurotransmitter

5. reuptake of neurotransmitter

6. transduction element (G protein)

7. effector system


Table 3.2. Classification psychotropics according to effects on mental functions



group of psychotropics


watchfulness (vigility)


psychostimulant drugs

amphetamine, amphetaminile, ephedrine, fenmetrazine, mazindole, mezokarb, pemoline, methylphenidate


hypnotic drugs

barbital, amobarbital, hexobarbital;

glutethimid, metachalone, clomethiazol;

nitrazepam, flunitrazepam, triazolam;

zopiclone, zolpidem




imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, citalopram, fluoxetine, fluvoxamine, mianserine, buspirone, moclobemide, Li+


guaifenezine, meprobamate; diazepam, alprazolam, oxazepam; neuroleptics and antidepressants


dysphoric drugs

reserpine, clonidine, a-methylDOPA

psychic integrations


neuroleptics, atypical antipsychotics

thioridazine, chlorpromazine, chlorprotixene, levopromazine, haloperidol, perfenazine, clozapine, amisulpride, risperidone, sertindole, quetiapine, olanzapine


hallucinogenic agents

lysergid, cocaine, amphetamines, ketamine, hashish, marihuana, phencyclidine, mescaline




piracetam, pyritinol, meclophenoxate


amnestic drugs


(See: Švestka J. a kol.: Psychofarmaka v klinické praxi. GRADA Publishing, 1995; Hynie S.: Psychofarmakologie v praxi. Galén, 1995.)


3.1.     Antipsychotics

Antipsychotics are divided into two groups (Table 3.3):

  1. Conventional antipsychotics (basal or incisive)
  2. Atypical antipsychotics


Incisive antipsychotics have high affinity to D2 receptors and low affinity to other types of receptors. They affect positive symptoms of schizophrenia mainly. They bring about extrapyramidal symptoms (EPS).


Basal antipsychotics have lower affinity to D2 receptors and higher affinity to other receptor types beside incisive antipsychotics. They affect positive and affective symptoms of schizophrenia. They have sedative effects, they bring about anticholinergic, antihistaminic and cardiovascular side effect, and extrapyramidal symptoms are less frequent.


Atypical antipsychotics (serotonin-dopamine antagonists) are antagonists of D2 and serotonin 2A receptors, but they can affect many other types of receptors (Table 3.5). They are much more efficient in treatment of negative symptoms of schizophrenia in comparison with conventional antipsychotics. Atypical antipsychotics have lower side effects (lower EPS or tardive dyskinesis)


Table 3.3. Classification of antipsychotics



conventional antipsychotics

(classical neuroleptics)

basal (sedative) antipsychotics

chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine

incisive antipsychotics

droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine

atypical antipsychotics

(antipsychotics of 2nd generation)

amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride

(See: Švestka J.: Nová (atypická) antipsychotika 2. generace. Remedia 9, 366-385, 1999.)


Table 3.4. Mechanisms of action of antipsychotics

conventional antipsychotics

ˇ     D2 receptor blockade of postsynaptic in the mesolimbic pathway

atypical antipsychotics

ˇ     D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms;

ˇ     enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms;

ˇ     other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia


Table 3.5. Receptor systems affected by atypical antipsychotics


D2, 5-HT2A, 5-HT7, a1, a2


D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, a1


D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT7, D3, a1, NRI, SRI


D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, a1, M1, H1, NRI


D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, a1, H1, NRI


D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D1, D3, D4, a1, a2, M1, H1


D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, a1, M1-5, H1


D2, 5-HT2A, 5-HT6, 5-HT7, a1, a2, H1

NRI - norepinephrine reuptake inhibitor, SRI – serotonin reuptake inhibitor

(See: Stahl S.M.: Psychopharmacology of Antipsychotics, Martin Dunitz, London, 1999.)


3.2.     Antidepressants

Molecular mechanisms of action of antidepressants are much more diverse than that of antipsychotics. Classification of antidepressants based on their acute pharmacological actions is shown in Table 3.6. Antidepressants are amphiphilic molecules; so, they easy permeate through the cell membrane and may affect molecules on the outer and inner membrane surface, cytoplasmic elements and nuclear molecules (Figure 3.2).


Table 3.6. Classification of antidepressants based on acute pharmacological actions

inhibitors of neurotransmitter catabolism

monoamine oxidase inhibitors (IMAO)

reuptake inhibitors

serotonin reuptake inhibitors (SRI)

norepinephrine reuptake inhibitors (NRI)

selective SRI (SSRI)

selective NRI (SNRI)

serotonin/norepinephrine (dual) inhibitors (SNRI)

norepinephrine and dopamine reuptake inhibitors (NDRI)

serotonin 2A antagonist/reuptake inhibitors (SARI)

agonists of receptors


antagonists of receptors

a2-AR, 5-HT2

inhibitors or stimulators of other components of signal transduction

G proteins, adenylyl cyclase (AC), phospholipase (PL), protein kinase (PK), phosphatase, ATPase, phospholipid dependent proteins, transcription factors, 2nd a 3rd messengers


Therapeutic response is observed after a few weeks of antidepressant treatment; so, many adaptive changes in cellular functions occur. The neurotransmitter receptor hypothesis of antidepressant action explains the ultimate mechanism of their therapeutic action by receptor sensitivity changes. Currently, there is focus on the gene expression that is activated by antidepressants (see Chapter 5).


Figure 3.2. Potential mechanisms of antidepressants action




Table 3.7. Examples of antidepressants




tricyclic (thymoleptics)


desipramine, nortriptyline, protriptyline, dosulepine

sedative, anxiolytic

imipramine, amitriptyline, trimipramine, clomipramine

II. a III. generation

II. generation - activating

viloxazine, buspirone, amineptine, maprotiline

II. generation - sedative, anxiolytic

mianserine, trazodone, nefazodone, pirlindol

III. generation - SSRI

citalopram, fluvoxamine, fluoxetine, sertraline, paroxetine

enhancing 5-HT uptake


MAO inhibitors

nonselective irreversible

phenelzine, tranylcypromine, isocarboxazid

selective MAOI-B irreversible


selective MAOI-B reversibile


selective MAOI-A irreversible


selective MAOI-A reversible

moclobemide, brofaromine, toloxatone, amiflamine



lithium, carbamazepine, sodium valproate, valpromide

(See: Švestka J. a kol.: Psychofarmaka v klinické praxi. GRADA Publishing, 1995.)


3.3.     Mechanism of action of antidepressants

Selective serotonin reuptake inhibitors (SSRI) are the most frequently used antidepressants. Their mechanism of action on serotonergic neuron in a depressed patient is shown on Figure 3.3.

Before treatment (Figure 3.3 A):

After acute administration of SSRI (Figure 3.3 B):

After chronic treatment by SSRI (Figure 3.3 C):


Mechanism of action of a2-adrenoceptor blockers is shown on Figure 3.4; mechanism of action of reversible inhibitors of monoamine oxidase A (RIMA) is on Figure 3.5.


Figure 3.3. Mechanism of action of selective serotonin reuptake inhibitors (SSRI)




Figure 3.4. Mechanism of action of a2-adrenoceptor blockers



Figure 3.5. Mechanism of action of reversible inhibitors of MAO-A (RIMA)