Drugs used in mood disorders

Mood disorder characterized by periods of low mood (depression) and periods of elevated mood(Bipolar affective disorder).

Treatment of bipolar disorder
The main aim of treating bipolar affective disorder to treat the acute episode  (mania/ bipolar depression) and prevent future relapses (depression/mania). The class of drug here we use is mood stabilizers.

Mood stabilizers
A drug that is used treat an acute episode of bipolar affective disorder and it will prevent recurrence. 
That is, a medication that keeps the mood ‘stable'.

Categories of mood stabilizers
1. Lithium
2. Anticonvulsants as mood stabilizers

• Sodium valproate
• Carbamazepine
• Lamotrigine

3. Other

Lithium

Lithium is used for more than 50 years. It has 4 main actions:

• To treat an acute manic episode.
• (with or without combination of antipsychotics).
• To prevent relapses of bipolar affective disorder (Manic/ depressive relapses).
• Can be added to an antidepressant (to augment antidepressant action) in resistant depression.

Lithium is a small ion. Mode of action of Lithium is uncertain but it may influence second messenger systems (e.g. phosphatidyl inositol system), modulate G proteins and it may affect gene expression of growth factors- and neuronal plasticity. Lithium is effective treatment for acute manic episodes, and to prevent relapse. But it is less effective to treat bipolar depression. It may also be used to control aggressive behaviour (e.g. in patients with learning disability).

Pharmacokinetics
Lithium is rapidly absorbed from gut and it is not metabolized in body. It is excreted unchanged via kidneys.  Lithium is filtered and partly reabsorbed from proximal tubule in kidney. When proximal convoluted tubule(PCT) reabsorbs more water, Li absorption also increases. Therefore DEHYDRATION causes increased Li reabsorption from PCT (and retention in the body). In PCT, Lithium is reabsorbed in competition with sodium.  Therefore if Sodium less- Li absorption more. Lithium has a narrow therapeutic index. The therapeutic and toxic plasma concentrations are close together. Therapeutic serum lithium range: 0.5 to 1.0 mmol/l  (12 hour post-dose sample), (towards higher end for acute episode treatment, and lower end for prophylaxis). Symptoms of Lithium toxicity may be seen with levels >1.2mmol/l. Serious toxic effects appear with levels >2 mmol/l.

Side effects of Lithium
Soon after starting treatment, it may cause mild diuresis (due to increased Sodium excretion), dry mouth, metallic taste in mouth and mild tremor of hands. Also Lithium blocks the effect of ADH on kidney and may cause mild polyuria but it is usually not clinically significant, except in a few patients who may develop a diabetes insipidus-like syndrome. Also Lithium cause weight gain and less commonly hair loss and coarsening of hair.

Medium term side effects
In up to 5%-  thyroid gland enlargement may occur with Lithium and the gland shrinks again after Li is stopped. About 20% may develop hypothyroidism (risk more in women). Therefore check thyroid functions every 6 months if patient is on Li. If hypothyroidism develops the patient can be given thyroxine to Lithium. Hyperparathyroidism is a rare side effect with Lithium. There are reversible effects on ECG can occur which are similar to changes of hypokalaemia such as flattening of t waves, broadening of QRS.

Long term side effects
Irreversible decline in glomerular tubular function is a very rare long term effect with Lithium. Usually any decline in glomerular function is rare, and associated with Li toxicity. However because of the risk of this side effect, if patient is on Li it is wise to monitor plasma creatinine levels regularly.

Lithium toxicity
Risk of Lithium toxicity increased by dehydration (e.g. nausea/ vomiting/ reduced fluid intake), sodium depletion and with certain drugs such as thiazide diuretics, NSAIDs.

Features of Lithium toxicity:
With mild Lithium toxicity the patient can develop nausea, vomiting and coarse tremor. With higher Lithium levels they may develop, confusion, slurred speech, nystagmus, ataxia, poor coordination and this could be life threatening.

Treatment:  Stop Lithium
Mild toxicity:  Rapid infusion of Normal saline
Severe toxicity:  may need haemodialysis

Monitoring with Lithium Treatment
Since Lithium has a narrow therapeutic index, and is toxic at high levels it is necessary to monitor serum lithium levels regularly. Also check serum Lithium weekly for first 2-3 weeks (until lithium level is stabilized). Thereafter monitor lithium levels ever 3-6 months. It is mandatory to check 12 hour post-dose, because of risk of side effects and also need to monitor the renal functions and thyroid functions every 6 months.

Sodium valproate

Sodium valproate is used both as an anticonvulsant and mood stabilizer. Sodium valproate is using for acute treatment of a manic episode and for longer term prophylaxis to prevent relapse.In comparison to valproate, Lithium has been used for a longer period, and has more evidence base to show that it is effective. But Sodium valproate may be better than Lithium in Bipolar patients who have more depressive episodes and rapid cycling more than 4 relapses per year.

Mode of action
Its exact mechanism uncertain, but it may act by inhibiting voltage gated sodium channels and by increasing action of GABA (inhibitory NT) in the CNS.

Pharmacokinetics
It is rapidly absorbed by gut and metabolized in the liver(toxic levels not an issue, unlike lithium).
Dosage of Sodium valproate starting from 400-600mg daily up to 1-2 g/daily. It can be given twice/thrice daily and there is a slow release preparation that can be given once daily.

Side effects
The common side effects of Sodium valproate includes nausea, sedation, tiredness, tremor, weight gain, transient hair loss and elevation of liver enzymes. This is usually mild and not associated with hepatic dysfunction.  Treatment maybe continued while carefully monitoring liver functions.

Less common side effects:
The less common side effects includes thrombocytopenia, acute pancreatitis, amenorrhea and edema.

Carbamazepine

Therapeutic uses of Carbamazepine includes as an anticonvulsant, as a mood stabilizer to treat acute mania and as prophylaxis, to prevent relapses of Bipolar affective disorder. Compared to Li and Valproate, it is less commonly used as a mood stabilizer. Its mode of action is to blocks neuronal sodium channels.

Pharmacokinetics
Carbamazepine is a potent liver enzyme inducer, and can lower plasma concentrations of many other drugs. Carbamazepine can be given twice daily, oral and monitoring of carbamazepine serum levels is NOT routinely done.

Side effects
Side effects are common at start of treatment. Patient can develop, sedation, unsteadiness, ataxia, dizziness, leucopenia(in first few weeks of treatment), agranulocytosis(very rare, but could be life threatening, skin rashes(Rarely SJ syndrome), changes in liver enzymes(rarely- liver toxicity) and changes in cardiac conduction.

Lamotrigine

Lamotrigine is also use to treat epilepsy and used as a mood stabilizer too. It is used to prevent the relapse of bipolar disorder plus to treat an acute episode of bipolar depression. Its mode of actions are to reduces levels of glutamate neurotransmitter and also block voltage gated sodium channels.

Side effects
Usually the Lamotrigine is well tolerated. It causes skin rashes especially in first few weeks of treatment. In about 3% of patients will develop macular papular rash with fever. Lamotrigine rarely causes Steven Johnson Syndrome, mild nausea, headache, dizziness and tremor.

Use of mood stabilizers in pregnancy and in breast feeding women
This is always problematic as during Pregnancy:

• Sodium valproate:  neural tube defects (1st trimester).
• Lithium:  Cardiac defects (1st trimester), Neonatal goitre (3rd trimester).

Breast feeding:
Lithium contra indicated (breastmilk- toxic levels in neonate).

Acute and chronic effects of alcohol abuse to central nervous system and behaviour

Alcohol, specifically ethanol, is a potent central nervous system depressant, with a range of side effects. The amount and circumstances of consumption play a large part in determining the extent of intoxication. Different concentrations of alcohol in the human body have different effects on the subject.


Euphoria (BAC = 0.03 to 0.12%)
Subject may experience an overall improvement in mood and possible euphoria. They may become more self-confident or daring; they may become more friendly or talkative, and/or social. Their attention span shortens. They may look flushed. Their judgment is not as good—they may express the first thought that comes to mind, rather than an appropriate comment for the given situation. They have trouble with fine movements, such as writing or signing their name.

Lethargy (BAC = 0.09 to 0.25%)
Subject may become sleepy. They have trouble understanding or remembering things, even recent events. They do not react to situations as quickly. Their body movements are uncoordinated; they begin to loose their balance easily, stumbling; walking is not stable. Their vision becomes blurry. They may have trouble sensing things (hearing, tasting, feeling, etc.).

Confusion (BAC = 0.18 to 0.30%)
Profound confusion—uncertain where they are or what they are doing. Dizziness and staggering occur. Heightened emotional state—aggressive, withdrawn, or overly affectionate. Vision, speech, and awareness are impaired. Poor coordination and pain response. Nausea and vomiting sometimes occurs.

Stupor (BAC = 0.25 to 0.40%)
Movement severely impaired; lapses in and out of consciousness. Subjects can slip into a coma; will become completely unaware of surroundings, time passage, and actions. Risk of death is very high due to alcohol poisoning and/or pulmonary aspiration of vomit while unconscious. Loss of bodily functions can begin, including bladder control, breathing, heart rate.

Coma (BAC = 0.35 to 0.50%)
Unconsciousness sets in.., pupils do not respond. Reflexes are depressed (i.epropriately to changes in light). Breathing is slower and more shallow. Heart rate drops. Death usually occurs at levels in this range.

The long term effects of alcohol in excessive quantities is capable of damaging nearly every organ and system in the body.


Nervous system

• Peripheral neuropathy
• Seizures
• Cerebellar degeneration
• Cognition and dementia
• Essential tremor
• Wernicke's EncephalopathyKorsakov's Psychosis
• Marchiafava Bignami Disease
• Central Pontine Myelinolysis (CPM) Midline Cerebellar Degeneration
• Subacute combined degeneration of the spinal cord
• Strokes

Seizures

• "Rum Fits": seizures in the alcoholic.
• Usually occur 48-72 hours after cessation of drinking.
• Usually uncomplicated, generalized seizure that requires no treatment.

Cognition and dementia

• Alcohol misuse can cause structural brain atrophy.
• Chronic excessive alcohol intake is also associated with serious cognitive decline.
• Acetaldehyde is produced by the liver during breakdown of ethanol. People who have a genetic deficiency for the subsequent conversion of acetaldehyde into acetic acid may have a greater risk of Alzheimer's disease.

Marchiafava Bignami Disease

• Degeneration with loss of myelin in the central aspect of the corpus callosum.
• Presumably nutritional, although exact etiology unknown.
• Clinical syndrome of personality change, seizures and dementia.

Central Pontine Myelinolysis (CPM)

• Approximately 75% of cases seen in alcoholics who are hospitalized for other reasons.
• CPM is associated with a clinical syndrome of declining mental status, quadriparesis and cranial nerve abnormalities.
• Recovery is rare.
• Excessively rapid correction of hyponatremia is thought to lead to an osmotic instability in the pons with marked edema and secondary demyelination. Macrophages containing digested myelin are a prominent pathologic feature.

Alcohol related Psychiatric disorders 

• Intoxication Phenomena
• Withdrawal phenomena
• Toxic or nutritional disorders
• Other

Intoxication Phenomena
Alcohol interact with neuronal membranes to increase their fluidity and give rise to release of range of neurotransmitters which will leads to various pharmacological effects.
e.g.
Pleasurable effects – mediated by release of dopamine & opioids in mesolimbic forebrain.
Anxiolytic effects – brain GABA activity.

Idiosyncratic alcohol intoxication
Marked maladaptive changes in behaviour occurring within minutes of taking an amount of alcohol insufficient to induce intoxication.

Short term amnesia
Usually occur after heavy drinking. The events of the night before are forgotten even though consciousness was maintained at the time. 

Withdrawal phenomena
Delirium tremens - Following alcohol withdrawal there is a dramatic & rapid changing picture of disordered mental activity.

• Clouding of consciousness
• Disorientation
• Memory loss
• Hallucinations
• Agitation
• Restlessness
• Insomnia
• Ataxia
• Autonomic disturbance

Toxic or nutritional disorders

• Korsakov’s psychosis
• Wernicke’s encephalopathy
• Alcoholic dementia

Korsakov’s psychosis

• Korsakov's is a separate entity caused by neuronal loss and degeneration in the dorsomedial nucleus of the thalamus.
• This is most likely a nutritional disorder secondary to chronic alcohol abuse.
• The clinical syndrome is confabulatory amnesia.

Wernicke’s encephalopathy

• Thiamine deficiency.
• Clinical triad of ataxia, ophthalmoplegia, and mental confusion of acute onset.
• Treatment with thiamine may completely reverse the clinical syndrome if given early in the course.
• Pathology involves mammillary bodies (confusion), periaqueductal gray area (ophthalmoplegia), and floor of the 4th ventricle (ataxia), and includes petechial haemorrhages, capillary vascular proliferation, and astrocytosis.

Alcoholic dementia

• Alcohol misuse can cause structural brain atrophy.
• Chronic excessive alcohol intake is also associated with serious cognitive decline and a range of neuropsychiatric complications.
• The elderly are the most sensitive to the toxic effects of alcohol on the brain.

Other associated psychiatric disorders

• Personality deterioration
• Mood disorder
• Depression
• Suicidal behavior
• Impaired psychosexual function
• Pathological jealousy
• Alcoholic hallucinations

Personality deterioration
As the patient addicted to alcohol interpersonal skills, interests & responsibilities may deteriorate.

Mood disorder
After the period of euphoria the patient goes into a low mood.

Depression
Induced by prolonged alcohol use.

Suicidal behaviour

Impaired psychosexual function
Erectile dysfunction or delayed ejaculation.
Impaired relationship with sexual partner.

Pathological jealousy
Non delusional suspiciousness.

Alcoholic hallucinations
Auditory hallucinations & delusional misinterpretation.

Social damage due to alcohol

• Family violence.
• Emotional & conduct problems in the patient’s children.
• Poor work performance.
• Unemployment.
• Road traffic accidents.

Effect of alcohol on motor driving

• Inability to deal with crisis.
• Prolonged reaction time & lack of color discrimination.
• Over confident or excessive caution.
• Increased distractibility.
• Bad judgement.

Sedatives and Hypnotics

• Sedatives and hypnotics- drugs used to induce sleep.

• Anxiolytics- drugs used to reduce anxiety.

• The action of hypnotics and anxiolytics often overlap.

Broad types.

• Benzodiazepines

• Non benzodiazpine ligands

• Barbiturates

• Other

Benzodiazepines

• Commonly used as both an anxiolytic and/or hypnotic.
• Benzodiazepines with a short t ½ (usually high potency) are preferred to for anxiety.
• Benzodiazepines with a longer t ½ are used as hypnotics.

Examples of benzodiazepines:
Diazepam                       
Chlordiazepoxide                   
Lorazepam                       
Temazepam                       
Alprazolam
Triazolam

Pharmocokinetics:

• Absorption:  rapidly absorbed.
• Strongly bound to plasma proteins.
• Lipophilic; cross blood brain barrier easily.
• Metabolism:  Liver.  Many metabolites formed.  BDZ with long half lives are broken down into ACTIVE metabolites, which continue to act therapeutically.  
• Excretion:  Conjugates in urine.

Benzodiapines- mode of action?
Acts as a positive allosteric modulator at the GABA-A receptor complex.

Actions of benzodiazepines

• Sedative and hypnotic action.

• Anxiolytic

                         E.g. used for anxiety disorders, such Generalized Anxiety Disorder.

• Muscle relaxant

                        E.g. may be used in general anaesthesia.

• Anticonvulsant

                         E.g. used to treat epilepsy.


Side effects of benzodiazepines

• Drowsiness ( e.g. ‘Hangover’ effect).

• Poor coordination, ataxia, dizziness (falls, injuries- e.g. in elderly).

• Confusion and/or brief amnesia- esp in elderly.

• Sometimes- Disinhibition.

• Tolerance and Dependence with prolonged use;  can get physical withdrawal when stopping prolonged treatment. Therefore limit use to short term (ideally less than 1 week; continuous use for over 3 weeks – sig. risk of dependence).

Toxic effects in overdose…

• Respiratory depression.

• Additive effect with other drugs that depress the CNS, such as alcohol.

Flumazenil (iv)

• BDZ receptor antagonist.

• Blocks actions of BDZ.

• Useful in reversing acute toxicity.

Non benzodiazepine ligands :
Relatively new;  commonly used as hypnotics.
E.g.
Zopiclone  (half life: 4-6 hours)
Zolpidem   (half life: 1.5- 2 hours)
Zaleplon    (half life:  1- 1.5 hours)

Act at/ close to the benzodiazepine receptor site.

Side effects include:

• Residual effects, e.g. drowsiness next day.

• Risk of tolerance and dependence?  seem less.

Barbiturates

1. Used widely in the past as a hypnotic and anxiolytic.  Use less now, due to side effects.
2. Unwanted effects:

• Similar to BDZ, but more prominent.

• E.g. Drowsiness, ataxia, irritability.

• Dependence and withdrawal symptoms marked.

• At large doses- significant risk of respiratory depression.

Antiepileptic drugs

Seizure
Seizure is defined as transient neurological dysfunction resulting from excessive depolarization of cerebral neurons. Predisposition to recurrent unprovoked seizures are called epilepsy.

Classification of seizures
Seizures are classified into partial and generalized. Again the partial seizures are subdivided into simple and complex.Generalized seizures are subdivided into absence, myoclonic, tonic, clonic, tonic-clonic and atonic.

Mechanisms of epilepsy
Seizure can be due to abnormal neuronal circuits(e.g. thalamocortical circuit in absence seizures), chanellopathies, increased excitation (increased Na+ influx, reduced K+ efflux, increased Ca2+ influx) or due to reduced inhibition (reduced GABA activity).


Antiepileptic drugs: mechanisms
All antiepileptic drugs depend on 3 mechanisms, they are to reduced glutamate activity, increase GABA activity and ion channel blockade.

Antiepileptic drugs
Phenobarbitone (1912)
Phenytoin (1938)
Ethosuximide (1953)
Carbamazepine (1963)
Sodium valproate (1968)
Clonazepam (1975)
Clobazam (1986)
Lamotrigine (1991)
Gabapentin (1993)
Topiramate (1995)


Phenytoin
Phenytoin is a use dependent Na+ channel blocker.It has slow absorption from GIT and bioavailability is about 85%. But its bioavailability is unpredictable after i.m injection.Phenytoin metabolized by the liver and T1/2 at low doses 12-36 h.

Phenytoin: adverse effects
The main adverse effect of phenytoin is cosmetic problems such as gum hyperplasia, acne, hirsutism, facial coarsening. It also cause cognitive impairment, osteomalacia, megaloblastic anemia, teratogenicity, drowsiness, diplopia, dysarthria, ataxia and act as CYP-450 inducer.

Carbamazepine
Carbamazepine is a Na+ channel blocker (use-dependent) and its oral bioavailability is about 80%.It is metabolized by liver and T1/2 is about 8-24 h.Carbamazepine is also a CYP-450 inducer and has autoinduction (pharmacokinetic tolerance) property.

Carbamazepine: adverse effects
Carbamazepine is known to cause skin rash, most are maculopapular but rarely cause Stevens Johnson syndrome. Other side effects include drowsiness, imbalance, diplopia, agranulocytosis and hyponatraemia.

Phenobarbitone
Phenobarbitone is the oldest antiepileptic drug. It is a potentiats GABA receptor activator. Its oral bioavailability is about 95% and it is metabolized by liver; 25% excreted unchanged. Its T1/2 72-144 h. Phenobarbitone is also a CYP-450 inducer. Side effects of phenobarbitone includes sedation, changes in cognition, mood & behavior problems.

Ethosuximide
This blocks T-type Ca++ channels in thalamic neurons. Its oral bioavailability is 95% and it is metabolized by liver; 25% excreted unchanged. Ethosuximide has a T1/2 of 20-60 h. Adverse effects of ethosuximide includes,dyspepsia, Ataxia and imbalance. 

Sodium valproate

Sodium valproate is very commonly used and its action is to block Na+, T-type Ca++ channels and potentiats GABA receptor activation.Oral bioavailability of sodium valproate is 95-100% and metabolize in the liver. Its T1/2 is 7-17 h and its a CYP-450 inhibitor.

Sodium valproate: adverse effects
Sodium valproate known to cause dyspepsia, tremor, weight gain, hair loss, hepatotoxicity and teratogenicity(Neural tube defects - reduced by folic acid). 

Clonazepam
Clonazepam enhances GABA receptor activation. Its oral bioavailability is 80% and metabolized by the liver. Sedation is a common side effect of clonazepam.

Lamotrigine
This blocks Na+ > T-type Ca++ channels. Recommendation is to use monotherapy / adjunctive therapy in partial or generalized tonic-clonic seizures. It is well absorbed from GIT and metabolized by the liver. It has longer T1/2 of 25 h. Adverse effects includes headache, nausea, vomiting and rash (more likely with high doses & valproate).

Gabapentin
Gabapentin inhibits glutamate release by blocking high-voltage-activated Ca2+ channels. It uses as adjunctive therapy for partial seizures. Gabapentin is well absorbed from GIT and eliminated unchanged in urine. Its T1/2 is 6 h and has adverse effects such as sedation, fatigue and weight gain.

Topiramate
Topiramate blocks Na+ channels, act as glutamate antagonist and has property of GABA potentiation. It is well absorbed from GIT and 70% eliminated unchanged in urine. The T1/2 is 21 h and has adverse effects such as sedation, fatigue, renal calculi and weight loss.

Antiepileptic drugs and pregnancy
Exposure to antiepileptic drugs in first trimester increases risk of congenital malformations.

• Valproate – neural tube defects

• Phenytoin – cleft palate

• Phenobarbitone – cardiac malformations

Polytherapy increases the risk further and Carbamazepine is a (if appropriate) relatively safe drug to use during pregnancy.

Antidepressants

Neurobiology
Depression is associated with a deficiency of 3 monoamine neuro-transmitters in the brain,they are, Serotonin, Noradrenaline and Dopamine. The principle action of  of effective antidepressants is to increase the synaptic action of one or more monoamine neurotransmitter.

Antidepressant medication
Antidepressants increase the synaptic action of one or more monoamine neurotransmitter but they also increase synaptic monoamine levels rapidly, and their clinical action (effect on patients) are felt weeks later.

1. Tricyclic antidepressants
This is a older type of antidepressants. Antidepressant properties of tricyclic antidepressants discovered in the 1950s-1960s. Their chemical structure contains three rings. The mode of action of tricyclic antidepressants is to block reuptake pumps for noradrenaline and/or serotonin. Examples of tricyclic antidepressants are:

• Amitriptyline
• Clomipramine (blocks reuptake of serotonin more)
• Imipramine
• Nortriptyline

Pharmacokinetics
Tricyclic antidepressants are administered orally. They absorbed well in the gut.The drug metabolized in liver and  T ½ can vary from 15-100 hrs, depending on medication. Tricyclic antidepressants have a good theraputic efficacy. Tricyclic antidepressants especially used to treat severe depression.

Side effects of Tricyclic Antidepressants 
Tricyclic antidepressants block muscarinic cholinergic receptors so they cause antimuscarinic effects such as dry mouth, blurred vision, urine retention (risk increased in elderly males), constipation, tremors and confusion, especially in elderly. They also block of alpha 1 receptors causing postural hypotension and dizziness. Sedation and weight gain can cause due to blockage of Histamine 1 receptors. Also they can precipitate mania, epilepsy and cardiac hazard such as blocks voltage gated sodium channels in heart (Eg: Sudden death in elderly, increased risk of cardiac arrhythmias).



Caution:
Tricyclic antidepressants must use with caution in elderly and those with cardiac disease.
Tricyclic antidepressants toxicity and overdose can cause cardiac arrhythmias, hypotension and fits.

Dosage: 
Once daily, usually at night (due to sedative effect)
   Gradually increase dose (e.g. starting with imipramine 50mg nocte, and working up to a maximum daily dose of 200mg nocte over 1-2 weeks).



2. Selective Serotonin Reuptake Inhibitors (SSRI)
This drug was introduced in the 1980s, now widely prescribed. It's mode of action is to selective inhibition of serotonin reuptake (at synapse), i.e inhibits the serotonin transporter (SERT). It is used in treatment of depression, anxiety disorders, eating disorders.

SSRIs in comparison to tricyclic antidepressants:
Selective serotonin reuptake inhibitors cause less severe side effects; patients may find it more tolerable. They are safer in overdose (less cardiotoxic) and SSRIs are not sedative; often have an activating effect.  Therefore selective serotonin reuptake inhibitors are given as a once daily dose in the morning. Examples of SSRI are:

• Fluoxetine (starting dose: Fluoxetine 20mg morn. This is an effective theraputic dose, but if needed can increase this gradually to maximum of fluoxetine 60mg morn).
• Sertraline
• Paroxetine
• Citalopram
• Escitalopram

Side effects of SSRI
Their side effects are usually due to activation of serotonin receptors in other areas of thebody: e.g. brain, spinal cord and gut.  They include nausea and vomiting (when starting treatment- tolerence develops quickly). Occasionally diarrhea and abdominal cramps can occur. Also they can cause headache (common- again when starting drug), increased agitation increased anxiety (when starting treatment), restlessness (akathisia), dystonic reactions and sexual dysfunction(e.g. delayed ejaculation in males).

3. Serotonin Noradrenaline Reuptake Inhibitors (SNRI s)
The drug blocks the re-uptake of noradrenaline and serotonin. Examples for SNRIs are:

• Venlafaxine (Used to treat both anxiety and depressive disorders.Dose: range from 75mg daily to a maximum of 300mg daily.Given as a bd dose;  or in the case of slow release preparations (XR)- once daily in morning.Caution in doses over 150mg daily:  may increase blood pressure; monitor BP and ECG).
• Duloxetine(Maybe more effective in treatment of depression presenting with physical pain symptoms).

4. Monoamine Oxidase Inhibitors (MAOIs)
This is also a older group of antidepressants. Antidepressant action of this class of drugs first described in the 1950s. This is an effective medication, but clinical use much less common now due high risk drug/food interactions. Examples are:

• Phenelzine
• Isocarboxazide
• Tranylcypromine
• Selegiline  (selective inhibitor MAO-B)

Mode of action:
They irreversibly inhibition of MAO enzyme. It has so-called ‘hit and run’ effect). Since the MAO is irreversibly inhibited, MAOI effects can last even 2-3 weeks after the drug is stopped (until the enzyme is re-synthesised).

MAO enzyme:  two types:

• MAO-A:  Found in brain, liver, intestine, lungs

                    Breaks down serotonin, NA, dopamine &
                    tyramine

• MAO-B:  Chiefly in brain.  Breaks down dopamine.

When MAO inhibitors are non selectively and irreversibly inhibited- increased serotonin & noradrenaline in central nervous system. It can also lead to dangerous dangerous interactions with other sympathomimetics such as cough syrups with ephedrine/ amphetamine and certain types of food that contain tyramine (cheese - “cheese reaction”), alcohol overripe fruit, smoked fish, etc


Drug/food interaction (“Tyramine reaction”)
This cause hypertensive crisis (due to vasoconstriction) causing severe throbbing head, palpitations, tachycardia. This could be life threatening. Therefore patients need to be warned ahead. Risk of interaction can last for 2-3 weeks after stopping treatment completely.

Alcohol dependence syndrome

Harmful use of alcohol
If the pattern of alcohol consumption has caused damage to the physical or mental health of the user, it is described as harmful use of alcohol. However this is not diagnosed if the patient is alcohol dependent. Those with the harmful use often have associated social problems, and are often criticized by others in their community about their level of alcohol use.

Alcohol dependence syndrome
This is a collection of physiological, behavioral and cognitive phenomena, in which the use of alcohol takes on a much higher priority for that individual, than other behaviors which once had greater value. The central characteristic of dependency is a strong desire or craving to take alcohol. A definite diagnosis of dependence should be made only if three or more ICD 10 criteria are present.

Features of acute alcohol withdrawal syndrome
Features of alcohol withdrawal occur with the fall in the blood alcohol levels. This could occur within hours of the last drink, and is commonest on waking from sleep and this is the reason why many dependent drinkers take an early morning drink or an eye opener to stave off withdrawal features on waking.

Common features of acute alcohol withdrawal syndrome:

• Tremor of hands, legs and trunk

• Restlessness, anxiety, easily startled, agitated and sweating

• Nausea, vomiting, retching, loss of appetite, and insomnia

• Tachycardia and systolic hypertension

Features of acute withdrawal syndrome can start within hours of the last drink and a peak in 24 to 48 hours; in most the symptoms are mild to moderate and disappear within 5 to 7 days. However 5% of dependent drinkers may develop delirium tremens which is a medical emergency.

Delirium tremens
In about 5% of dependent patients, the withdrawal syndrome becomes severe; 36 to 48 hours after the last drink they delirium tremens may develop.

Features of delirium tremens

• The patient Is disoriented/confused. He may be very agitated, and in his confusion may be of harm to himself and a disturbance to the patients in the ward.

• Objects may appear distorted in shape. Illusions, visual and auditory hallucinations may occur. There may be frightening in nature. Commonly described visual hallucinations include those of colorful animals, snakes etc. Auditory hallucinations may be disorganized voices, shouting or snatches of music. Paranoid ideation can also occur.

• Tachycardia and hypertension

• Fever

• Generalized fits her

Risk factors for development of delirium tremens and fits:

• Severe alcohol dependence or severe withdrawal features when presenting for treatment.

• Past history of long standing alcohol dependency with previous episodes of inpatient treatment for withdrawal features.

• Past experience of delirium tremens or fits.

• Older age and concomitant acute illness.

Types of delusions

Delusions have been classified in many different ways. One way is based on the content of the delusion. Some of the commoner types of delusions are described below.

Delusions of persecution
The patient has a deluded belief that others are trying to harm him. can present in different ways in different patients. Delusions of persecution are common, but may not be very helpful in diagnosis, because they can occur in many types of psychotic disorders for example severe mood disorders, schizophrenia and organic states. However the patient's attitudes to the delusion may point to the diagnosis. For example in depression the delusions of persecution is usually mood congruent for example accompanied by feelings of guilt and worthlessness; the patient may belief he is persecuted because he is wicked. Whereas in the schizophrenia, the patient often resents the "persecutions". It should be also recalled that in many cultures people often believe that their misfortunes are due to evil charms/malign activities of other people in their community. This is often culturally shared, culturally accepted belief and therefore is not a delusion.

Delusions of reference
With this delusion, the patient believes that other people's actions, and even other events have a special significance or reference to himself. For example when a schizophrenic patient sees his family members talking among themselves, he may deludedly believe that there are talking about him, plotting to harm him. Another patient may believe that the news telecast on television had special reference to him. Yet another patient might claim that political posters pasted on the wall outside the hospital are referring to him. Delusions of reference are very common, and may be seen in schizophrenia, delusional disorder and severe mood disorders. They often have persecutory associations, but may also relate to grandiose themes.

Delusions of jealousy
The patient firmly believes that his partner is unfaithful to him. This belief is not based on logical evidence. The patient may act on his delusion for example always check on the suspected partner or accuse the partner and physically abused the partner. Delusions of jealousy are dangerous because they could lead to violence towards the partner. Delusions of jealousy is again common, and may form part of the schizophrenic illness, delusional disorder or mood disorder. It should be noted that delusions of jealousy are also associated with alcohol dependency.

Grandiose delusions
The patient has a deluded belief that he has special abilities or that he is a special person. Grandiose delusions are common, often seen in mania with psychotic features. It is also seen in other situations such as schizophrenia (the the patient may have bizarre grandiose delusions) and also in some organic illnesses such as general paresis of the insane.

Obsessions and compulsions

An Obsession is a recurrent thought/image/impulse which the patient cannot get rid of. It occurs repeatedly, and dominates the patient's consciousness, although the patient realizes it is senseless and tries to resist it. There is a subjective sense of struggle -the patient resists the obsession, but it intrudes into his awareness. The patient is also aware that the obsession are his own thoughts. If the delusion and an obsession were compared, it is clear that unlike in a delusion, a patient with an obsession does not believe his thoughts is true; and unlike in a deluded patient, the patient with obsessions tries to resists his obsessive thoughts.

For example, a patient gets the recurrent obsessive thoughts that her skin will become dirty and leads to disease. She is aware that this is a senseless thought, and tries to resist it, but she gets this thought again and again and this causes her distress.

A compulsion can be described as an obsessional motor act. Here the patient carries out a stereotyped motor act repeatedly, and feels a strong urgent to do so. At the same time, he knows that the act is senseless, it causes him distress and he tries to resist it unsuccessfully. A compulsion might be secondary to an obsessive idea/image. For example the woman who has recurrent obsessive thoughts of becoming contaminated might also have a compulsion to wash.

Often these compulsions or motor acts are carried out in stereotypic ritualistic ways-hence they are often referred to as compulsive rituals. For example if the compulsion is to wash, the patient may have a ritualistic way of washing, such as pouring water five times, applying soap twice, and pouring water 15 times and so on. The ritual is usually individualistic to each patient. Compulsive acts are of many kinds; the commoner kinds are checking rituals, washing rituals, counting rituals and dressing rituals.

Obsessions and/or compulsions are the key feature of obsessive compulsive disorder. Obsessive phenomena may also form part of the symptomatology of other disorders such as depression, schizophrenia and some post encephalitic states. Obsessive traits are also often seen in healthy people where it does not account to a disorder.

Delusions

Delusions

This is a firmly held belief, which is not based on logic and not amenable to logical argument, which cannot be explained in terms of a patient's social or cultural background. A delusion is usually false. For example a person may claim his neighbor is sending rays to kill him. In order for this to be a delusion, the person should believe this very firmly, even though he had no logical evidence to support this belief; he might even act on this belie (for example he may take steps to protect himself). It is also not possible to change his belief by logical argument, and his belief is not shared by others in this community.

There are many different types of delusions, and delusions may be seen in many different types of psychotic disorders. Patients with severe mood disorders often have delusions that are mood congruent that is which match their mood. For example:
A manic patient may have delusions of grandiosity (for example he is the president of his country) or delusions of persecution (for example people are trying to kill him because he is so powerful).
A severely depressed patient too may have delusions, but these would be with negative themes; for example delusions of persecution(e.g. people are trying to kill him; and he deserves to die because he is wicked), or nihilistic delusions(for example his family is dead; he has lost everything).

Delusions are also seen in schizophrenia and delusional or disorder. Certain types of delusions are typical of schizophrenia, and are induced in Schneider's first rank symptoms of schizophrenia. They include delusions of control, delusional perception, thought insertion, thought withdrawal, thought broadcasting and thought echo.

Terms used to describe disorders of perception

Illusion
a stimulus from a perceived object is combined with a mental image to produce a false perception. They often occur in normal people. For example the normal person walking on lonely road in the dark may get frightened; he may see the shadows of the trees and interprets them as threatening people. Illusions could also occur in psychiatric illness for example severe depression, acute confusional and others.

Hallucinations
This Is a false perception; the perception occurs in the absence of an external stimulus. This appears in the patient's external objective space (that is seems to be situated outside the patient) and is clearly defined. Hallucinations are described as being independent of the person's will, i.e. they cannot be voluntarily recalled or changed.

Hallucinations can occur of the different sense modalities:

• Auditory hallucinations

• Visual hallucinations

• Olfactory hallucinations

• Gustatory hallucinations

• Tactile hallucinations

Auditory hallucinations are common. They could occur in normal people(for example when falling sleep/wakeing up). In patients they could be simple hallucinations (noises, catches of song) or complex(voices talking, arguing). Complex hallucinations can be further divided:

• Second person auditory hallucinations - the patient hears a voice talking to him. This is common, and could occur in mood disorders with the psychotic features or schizophrenia.

• Third person auditory hallucinations - the patient hears several voices, talking about him (among themselves). This type of hallucinations is usually but not always seen in schizophrenia.

Prominent visual hallucinations are often more commonly seen in organic disorders such as acute alcohol withdrawal, acute confusional state, certain types of dementias. Although visual hallucinations could occur in psychiatric disorders per sae, prominent visual hallucinations should always raise the suspicion of an underlying organic pathology.

Terms used to describe behavior and movement

Psychomotor retardation
this is seen in depression. The patient subjectively feels that all actions have become much more difficult to initiate and carry out. There is a slowing down of all motor acts and thoughts. With severe psychomotor retardation, the observer will notice that the patient's movements are slow and dragging. Psychomotor retardation has been compared to the uniform slowing down of a vehicle produced by the steady application of brake.

Agitation
a state of restlessness and motor overactivity. The patient is easily distracted, so he may be unable to carry through the complicated pattern of voluntary movements.

Apathy
A State of under activity with the reduced responsiveness to stimuli and inability to feel pleasure, which the observer has good reason to distribute to loss of interest or concern, rather than to any intrinsic difficultly in responding.

Tics
Brief, repeated contractions of a muscle or small group of muscles. For example repetitive blinking, distortions of the or nose, shrugging of the shoulders, sniffing, grunting, clearing the throat. It is thought to occur with stress, and is common during childhood. Tics could also occur after encephalitis, in Huntington's chorea, and in Gilles de la Tourette syndrome.

Rest tremor
In a tremor there is a constant rhythm,which produces a steady oscillation of the affected part of the body. The rest tremor is seen when the subject is at rest. Most commonly seen in the hands, but could also affect the trunk, and head. It could be a normal movement seen in anxious subject. Static tremor also occur in alcohol withdrawal, Parkinson's disease, thyrotoxicosis and as a familial condition in benign essential tremor. Even such organic tremor can vary in intensity from day to day and maybe worsened by emotional stress. Static tremor could also be entirely psychogenic in origin.

Action tremor
This is a tremor made worse by action.

Athetosis
Slow, twisting, sinus movements of arms and legs made more prominent when the patient attempts movement.May be seen in children with cerebral palsy.

Chorea
Sudden, rapid, involuntary, purposeless jerks of fragments of movements. They continually intrude into the patient's normal activity. In Huntington's chorea the face. upper trunk and arms are the most affected. During the early stage of this disease, the patient may try to disguise the choreoform movements by tuning them into a voluntary movement.

Terms used to describe changes in speech

Mutism
This is the complete loss of speech. It could occur in depression,schizophrenia, dissociative disorders, disturbed children and patient with coarse brain disease. For example, a severely depressed patient may be mute. Some children may have elective mutism - i.e. the child speaks in certain environments only. For example he speaks normally at home, but does not speak at all at the school.
In motor aphasia, the patient's use of words may be severely restricted, but he may not be completely mute, i.e. he may be able to use 1 to 2 words. In akinetic mutism the patient appears to be aware of their environment, but is mute.

Pressure of speech
A state where there is an increased flow of speech. This speech is difficult to interrupt or stop. Pressure of speech is common in mania, where it is often associated with flight of ideas. Pressure of speech may also be seen in schizophrenia.

Flight of ideas
Flight of ideas are changes in the flow of speech which is typically seen in mania. In flight of ideas, the patient's thoughts occur very fast. The patient is very distractible, and the thoughts change very quickly, but there is an understandable association or connection between one thought and the next. These rapidly changing thoughts are manifested in the way the patient speaks very rapidly, jumping from subject to subject.

Terms used to describe emotions

Mood
Strictly speaking, the term mood refers to the emotional state that prevails in a person at any given time. However in psychiatry the term mood is often used to describe the emotional state that has lasted for a period of time and which has colored much of the patient's recent experiences.

Diurnal variations of mood
This describes a variation of the mood which shows a consistent 24 hour cycle. For example in a depressed patient, the mood may be lowest in the early hours of the day and the patient may feel a little better towards the evenings. If this variation of mood is seen consistently everyday it is referred to as his diurnal variation of mood.

Elation
This is an abnormally elevated mood,which is persistent and not due to any obvious reason. An elevated mood is one of the main features of mania. These patients appear very cheerful,having a strong sense of well being and self confidence and they do not respond to external depressing influence. This elation of mood is often accompanied by over activity,pressure of speech and flight of ideas. The elevated mood in manic patients shows an infectious gaiety -i.e, the observer often gets caught up in the patient's gay mood.Elated mood can also occur in schizophrenia and certain organic states such as general paresis of the insane.

Euphoria
A state of unconcern and contentment which is not justified by circumstances. Unlike elation euphoria is not infectious. Euphoria may be seen in organic illnesses such as disseminated sclerosis, amnestic syndrome and frontal lobe lesions.

Lability of affect
Here the patient's emotions change rapidly. The patient has difficult in controlling his emotions.