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Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
•Antidepressants
•Mood stabilizers
•Psychostimulants
•Nootropic drugs
•CNS stimulants
(Abstract)
Assoc. Prof. Iv. Lambev
www.medpharm-sofia.eu
Depression is a heterogeneous disorder. A simplified
classification based on presumed origin is as follows:
(1) brief reactive or secondary depression (most common),
occurring in response to real stimuli such as grief, illness, etc;
(2) major depression (melancholic and recurrent depression)
a genetically determined biochemical disorder manifested
by an inability to experience ordinary pleasure or to cope with
ordinary life events;
(3) manic-depressive depression (depression associated with
bipolar affective disorder)
Pharmacologic treatment of depressions is very important, although
a continuing role for electroconvulsive therapy for severe forms of
life-threatening depression is also noted.
manic
Depression is one of the most common psychiatric disorders.
At any given moment, about 3–5% of the population is depressed,
and an estimated 10% of people may become depressed during
their lives. The symptoms of depression are often subtle and
unrecognized both by patients and by physicians. Patients with
vague complaints that resist explanation as manifestations of
somatic disorders and those who might be simplistically described
as “neurotic” should be suspected of being depressed.
Soon after the introduction of reserpine (1948), it became
apparent that the drug could induce depression by inhibiting the
neuronal storage of amine neurotransmitters 5-HT and NE.
Reserpine-induced depression and depleted stores of amine neurotransmitters. It was reasoned, depression must be associated
with decreased functional amine-dependent synaptic transmission.
NA (noradrenaline) = NE (norepinephrine)
Rauwolfia serpentina
(a small indian shrub)
•Reserpine
•Ajmaline
Pathogenesis of depression
The idea that depression must be associated with decreased
functional amine-dependent synaptic transmission
provided the basis for amine hypothesis of depression.
By extension, drugs that increased amine function in appropriate
synaptic areas would relieve depression.
The amine hypothesis has provided the major experimental
models for the discovery of new antidepressants.
All currently available antidepressants, except bupropion,
are classified as having their primary actions on the
metabolism, reuptake, or selective receptor antagonism
of 5-HT, NA, or both.
(5-HT)
(NE)
(DA)
The effects of DA, 5-HT and NE on the brain functions
Raised neurotransmitter concentrations produce
immediate alterations in postsynaptic receptor
activation, leading to changes in second messenger
(intracellular) systems and to gradual modifications
in cellular protein expression. Antidepressants
increase a cyclic AMP response-element binding
(CREB) protein which in turn is involved in
regulating the transcription of genes that influence
survival of other proteins including brain derived
neurotrophic factor (BDNF) which exerts effects on
neuronal growth. The role of BDNF in depression
is supported by the observation that stress both
reduces its expression and impairs neurogenesis.
The monoamine hypothesis of depression is an
oversimplification (only deficieny of NA, 5-HT, and
DA) of a complicated picture. Other systems that
are implicated in the etiology of depression (and
which provide potential targets for drug therapy)
include the hypothalamo-pituitarythyroid axis and
the hypothalamo-pituitary-adrenal axis (HPA).
The finding that 50% of depressed patients have
elevated plasma cortisol concentrations constitutes
evidence that depression is associated with
increased HPA drive.
Structural relationships between
various tricyclic antidepressants (TCAs).
Their structures are similar to phenothiazines.
Selective serotonin reuptake inhibitors (SSRIs).
Pharmacokinetics
The antidepressants are generally well absorbed
after oral administration. Steady-state plasma
concentrations of TCAs show great individual
variation but correlate with therapeutic effect.
Antidepressants in general are inactivated principally by metabolism by hepatic cytochrome P450
enzymes (2D6 and 3A4). Other cytochrome
enzymes are CYP 1A2 inhibited by the SSRI
fluvoxamine, and induced by cigarette smoking,
caffeine and the atypical antipsychotics (clozapine
and olanzapine).
Several of these drugs produce active metabolites
which prolong their action (e.g. fluoxetine is
metabolized to norfluoxetine, t1/2 200 h). The metabolic products of certain TCAs are antidepressants
too, e.g. nortriptyline (from amitriptyline),
desipramine (from imipramine).
Half-lives of TCAs and SSRIs are long (> 15 h).
Around 7% of the Caucasian population have
very limited CYP 2D6 enzyme activity.
Such “poor metabolizers” may find standard
doses of tricyclic antidepressants intolerable and
it is often worth starting at a very low dose.
Clinical indications
The major indication is to treat depression, but a number of
other uses have been established by clinical experience.
Antidepressants may benefit most forms of anxiety disorder
(panic disorder, generalized anxiety disorder, post-traumatic
stress, obsessive-compulsive disorder, and social phobia),
migraine.
SSRIs are effective in milder cases of the eating disorder
bulimia nervosa, particularly fluoxetine (in higher doses than
are required for depression). Antidepressants appear to be
ineffective in anorexia nervosa.
SSRIs (selective serotonin
reuptake inhibitors)
are used in:
•panic disorders
•chronic anxiety
•depression
•bulimia neurosa
(fluoxetine – in higher doses)
Schematic representation of the time course of panic treatments
Adapted from Bennett and Brown (2003)
Mode of use
The action of TCAs in ameliorating mood is usually
absent in the first 2 weeks of therapy and at least 4
weeks must elapse to constitute an adequate trial.
Where a minimal response is noted in this period, it
is reasonable to extend the trial to 6 weeks to see
if further benefit is achieved. Dose titration is often
necessary. By contrast, patients may
experience unwanted drug effects immediately
on starting treatment (and they should be warned),
but such symptoms often diminish with time.
TCAs are given either in divided doses or, for the
more sedative compounds, as a single evening dose.
SSRIs have advantages over tricyclics in simplicity
of introduction and use. Dose titration is often
unnecessary since the minimum therapeutic dose
can usually be tolerated as a starting dose. Divided
doses are not required and administration is by a
single morning or evening dose.
Patients commencing treatment on SSRIs are
more likely to reach an effective dose than those
starting on TCAs.
Venlafaxine is licensed for treatment-resistant
depression by gradual dose titration. There is
some need for dose titration when using MAOIs.
Side effects of TCAs
Anticholinergic (atropine-like): dry mouth, blurred vision,
accommodation disturbances, increased ocular pressure, constipation, urinary retention, sweating, adynamic ileus (very rare).
CNS: dizziness, tiredness, confusion, tremor, insomnia,
seizures, exacerbation of psychotic symptoms.
CVS: postural hypotension, sinus tachycardia, arrhythmia.
Blood: leucopenia, agranulocytosis, thrombocytopenia,
Haemolytic anaemia.
Other ADRs: impaired respiration, libido changes, tinnitus, GI
complaints, liver function disturbances, increased body weight.
TCAs – Interactions: Potential Results
MAOIs
hyperthermia, palpitations, excitation
Adrenomimetics
hypertension, hyperthermia, tachycardia
Alcohol
effect of alcohol may be increased
Clonidine,
Methyldopa
T3, T4
decreased hypotensive effects
Physostigmine
antagonism
Anticholinergics
additional anticholinergic activity
Neuroleptics
inhibition of metabolism of antidepressants
Levodopa
overreaction of levodopa
Lithium
the therapeutic response is increased in some
cases and suppressed in others
enhanced potential for CV toxicity
Precautions: close supervision, especially in early phase of
treatment (suicide risk of TCAs). The possibility of unmasking
a latent psychosis should be considered. A switch into a manic
or hypomanic condition may occur (“switch process”).
Caution should be exercised in CVD, history of urinary retention,
narrow-angle glaucoma, and thyroid disease.
Side-effects of SSRIs
(mainly during the 1st and 2nd weeks of treatment): CNS: headache, restleness; CVS: bradycaria; GIT: nausea, diarrhoea
The serotonin syndrome is a rare but dangerous complication
with features restlessness, tremor, hуperthermia, convulsions,
coma and death. Risk is increased by co-administration with
MAOIs, the antimigraine drug sumatriptan, and St. John’s Wort.
Side-effects of MAOIs (Moclobemide)
CNS: insomnia, restlessness, confusion, dizziness.
CVS: arrhythmia, tachycardia, palpitations,
high blood pressure.
The following foods and beverages should
be avoided – tyramine containing nutrition:
maturated cheese (“cheese syndrome” –
high blood pressure), broad beans, smoked or
pickled fish, meat extracts containing
brewer's yeast, fermented sausages (e.g. salami);
red wine, sherry, beer and excessive amounts of alcohol.
Trazodone acts by antagonism of central
presynaptic alpha-2-adrenoceptors.
It is an option for depressed patients where heavy
sedation is required. Trazodone also has the
advantages of lacking antimuscarinic effects and being
relatively safe in overdose. Males should be warned
of the possibility of priapism (painful penile erections),
due to the blockade of peripheral postsynaptic
alpha-1-adrenoceptors.
Mianserin has the advantages of lacking antimuscarinic
effects too, but can cuases aplastic anaemia.
Agomelatine (Valdoxan®) is
a melatonergic agonist
(MT1- and MT2-receptors) and 5-HT2C
antagonist. It has no effect on monoamine
reuptake and no affinity for α, β adrenergic,
histaminergic, cholinergic, dopaminergic
and benzodiazepine receptors.
Agomelatine is indicated for the treatment
of major depressive episodes in adults.
It not use in chlidren below 18 years of age
due to a lack of data on safety and efficacy.
Many patients with mild to moderate depression are
aware of the benefits of the herbal remedy St. John’s
Wort. The major active antidepressive constituents are
thought to be hyperforin and hypericin. Some believe
that hyperforin is the
major constituent responsible
for antidepressant activity.
It inhibits the reuptake
of 5-HT, DA, and NA.
Hyperforin also has affinity
for GABA and glutamate
receptors.
Hypericum perforatum L.
St. John’s Wort
Many patients with mild to moderate depression are
aware of the benefits of the herbal remedy St. John’s
Wort. The major active antidepressive constituents are
thought to be hyperfurin and hypericin . Some believe
That hyperfurin is the major constituent responsible for
antidepressant activity. It inhibits the reuptake of
5-HT, DA, and NA (NE).
Hyperfurin also has affinity for GABA and glutamate
receptors.
Use of St. John’s Wort is complicated by the
lack of standardization of the ingredients. Those
who wish to take St. John's Wort should be made
aware that it may cause dry mouth, dizziness,
sedation, GI disturbance and confusion.
It induces hepatic CYP 1A2 and CYP 3A4
with the result that the plasma concentration and
therapeutic efficacy of warfarin, oral contraceptives,
some anticonvulsants,antipsychotics and HIV
protease/reverse transcriptase inhibitors are
reduced. Concomitant use of tryptophan and
St. John’s Wort may cause serotoninergic
effects including nausea and agitation.
Electroconvulsive therapy (ECT) involves the
passage of a small electric charge across the brain by electrodes
applied to the frontotemporal aspects of the scalp with the aim of
inducing a tonic-clonic seizure. ECT requires the patient to be
receiving a general anaesthetic. It may cause memory deficit
although this is generally transient.
ECT is usually reserved for psychiatric illness where
pharmacotherapy has been unsuccessful for instance
the severely depressed patient who has stopped eating or
drinking. Modern-day ECT is a safe and effective alternative
to pharmacotherapy and remains a first-line option in clinical
circumstances where rapid, response is desired, when it can
be life-saving.
Mood stabilizers
In bipolar affective disorder patients suffer episodes
of mania, hypomania and depression, classically
with periods of normal mood in between. Manic
episodes involve greatly elevated mood, often
interspersed with periods of irritability or undue
excitement, accompanied by biological symptoms
(increased energy, restlessness, decreased need for
sleep, increased sex drive), loss of social inhibitions,
irresponsible behaviour and grandiosity. Psychotic
features may be present, particularly disordered
thinking, manifested by grandiose delusions and
“flight of ideas” with rapid speech.
Hypomania is a less dramatic and dangerous
presentation but retains the features of elation or
irritability and the biological symptoms, abnormalities
in speech and in social conduct to overfamiliarity
and mild recklessness.
Depressive episodes include depressive symptoms
described before and may include psychotic features.
Lithium salts are ineffective for prophylaxis of
bipolar affective disorder in around 35% of patients
and cause severe unwanted effects. The search
for alternatives has produced drugs that are more
famous as anticonvulsants (carbamazepine
and sodium valproate, and possibly lamotrigine).
The main effect of lithium is probably to inhibit
hydrolysis of inositol phosphate, so reducing the
recycling of free inositol for synthesis of
phosphatidylinositides. These intracellular molecules
are part of the transmembrane signaling system that
is important in regulating intracellullar calcium ion
concentration, which subsequently affects
neurotransmitter release. Other putative mechanisms
involve the cyclic AMP “second messenger” system
and monoaminergic and cholinergic neurotransmitters.
Action of lithium on the IP3 and DAG second-messenger system.
The schematic diagram shows the synaptic membrane of a neuron.
(PIP2 – phosphatidylinositol-4,5-bisphosphate; PLC – phospholipase-C;
G – G-coupling protein). Result: activation of protein kinase C, mobilization
of intracellular Ca2+, etc. Lithium, by inhibiting the recycling of inositol
substrates, may cause depletion of the second-messenger source PIP2
and therefore reduce the release of IP3 and DAG.
The therapeutic plasma concentration is close to
the toxic concentration (low therapeutic index). Lithium
is a small ion that, given orally, is rapidly absorbed
throughout the gut. High peak plasma concentrations
are avoided by using sustained-release formulations
which deliver the peak plasma lithium concentrations in 5 h.
With chronic use the plasma t1/2 of lithium is 15–30 h.
Lithium is usually given 12-hourly to avoid unnecessary
fluctuation (peak and trough concentrations) and to
maintain a plasma concentration just below the toxic
level. A steady-state plasma concentration will be
attained after about 5–6 days (i.e. 5 x t1/2).
Lithium carbonate is effective treatment in 75%
of episodes of acute mania or hypomania.
Because its therapeutic action takes 2–3 weeks
to develop, lithium is generally used in combination
with lorazepam or diazepam (or with a neuroleptics
where there are also psychotic features).
For prophylaxis, lithium is indicated when there
have been two episodes of mood disturbance in
two years.
Lithium is also used to augment the action of
antidepressants in treatment-resistant depression.
The difference between therapeutic and toxic doses
is narrow and therapy must be guided by monitoring
of the plasma concentration once a steady state
is reached. Increments are made at weekly intervals
until the concentration lies within the range of
0.4–1 mmol/L (maintenance at the lower level is
preferred for elderly patients). The plasma
concentration should be checked every 3 months.
Thyroid function and renal function (plasma
creatinine and electrolytes) should be measured
before initiation and every 3 months during therapy.
Side-effects of Lithium
CNS: ataxia, dysarthria, choreoathetoid disturbances,
extrapyrimidal symptoms, confusion, tremor, epileptic
seizures, spasms, stupor, sedation, lethargy.
CVS: arrhythmia, hypertension, circulatory collapse.
Other effects: weight increase, muscular hypotonia,
anorexia, nausea, vomiting, thirst, rash etc.
The manic phase in bipolar affective disorder
often requires treatment with neuroleptics
(chlorpromazine, haloperidol), though lithium or
valproic acid supplemented with high-potency
benzodiazepines (eg, lorazepam or clonazepam)
may suffice in milder cases.
Recent controlled trials support the efficacy of
monotherapy with atypical antipsychotics
(olanzapine) in the acute phase (up to 4 weeks)
of mania.
Psychostimulants
Psychostimulants have predominant cortical action. Their psychic
effects are more important than those on medullary vital centres.
(1) Methylxanthines
Three methylxanthines are pharmacologically
important: caffeine, theophylline, and theobromine.
All of them occur naturally in certain plants.
Only caffeine is used as a CNS stimulant. It is widely
consumed in the form of beverages, including as
infusions or decoctions, derived from these plants.
Methylxanthines (purine alkaloids)
Caffeine, Theophylline, Theobromine
Coffea
arabica (seeds)
In an average
cup of coffee:
Caffeine 75 mg
Theobroma
Cola acuminata
cacao (cocoa) (Guru nuts)
In an average
In 330 ml bottle
cup of cocoa:
of cola drink:
Caffeine 4 mg Caffeine 50 mg
Theobromine 200 mg
Thea sinensis
(leaves)
In an average
cup of tea:
Caffeine 50 mg
Theophylline 1 mg
Actions of methylxanthines
They block adenosine-1-receptors. Adenosine acts as a local
mediators in CNS, CVS and other systems. Adenosine contracts
bronchial muscles, dilates cerebral blood vessels, depresses
cardiac pacemaker and inhibits gastric secretions.
Methylxanthines inhibit phosphodiesterase which degrades
intracelullarly cAMP. Theophylline-containing preparations
enhance cAMP accumulation. It results in bronchodilation,
vasodilation and cardiac stimulation (including tachycardia).
Caffeine and theophylline are CNS stimulants, primarily affect the
higher centres. Caffeine (150 to 250 mg) produces a sense of
wellbeing, alertness, beats boredom, alleviates fatigue; thinking
becomes clear, improves performance and increases motor
activity.
As a CNS stimulant caffeine is more active than theophylline.
In higher doses caffeine causes nervousness, restlessness,
panic, insomnia, and excitement. Still higher doses produces
tremor, arrhythmia, delirium, and convulsions.
Methylxanthines, especially caffeine, also stimulate medullary
vagal, respiratory and vasomotor centres (analeptic effect).
Vomiting in higher doses is due to both to gastric irritation and
stimulation of chemoreceptor trigger zone (CTZ).
Methylxanthines directly stimulate the heart and increase force
of myocardial contraction. They tend to increase heart rate by
direct action, but also decrease it by vagal stimulation. Net effect
is variable. Tachycardia is more common with theophylline.
Cardiac output is increased.
This action is more marked in CHF patients. At high
doses cardiac arrhythmias may be produced.
Methylxanthines, especially theophylline, dilate systemic blood
vessels, including coronaries. Cranial vessels are constricted
by caffeine: this is one of the bases of its use in migraine.
Effect of blood pressure is variable and unpredictable. Usually
a rise in systolic and fall in diastolic BP is observed.
Antiasthmatic (bronchodilatation) effect of theophylline is
more potent then those of caffeine.
Caffeine > 300 mg/d:
5–6 coffee cups daily
(–)
ATP
AC
cAMP
3’, 5’-AMP
Hypercholesterolemia
(+)
Lipolysis
PD
(+)
Cholesterol synthesis
Methylxanthines are mild diuretics. They act by inhibiting tubular
reabsorption of Na+ and water. Theophylline and theobromine
are more potent diuretics than caffeine.
At high dose caffeine enhances the contractile power of skeletal
muscle: it increases release of Ca2+ from sarcoplasmatic
reticulum by direct action. In addition, caffeine facilitates
neuromuscular transmission by increasing ACh release. Its
central action relieves fatigue and increases muscular work.
Methylxanthines enhance secretion of acid and pepsin in the
stomach, even on parenteral application. They are gastric
irritants – theophylline more than caffeine.
Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed after
oral administration. It is < 50% bound to plasma proteins. Its
t1/2 is 4 h. Caffeine is nearly completely metabolized in the liver by
demethylation and oxidation, and excreted in urine. Caffeine is
to be avoided in peptic ulcer patients. It is not contraindicated
in gout because it is not converted in the body to uric acid.
Moderate coffee drinking does not contribute to
development of hypertension.
Uses of caffeine
• In analgesic drug combinations: caffeine benefits headache
probably by allaying fatigue and boredom.
• Migraine attacks: in combination with ergotamine.
• To counteract hypnotic overdose, but its value is doubtful,
better not to be used.
Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed after
oral administration. It is < 50% bound to plasma proteins. Its
t1/2 is 4 h. Caffeine is nearly completely metabolized in the liver by
demethylation and oxidation, and excreted in urine. Caffeine is
to be avoided in peptic ulcer patients. It is not contraindicated
in gout because it is not converted in the body to uric acid.
Moderate coffee drinking does not contribute to
development of hypertension.
Uses of caffeine
• In analgesic drug combinations: caffeine benefits headache
probably by allaying fatigue and boredom.
• Migraine attacks: in combination with ergotamine.
• To counteract hypnotic overdose, but its value is doubtful,
better not to be used.
(2) Amphetamines
Amphetamines are central indirect adrenomimetics. Higher
central and peripheral activity ratio is exhibited by dextroamphetamine and methylamphetamine (methamphetamine).
Amphetamines stimulate mental than motor activity.
Convulsive doses are much higher.
Abuse potential of the amphetamines is very high!
Methylphenidate is chemically and pharmacologically similar
to amphetamine. Both act by releasing NA and DA in the brain.
Both produce increase in mental activity at doses which have
little action on other central and peripheral functions.
Methylphenidate is considered superior to amphetamine for
treatment of hyperkinetic children (attention deficit disorder)
because it causes less tachycardia and growth retardation.
Behaviour and learning ability are improved in 75% of cases.
Methylphenenidate can also be used for concentration and
attention defect in adults, and for narcolepsy.
Side effects of methylphenidate are anorrhexia, insomnia,
abdominal discomfort, and bowel upset.
(3) Cocaine is an alkaloid from the leaves of Erythroxylon coca,
a South American plant. The natives of Peru and Bolivia habitually
chew these leaves. Cocaine is used sometimes in ocular
anaesthesia as eyes drops. It should be never be
injected because it can causes tissue necrosis.
After system absorption cocaine produces prominent CNS
stimulation with marked effect on mood and behaviour (a sense
of wellbeing, delays fatigue and increases power of endurance).
In susceptible individuals it produces strong psychological,
but not physical dependence. Cocaine is unique among drugs of
abuse, because it is does not produce tolerance on repeuted
use. It also stimulate vagal, vasomotor, vomiting and
thermoregulatory centres. In periphery it blocks reuptake of NA
and adrenaline and acts indirectly as a sympathomimetic.
Nootropic drugs
(cognition enhancers)
Piracetam is a cyclic GABA derivative without
GABA like activity. Piracetam selective
improves efficiency of higher encephalic
integrative activity by:
• Enhancement of learning and memory
• Facilitation of interhemisphere information transfer
• Increased tonic cortical control of subcortical areas
• Improves ATP/ADP ratio in encephalon
• Stimulates synaptic transmission, etc.
The indications of piracetam are:
• Senile dementia of Alzheimer type, multi-infarct dementia, etc.
• Mental retardation and learning problems in children
• Cerebrovascular accident: to hasten recovery
• To reduce impairment of consciousness following brain trauma
or brain surgery, memory impairment after electroconvulsive
therapy, and central vertigo.
The validity of evidence for drug induced cognition
enhancement has not been established.
ADRs: gastric discomfort, excitement, insomnia, dizziness,
skin rash.
Pramiracetam has similar properties and indications.
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