Psychopharmacologicals

Benzodiazepines
Benzodiazepines modify affective responses
to sensory perceptions; specifically,
they render a subject indifferent
towards anxiogenic stimuli, i.e., anxiolytic
action. Furthermore, benzodiazepines
exert sedating, anticonvulsant,
and muscle-relaxant (myotonolytic, p.
182) effects. All these actions result
from augmenting the activity of inhibitory
neurons and are mediated by specific
benzodiazepine receptors that
form an integral part of the GABAA receptor-
chloride channel complex. The
inhibitory transmitter GABA acts to
open the membrane chloride channels.
Increased chloride conductance of the
neuronal membrane effectively shortcircuits
responses to depolarizing inputs.
Benzodiazepine receptor agonists
increase the affinity of GABA to its receptor.
At a given concentration of
GABA, binding to the receptors will,
therefore, be increased, resulting in an
augmented response. Excitability of the
neurons is diminished.
Therapeutic indications for benzodiazepines
include anxiety states associated
with neurotic, phobic, and depressive
disorders, or myocardial infarction
(decrease in cardiac stimulation
due to anxiety); insomnia; preanesthetic
(preoperative) medication;
epileptic seizures; and hypertonia of
skeletal musculature (spasticity, rigidity).
Since GABA-ergic synapses are confined
to neural tissues, specific inhibition
of central nervous functions can be
achieved; for instance, there is little
change in blood pressure, heart rate,
and body temperature. The therapeutic
index of benzodiazepines, calculated
with reference to the toxic dose producing
respiratory depression, is greater
than 100 and thus exceeds that of barbiturates
and other sedative-hypnotics
by more than tenfold. Benzodiazepine
intoxication can be treated with a specific
antidote (see below).
Since benzodiazepines depress responsivity
to external stimuli, automotive
driving skills and other tasks requiring
precise sensorimotor coordination
will be impaired.
Triazolam (t1/2 of elimination
~1.5–5.5 h) is especially likely to impair
memory (anterograde amnesia) and to
cause rebound anxiety or insomnia and
daytime confusion. The severity of these
and other adverse reactions (e.g., rage,
violent hostility, hallucinations), and
their increased frequency in the elderly,
has led to curtailed or suspended use of
triazolam in some countries (UK).
Although benzodiazepines are well
tolerated, the possibility of personality
changes (nonchalance, paradoxical excitement)
and the risk of physical dependence
with chronic use must not be
overlooked. Conceivably, benzodiazepine
dependence results from a kind of
habituation, the functional counterparts
of which become manifest during abstinence
as restlessness and anxiety; even
seizures may occur. These symptoms
reinforce chronic ingestion of benzodiazepines.
Benzodiazepine antagonists, such
as flumazenil, possess affinity for benzodiazepine
receptors, but they lack intrinsic
activity. Flumazenil is an effective
antidote in the treatment of benzodiazepine
overdosage or can be used
postoperatively to arouse patients sedated
with a benzodiazepine.
Whereas benzodiazepines possessing
agonist activity indirectly augment
chloride permeability, inverse agonists
exert an opposite action. These substances
give rise to pronounced restlessness,
excitement, anxiety, and convulsive
seizures. There is, as yet, no
therapeutic indication for their use.


Pharmacokinetics of Benzodiazepines
All benzodiazepines exert their actions
at specific receptors (p. 226). The choice
between different agents is dictated by
their speed, intensity, and duration of
action. These, in turn, reflect physicochemical
and pharmacokinetic properties.
Individual benzodiazepines remain
in the body for very different lengths of
time and are chiefly eliminated through
biotransformation. Inactivation may entail
a single chemical reaction or several
steps (e.g., diazepam) before an inactive
metabolite suitable for renal elimination
is formed. Since the intermediary
products may, in part, be pharmacologically
active and, in part, be excreted
more slowly than the parent substance,
metabolites will accumulate with continued
regular dosing and contribute
significantly to the final effect.
Biotransformation begins either at
substituents on the diazepine ring (diazepam:
N-dealkylation at position 1;
midazolam: hydroxylation of the methyl
group on the imidazole ring) or at the
diazepine ring itself. Hydroxylated midazolam
is quickly eliminated following
glucuronidation (t1/2 ~ 2 h). N-demethyldiazepam
(nordazepam) is biologically
active and undergoes hydroxylation
at position 3 on the diazepine
ring. The hydroxylated product (oxazepam)
again is pharmacologically active.
By virtue of their long half-lives, diazepam
(t1/2 ~ 32 h) and, still more so, its
metabolite, nordazepam (t1/2 50–90 h),
are eliminated slowly and accumulate
during repeated intake. Oxazepam
undergoes conjugation to glucuronic acid
via its hydroxyl group (t1/2 = 8 h) and
renal excretion (A).
The range of elimination half-lives
for different benzodiazepines or their
active metabolites is represented by the
shaded areas (B). Substances with a
short half-life that are not converted to
active metabolites can be used for induction
or maintenance of sleep (light
blue area in B). Substances with a long
half-life are preferable for long-term
anxiolytic treatment (light green area)
because they permit maintenance of
steady plasma levels with single daily
dosing. Midazolam enjoys use by the i.v.
route in preanesthetic medication and
anesthetic combination regimens.
Benzodiazepine Dependence
Prolonged regular use of benzodiazepines
can lead to physical dependence.
With the long-acting substances marketed
initially, this problem was less obvious
in comparison with other dependence-
producing drugs because of the
delayed appearance of withdrawal
symptoms. The severity of the abstinence
syndrome is inversely related to
the elimination t1/2, ranging from mild
to moderate (restlessness, irritability,
sensitivity to sound and light, insomnia,
and tremulousness) to dramatic (depression,
panic, delirium, grand mal seizures).
Some of these symptoms pose
diagnostic difficulties, being indistinguishable
from the ones originally treated.
Administration of a benzodiazepine
antagonist would abruptly provoke abstinence
signs. There are indications
that substances with intermediate elimination
half-lives are most frequently
abused (violet area in B).

Therapy of Manic-Depressive Illness
Manic-depressive illness connotes a
psychotic disorder of affect that occurs
episodically without external cause. In
endogenous depression (melancholia),
mood is persistently low. Mania refers
to the opposite condition (p. 234). Patients
may oscillate between these two
extremes with interludes of normal
mood. Depending on the type of disorder,
mood swings may alternate
between the two directions (bipolar depression,
cyclothymia) or occur in only
one direction (unipolar depression).
I. Endogenous Depression
In this condition, the patient experiences
profound misery (beyond the
observer’s empathy) and feelings of severe
guilt because of imaginary misconduct.
The drive to act or move is inhibited.
In addition, there are disturbances
mostly of a somatic nature (insomnia,
loss of appetite, constipation, palpitations,
loss of libido, impotence, etc.). Although
the patient may have suicidal
thoughts, psychomotor retardation prevents
suicidal impulses from being carried
out. In A, endogenous depression is
illustrated by the layers of somber colors;
psychomotor drive, symbolized by
a sine oscillation, is strongly reduced.
Therapeutic agents fall into two
groups:
! Thymoleptics, possessing a pronounced
ability to re-elevate depressed
mood e.g., the tricyclic antidepressants;
! Thymeretics, having a predominant
activating effect on psychomotor
drive, e g., monoamine oxidase inhibitors.
It would be wrong to administer
drive-enhancing drugs, such as amphetamines,
to a patient with endogenous
depression. Because this therapy fails to
elevate mood but removes psychomotor
inhibition (A), the danger of suicide
increases.
Tricyclic antidepressants (TCA;
prototype: imipramine) have had the
longest and most extensive therapeutic
use; however, in the past decade, they
have been increasingly superseded by
the serotonin-selective reuptake inhibitors
(SSRI; prototype: fluoxetine).
The central seven-membered ring
of the TCAs imposes a 120° angle
between the two flanking aromatic
rings, in contradistinction to the flat
ring system present in phenothiazine
type neuroleptics (p. 237). The side
chain nitrogen is predominantly protonated
at physiological pH.
The TCAs have affinity for both receptors
and transporters of monoamine
transmitters and behave as antagonists
in both respects. Thus, the neuronal reuptake
of norepinephrine (p. 82) and serotonin
(p. 116) is inhibited, with a resultant
increase in activity. Muscarinic
acetylcholine receptors, !-adrenoceptors,
and certain 5-HT and histamine(
H1) receptors are blocked. Interference
with the dopamine system is
relatively minor.
How interference with these transmitter/
modulator substances translates
into an antidepressant effect is still hypothetical.
The clinical effect emerges
only after prolonged intake, i.e., 2–3 wk,
as evidenced by an elevation of mood
and drive. However, the alteration in
monoamine metabolism occurs as soon
as therapy is started. Conceivably, adaptive
processes (such as downregulation
of cortical serotonin and "-adrenoceptors)
are ultimately responsible. In
healthy subjects, the TCAs do not improve
mood (no euphoria).
Apart from the antidepressant effect,
acute effects occur that are evident
also in healthy individuals. These vary
in degree among individual substances
and thus provide a rationale for differentiated
clinical use (p. 233), based
upon the divergent patterns of interference
with amine transmitters/modulators.
Amitriptyline exerts anxiolytic,
sedative and psychomotor dampening
effects. These are useful in depressive
patients who are anxious and agitated.
In contrast, desipramine produces
psychomotor activation. Imipramine



occupies an intermediate position. It
should be noted that, in the organism,
biotransformation of imipramine leads
to desipramine (N-desmethylimipramine).
Likewise, the desmethyl derivative
of amitriptyline (nortriptyline) is
less dampening.
In nondepressive patients whose
complaints are of predominantly psychogenic
origin, the anxiolytic-sedative
effect may be useful in efforts to bring
about a temporary “psychosomatic uncoupling.”
In this connection, clinical
use as “co-analgesics” (p. 194) may be
noted.
The side effects of tricyclic antidepressants
are largely attributable to the
ability of these compounds to bind to
and block receptors for endogenous
transmitter substances. These effects
develop acutely. Antagonism at muscarinic
cholinoceptors leads to atropinelike
effects such as tachycardia, inhibition
of exocrine glands, constipation,
impaired micturition, and blurred vision.
Changes in adrenergic function are
complex. Inhibition of neuronal catecholamine
reuptake gives rise to superimposed
indirect sympathomimetic
stimulation. Patients are supersensitive
to catecholamines (e.g., epinephrine in
local anesthetic injections must be
avoided). On the other hand, blockade
of !1-receptors may lead to orthostatic
hypotension.
Due to their cationic amphiphilic
nature, the TCA exert membrane-stabilizing
effects that can lead to disturbances
of cardiac impulse conduction
with arrhythmias as well as decreases in
myocardial contractility. All TCA lower
the seizure threshold. Weight gain may
result from a stimulant effect on appetite.
Maprotiline, a tetracyclic compound,
largely resembles tricyclic
agents in terms of its pharmacological
and clinical actions. Mianserine also
possesses a tetracyclic structure, but
differs insofar as it increases intrasynaptic
concentrations of norepinephrine
by blocking presynaptic !2-receptors,
rather than reuptake. Moreover, it has
less pronounced atropine-like activity.
Fluoxetine, along with sertraline,
fluvoxamine, and paroxetine, belongs to
the more recently developed group of
SSRI. The clinical efficacy of SSRI is considered
comparable to that of established
antidepressants. Added advantages
include: absence of cardiotoxicity,
fewer autonomic nervous side effects,
and relative safety with overdosage.
Fluoxetine causes loss of appetite and
weight reduction. Its main adverse effects
include: overarousal, insomnia,
tremor, akathisia, anxiety, and disturbances
of sexual function.
Moclobemide is a new representative
of the group of MAO inhibitors. Inhibition
of intraneuronal degradation of
serotonin and norepinephrine causes an
increase in extracellular amine levels. A
psychomotor stimulant thymeretic action
is the predominant feature of MAO
inhibitors. An older member of this
group, tranylcypromine, causes irreversible
inhibition of the two isozymes
MAOA and MAOB. Therefore, presystemic
elimination in the liver of biogenic
amines, such as tyramine, which are ingested
in food (e.g., aged cheese and
Chianti), will be impaired. To avoid the
danger of a hypertensive crisis, therapy
with tranylcypromine or other nonselective
MAO inhibitors calls for stringent
dietary rules. With moclobemide,
this hazard is much reduced because it
inactivates only MAOA and does so in a
reversible manner.


II. Mania
The manic phase is characterized by exaggerated
elation, flight of ideas, and a
pathologically increased psychomotor
drive. This is symbolically illustrated in
A by a disjointed structure and aggressive
color tones. The patients are overconfident,
continuously active, show
progressive incoherence of thought and
loosening of associations, and act irresponsibly
(financially, sexually etc.).
Lithium ions. Lithium salts (e.g.,
acetate, carbonate) are effective in controlling
the manic phase. The effect becomes
evident approx. 10 d after the
start of therapy. The small therapeutic
index necessitates frequent monitoring
of Li+ serum levels. Therapeutic levels
should be kept between 0.8–1.0 mM in
fasting morning blood samples. At higher
values there is a risk of adverse effects.
CNS symptoms include fine tremor,
ataxia or seizures. Inhibition of the renal
actions of vasopressin (p. 164) leads to
polyuria and thirst. Thyroid function is
impaired (p. 244), with compensatory
development of (euthyroid) goiter.
The mechanism of action of Li ions
remains to be fully elucidated. Chemically,
lithium is the lightest of the alkali
metals, which include such biologically
important elements as sodium and potassium.
Apart from interference with
transmembrane cation fluxes (via ion
channels and pumps), a lithium effect of
major significance appears to be membrane
depletion of phosphatidylinositol
bisphosphates, the principal lipid substrate
used by various receptors in
transmembrane signalling (p. 66).
Blockade of this important signal transduction
pathway leads to impaired ability
of neurons to respond to activation
of membrane receptors for transmitters
or other chemical signals. Another site
of action of lithium may be GTP-binding
proteins responsible for signal transduction
initiated by formation of the agonist-
receptor complex.
Rapid control of an acute attack of
mania may require the use of a neuroleptic
(see below).
Alternate treatments. Mood-stabilization
and control of manic or hypomanic
episodes in some subtypes of
bipolar illness may also be achieved
with the anticonvulsants valproate and
carbamazepine, as well as with calcium
channel blockers (e.g., verapamil, nifedipine,
nimodipine). Effects are delayed
and apparently unrelated to the mechanisms
responsible for anticonvulsant
and cardiovascular actions, respectively.
III. Prophylaxis
With continued treatment for 6 to 12
months, lithium salts prevent the recurrence
of either manic or depressive
states, effectively stabilizing mood at a
normal level.

Therapy of Schizophrenia
Schizophrenia is an endogenous psychosis
of episodic character. Its chief
symptoms reflect a thought disorder
(i.e., distracted, incoherent, illogical
thinking; impoverished intellectual
content; blockage of ideation; abrupt
breaking of a train of thought: claims of
being subject to outside agencies that
control the patient’s thoughts), and a
disturbance of affect (mood inappropriate
to the situation) and of psychomotor
drive. In addition, patients exhibit delusional
paranoia (persecution mania) or
hallucinations (fearfulness hearing of
voices). Contrasting these “positive”
symptoms, the so-called “negative”
symptoms, viz., poverty of thought, social
withdrawal, and anhedonia, assume
added importance in determining the
severity of the disease. The disruption
and incoherence of ideation is symbolically
represented at the top left (A) and
the normal psychic state is illustrated as
on p. 237 (bottom left).
Neuroleptics
After administration of a neuroleptic,
there is at first only psychomotor dampening.
Tormenting paranoid ideas and
hallucinations lose their subjective importance
(A, dimming of flashy colors);
however, the psychotic processes still
persist. In the course of weeks, psychic
processes gradually normalize (A); the
psychotic episode wanes, although
complete normalization often cannot be
achieved because of the persistence of
negative symptoms. Nonetheless, these
changes are significant because the patient
experiences relief from the torment
of psychotic personality changes;
care of the patient is made easier and
return to a familiar community environment
is accelerated.
The conventional (or classical) neuroleptics
comprise two classes of compounds
with distinctive chemical structures:
1. the phenothiazines derived
from the antihistamine promethazine
(prototype: chlorpromazine), including
their analogues (e.g., thioxanthenes);
and 2. the butyrophenones (prototype:
haloperidol). According to the chemical
structure of the side chain, phenothiazines
and thioxanthenes can be subdivided
into aliphatic (chlorpromazine,
triflupromazine, p. 239 and piperazine
congeners (trifluperazine, fluphenazine,
flupentixol, p. 239).
The antipsychotic effect is probably
due to an antagonistic action at dopamine
receptors. Aside from their main
antipsychotic action, neuroleptics display
additional actions owing to their
antagonism at
– muscarinic acetylcholine receptors !
atropine-like effects;
– !-adrenoceptors for norepinephrine
! disturbances of blood pressure
regulation;
– dopamine receptors in the nigrostriatal
system ! extrapyramidal motor
disturbances; in the area postrema !
antiemetic action (p. 330), and in the
pituitary gland !increased secretion
of prolactin (p. 242);
– histamine receptors in the cerebral
cortex ! possible cause of sedation.
These ancillary effects are also elicited
in healthy subjects and vary in intensity
among individual substances.
Other indications. Acutely, there is
sedation with anxiolysis after neuroleptization
has been started. This effect can
be utilized for: “psychosomatic uncoupling”
in disorders with a prominent
psychogenic component; neuroleptanalgesia
(p. 216) by means of the butyrophenone
droperidol in combination
with an opioid; tranquilization of overexcited,
agitated patients; treatment of
delirium tremens with haloperidol; as
well as the control of mania (see p. 234).
It should be pointed out that neuroleptics
do not exert an anticonvulsant
action, on the contrary, they may lower
seizure thershold.


Because they inhibit the thermoregulatory
center, neuroleptics can be employed
for controlled hypothermia
(p. 202).
Adverse Effects. Clinically most
important and therapy-limiting are extrapyramidal
disturbances; these result
from dopamine receptor blockade.
Acute dystonias occur immediately after
neuroleptization and are manifested
by motor impairments, particularly in
the head, neck, and shoulder region. After
several days to months, a parkinsonian
syndrome (pseudoparkinsonism)
or akathisia (motor restlessness) may
develop. All these disturbances can be
treated by administration of antiparkinson
drugs of the anticholinergic type,
such as biperiden (i.e., in acute dystonia).
As a rule, these disturbances disappear
after withdrawal of neuroleptic
medication. Tardive dyskinesia may become
evident after chronic neuroleptization
for several years, particularly
when the drug is discontinued. It is due
to hypersensitivity of the dopamine receptor
system and can be exacerbated
by administration of anticholinergics.
Chronic use of neuroleptics can, on
occasion, give rise to hepatic damage associated
with cholestasis. A very rare,
but dramatic, adverse effect is the malignant
neuroleptic syndrome (skeletal
muscle rigidity, hyperthermia, stupor)
that can end fatally in the absence of intensive
countermeasures (including
treatment with dantrolene, p. 182).
Neuroleptic activity profiles. The
marked differences in action spectra of
the phenothiazines, their derivatives
and analogues, which may partially resemble
those of butyrophenones, are
important in determining therapeutic
uses of neuroleptics. Relevant parameters
include: antipsychotic efficacy
(symbolized by the arrow); the extent
of sedation; and the ability to induce extrapyramidal
adverse effects. The latter
depends on relative differences in antagonism
towards dopamine and acetylcholine,
respectively (p. 188). Thus,
the butyrophenones carry an increased
risk of adverse motor reactions because
they lack anticholinergic activity and,
hence, are prone to upset the balance
between striatal cholinergic and dopaminergic
activity.
Derivatives bearing a piperazine
moiety (e.g., trifluperazine, fluphenazine)
have greater antipsychotic potency
than do drugs containing an aliphatic
side chain (e.g., chlorpromazine, triflupromazine).
However, their antipsychotic
effects are qualitatively indistinguishable.
As structural analogues of the
phenothiazines, thioxanthenes (e.g.,
chlorprothixene, flupentixol) possess a
central nucleus in which the N atom is
replaced by a carbon linked via a double
bond to the side chain. Unlike the phenothiazines,
they display an added thymoleptic
activity.
Clozapine is the prototype of the
so-called atypical neuroleptics, a group
that combines a relative lack of extrapyramidal
adverse effects with superior
efficacy in alleviating negative symptoms.
Newer members of this class include
risperidone, olanzapine, and sertindole.
Two distinguishing features of
these atypical agents are a higher affinity
for 5-HT2 (or 5-HT6) receptors than
for dopamine D2 receptors and relative
selectivity for mesolimbic, as opposed
to nigrostriatal, dopamine neurons.
Clozapine also exhibits high affinity for
dopamine receptors of the D4 subtype,
in addition to H1 histamine and muscarinic
acetylcholine receptors. Clozapine
may cause dose–dependent seizures
and agranulocytosis, necessitating close
hematological monitoring. It is strongly
sedating.
When esterified with a fatty acid,
both fluphenazine and haloperidol can
be applied intramuscularly as depot
preparations.


Psychotomimetics
(Psychedelics, Hallucinogens)
Psychotomimetics are able to elicit psychic
changes like those manifested in
the course of a psychosis, such as illusionary
distortion of perception and
hallucinations. This experience may be
of dreamlike character; its emotional or
intellectual transposition appears inadequate
to the outsider.
A psychotomimetic effect is pictorially
recorded in the series of portraits
drawn by an artist under the influence
of lysergic acid diethylamide (LSD). As
the intoxicated state waxes and wanes
like waves, he reports seeing the face of
the portrayed subject turn into a grimace,
phosphoresce bluish-purple, and
fluctuate in size as if viewed through a
moving zoom lens, creating the illusion
of abstruse changes in proportion and
grotesque motion sequences. The diabolic
caricature is perceived as threatening.
Illusions also affect the senses of
hearing and smell; sounds (tones) are
“experienced” as floating beams and
visual impressions as odors (“synesthesia”).
Intoxicated individuals see themselves
temporarily from the outside and
pass judgement on themselves and
their condition. The boundary between
self and the environment becomes
blurred. An elating sense of being one
with the other and the cosmos sets in.
The sense of time is suspended; there is
neither present nor past. Objects are
seen that do not exist, and experiences
felt that transcend explanation, hence
the term “psychedelic” (Greek delosis =
revelation) implying expansion of consciousness.
The contents of such illusions and
hallucinations can occasionally become
extremely threatening (“bad” or “bum
trip”); the individual may feel provoked
to turn violent or to commit suicide. Intoxication
is followed by a phase of intense
fatigue, feelings of shame, and humiliating
emptiness.
The mechanism of the psychotogenic
effect remains unclear. Some hallucinogens
such as LSD, psilocin, psilocybin
(from fungi), bufotenin (the cutaneous
gland secretion of a toad), mescaline
(from the Mexican cactuses Lophophora
williamsii and L. diffusa; peyote) bear a
structural resemblance to 5-HT (p. 116),
and chemically synthesized amphetamine-
derived hallucinogens (4-methyl-
2,5-dimethoxyamphetamine; 3,4-dimethoxyamphetamine;
2,5-dimethoxy-
4-ethyl amphetamine) are thought to
interact with the agonist recognition
site of the 5-HT2A receptor. Conversely,
most of the psychotomimetic effects are
annulled by neuroleptics having 5-HT2A
antagonist activity (e.g. clozapine, risperidone).
The structures of other
agents such as tetrahydrocannabinol
(from the hemp plant, Cannabis sativa—
hashish, marihuana), muscimol (from
the fly agaric, Amanita muscaria), or
phencyclidine (formerly used as an injectable
general anesthetic) do not reveal
a similar connection. Hallucinations
may also occur as adverse effects
after intake of other substances, e.g.,
scopolamine and other centrally active
parasympatholytics.
The popular psychostimulant, methylenedioxy-
methamphetamine (MDMA,
“ecstasy”) acutely increases neuronal
dopamine and norepinephrine release
and causes a delayed and selective
degeneration of forebrain 5-HT nerve
terminals.
Although development of psychological
dependence and permanent psychic
damage cannot be considered established
sequelae of chronic use of psychotomimetics,
the manufacture and
commercial distribution of these drugs
are prohibited (Schedule I, Controlled
Drugs).