A comprehensive review introduction

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Table 4: General effects of psychotropic drugs on the CNS

Overview of Goals in Management

Management of mental illness encompasses a broad field of medical practice that includes pharmacology, psychiatry and behavioral science. The management and treatment plans for mental illness depends on its type, severity and individual history and preference. The full discussion is outside the scope of this article, but students may wish to defer to later study to address the cumulative approach to the management of mental illness.

Generally, however, the management and treatment plans may include one or more of these interventions (30):


  1. Psychopharmacologic treatment

  2. Psychotherapy approaches

    • Brain stimulation

    • Institutionalization / rehabilitation programs

    • Psychodynamic therapy

    • Cognitive-behavioral therapy

    • Group therapy

    • Family intervention

    • Social rhythm therapy

  3. Self-care

Other interventions and services may include (31):

      1. Employment assistance

      2. Housing assistance

      3. Reintegration measures into society

      4. Psychosocial rehabilitation

      5. Assertive community treatment

Additionally, several healthcare personnel may be involved in the execution of the management and treatment plans such as:

  1. Family clinician

  2. Psychotherapist

  3. Psychiatrist

  4. Pharmacist

  5. Social worker

  6. Family members

  7. Guardian

The psychopharmacologic treatment plan used will depend on the type of mental illness and may include any or more of the following:


  1. Antidepressants

  2. Antipsychotics

  3. Nootropics

  4. Anxiolytics

  5. Mood stabilizers

An example of how treatment plans often evolve and might be revised based upon organic and other causes is well known in therapies for individuals with a diagnosis of substance abuse and addiction. Recovering drug addicts are often beset with comorbid mental disorders (depression, anorexia nervosa, insomnia) and may require an antidepressant and a sleep aid. These patients may receive and require enrolment in:

  • Psychotherapy

  • Psychopharmacologic drugs

  • Detoxification

  • Support groups

  • Partial hospitalization programs

Psychopharmacologic Treatment Plan

Psychopharmacologic treatment plans are based on 3 fundamental needs of the mentally ill patient. These are:



  • Resolution of acute episodes

  • Long term symptom control

  • Improvement quality of life

Chronic psychopharmacologic treatment presents a mixture of trepidation and warm anticipation to both clinician and patients. Trepidation because psychoactive drugs are known to cause physical and physiological dependence even at therapeutic doses, and warm anticipation because these drugs are backed by evidence-based studies that prove their effectiveness in improving the quality of life. Needless to say, important in the diagnosis of mentally ill individuals, such as those with schizophrenia, mood and anxiety disorders, is to distinguish which patients requires short term and long term maintenance medications.

In general, there are three characteristic features of mental disorders that indicate the need for maintenance therapy on psychoactive medications. These are:


  • Early onset


  • Persistence

  • Risk of relapse

The standard approach is to differentiate acute symptom relief from partial remission. If the episode occurred while on maintenance medication, the clinician should consider the probability of recurrence (and its implications) against the consequences of maintenance medication (e.g. adverse effects). A rational strategy in this case is to maintain medications for six months after full remission is achieved. If the symptoms occur more than once (recurrence), the strategy should shift to maintaining medications for more than six months after the initial episode (31).

General goals of short term and long term treatments are compared, below (31):



Long term

Short term

Minimization of relapse risk

Reduction of symptoms

Reduction of symptom exacerbation

Alliance with patient and family

Maintenance of effective dose

Patient and family education

Frequent monitoring of side effects

Return to premorbid condition

Maximization of compliance




Reduction of the social burdens of mental illness


Table 5: General goals of short term and long term treatments

The table below lists the specific mental disorders and the more specific and rational approaches to their long-term and short-term treatments. While they are included in a separate category of personality disorders, Developmentally delayed (DD) and Antisocial Personality Disorder are also worth mentioning here as they also have their own specific set of short/long-term treatment approaches.



Mental disorder

Short term treatment

Long term treatment

Schizophrenia

Reduction of severe psychotic symptoms (acute phase); sustenance of therapeutic gains (resolving phase)

Prevention of relapse; rehabilitation; tardive dyskinesia prevention / minimization; cognitive and negative symptoms management; Facilitation of compliance to therapy

Depression

Rapid reduction of affective symptoms; return to premorbid state; frequent monitoring

Facilitation of mood and functioning recovery; facilitation of indefinite psychopharmacologic treatment with tapering of doses at end and initiation of each drug

Bipolar disorder

Acute treatment; identification of and removal of exogenous triggers

Aggressive treatment of residual subsyndromal symptoms; facilitation of compliance to therapy

Anxiety disorders


Remission of symptoms; restoration to normal levels of psychosocial function

Prevention of withdrawal symptoms by tapering of doses between drugs; maintenance of psychosocial function, employment and relationships

Table 6: Different mental disorders and their treatment approaches

Overview of newer vs. older psychotropic medications

The 19th and 20th centuries saw the emergence of psychotropic drugs that were initially used to treat other medical conditions. Bromides were introduced in 1857 as an anticonvulsant, and the oldest group of depressants, barbiturates, in 1912 for insomnia. These two groups of drugs were found to have sedative effects. Other drugs soon emerged such as amphetamines for depression and lithium for agitation in manic states. The first antipsychotic, chloropromazine, was first studied for its sedative properties in anesthesiology. Tricyclic antidepressants and monoamine oxidase inhibitors became the standard of treatment for depression in the 1950s. The most widely prescribed anxiolytics today, benzodiazepines, were introduced in the 1960s (32).

Initial studies on chlorpromazine showed improved behavior and intellectual performance however, subsequent clinical reports employing more thorough scientific methods did not corroborate these findings. Symptoms such as aggression, hyperactivity, anxiety and intellectual function were not improved with chlorpromazine use. The positive therapeutic outcome of chlorpromazine was attributed largely of its sedating properties.

The first report on the adverse effects of antipsychotics emerged in the 1960s. It was reported that the confined mentally ill on psychotropic medications were experiencing serious side effects ranging from sedation, seizures to tardive dyskinesia. Growing concern amid overuse and misuse of psychotropic medications led to several lawsuits in the 1970s and 1980s.

Chemical restraints

The 1970s saw the advent of psychotropic drugs as “chemical restraints”. According to the Accreditation Council for Facilities for the Mentally Retarded (ACMR) Standards for Institutions (1971), chemical restraints are (33):

(a) For staff convenience

(b) Drugs that restrict patient activities and movement (e.g. benzodiazepines)

Presently, the FDA approves no drugs for these purposes anymore. According to the Federal Nursing Home Reform Act, patients have the right to be free from physical or chemical restraints imposed for purposes of discipline or convenience and not required to treat their medical symptoms. The list below summarizes the consequences of chemical restraints (34).


  • Agitation

  • Gait disturbance

  • Memory impairment

  • Sedation

  • Withdrawal

  • Functional decline

  • Movement disorders

  • Orthostatic hypotension

The last 20 years have seen the emergence of evidence that indicate dual diagnosis of illness. Patients with developmental disabilities (e.g. mental retardation) may also most likely have a comorbid psychiatric disorder. The newfound knowledge has resulted in a multidisciplinary approach in the treatment of both mental illness and retardation. Another example of a dual diagnosis is substance abuse and mental illness. The presence of both mental illnesses in a patient requires a complex treatment strategy than that of either condition alone. The primary goal of treatment is to prevent life-threatening complications of intoxication (35).

In 1987, the Psychotropic Monitoring Checklist for Rule 34 facilities was established to tackle psychotropic drug use in mental institutions and community facilities. The 1990s showed a shift in treatment approach of the mentally ill which was exemplified by the Accreditation Council on Services for People with Disabilities (ACD). The ACD took an outcome-based performance strategy, with the patient’s personal quality of life at the center of it. It primarily centered on patient personal goals, choice, social inclusion, relationships, rights, dignity, respect, health, environment, security, and satisfaction (36).

Presently, standard practice requires the thorough assessment of function and behavior, which then forms the basis of psychopharmacologic treatment plans. The assessment includes:

(a) Eliminating possible medical variables

(b) Evaluation of environmental triggers

(c) Assessment of organic causes of illness


CLASSIFICATION OF PSYCHOTROPIC DRUGS

In a medical context, psychotropic drugs refer to a class of prescription medications that primarily exert their therapeutic effects on the central nervous system. Whether taken orally or administered intravenously, psychotropic drugs are absorbed by the blood and transported into the brain. They pass through the protective membrane, the blood brain barrier (BBB) and into the brain circulation.

The BBB comprises of capillaries made of tight junctions that do not allow free mixing of substances contained within the blood with the extra cellular fluid. Most drugs cannot filter through the BBB and do not affect brain function. Psychotropic drugs, on the other hand, are formulated especially to cross the BBB and act directly on the brain to alter perception and mood, induce behavioral changes and affect consciousness along with cognition [37]. The basic purpose of these drugs is to bring about the desired changes in mood and behavior to treat and manage psychiatric disorders.

Classifying psychotropic drugs into particular groups that is universally acceptable is difficult and yet needs to be done. Many of these medications have different primary functions but may eventually exert a wide range of pharmacologic effects on the user. Many strategies have been proposed, however, a definite classification with little or no overlap is yet to be defined.

Psychotropic medications are generally categorized into the following:


  • Antipsychotics

  • Antidepressants

  • Anxiolytics

  • Mood stabilizers

  • Prescription stimulants

  • Sedative-hypnotics

  • Miscellaneous drugs (e.g. herbal supplements)

Antipsychotics

This subgroup contains a large number of medications that are used to treat psychosis. Psychosis is a generic term that encompasses disorders resulting from abnormal perception of reality accompanied by a defective insight. Psychotic patients primarily experience these two characteristics:



  • Hallucinations: Sensory perceptions without an actual stimulus being present

  • Delusions: False beliefs about reality

Psychotic patients also present with social cognition impairments, personality changes and thought disorders.

Antipsychotics are used in the treatment of mental illnesses such as schizophrenia, bipolar disorder, delusional disorders, and also wide range of non-psychotic disorders such as Tourette syndrome, autism, and dementia.

Antipsychotics work differently from regular medications in a way that they may not always produce the same effect in different patients despite the similarities in their psychotic states. They may very well exhibit different efficacies and duration of treatment across different patient groups. Interestingly, some atypicals are prescribed in lower doses in people prone to weight gain and depression and anxiety; they can also be used for pain management and insomnia in some patients. In short, they are unpredictable, just like the disease they have been designed to manage.

Psychosis proceeds in an unpredictable pattern and symptomatic relief of a particular state is by no means a criterion to discontinue an antipsychotic drug. Patients need to be thoroughly assessed by their clinician before any changes to the dosage and timing of the medication can be taken. Additionally, patients need to be educated about the need for these drugs to be tapered down slowly over a period of time to avoid serious drug withdrawal responses associated with their sudden discontinuation. Withdrawal symptoms and manifestations of relapse such as insomnia, agitation and, motor disorders can ensue and seriously undermine the progress made during the duration of treatment [38].

However, premature discontinuation is a reality and clinicians must then realign their treatment strategies in order to accommodate the patient’s level of comfort regarding the therapy. Individuals with sensitivities relative to their mental illness and medication management are a huge part of the clinical follow up plan. Educating them and persuading them to follow the treatment strategy of “starting low and going slow”, may be a challenge. Also, some people are attached to their routine drug of choice, i.e. Ativan at bedtime or anti-depressant, and may be resistant to a change in medication and its dosing schedule. In these individuals, resistance and self-sabotage to a newly improved drug therapy often turns into a negotiation between the therapist and client.

Patients on antipsychotics need to be mindful of their diet and over the counter (OTC) medications or nutrient product use (including “health” products) since they are notoriously known to interact with many drugs including vitamins. The clinician’s opinion should be sought prior to commencing OTC medications or products if the patient is already on antipsychotics.

Antipsychotics are broadly classified into two subcategories i.e. typical and atypical (first generation and second generation). The major difference between the two groups lies in their mechanisms of action. In general, psychosis is believed to be a product of excessive dopamine activation and although all antipsychotics mainly block the pathway leading to this, the atypical antipsychotics also act on the serotonin receptors. The dual action results in fewer side effects.

The first atypical antipsychotic that gained FDA approval was clozapine (Clozaril) in 1989 (39). It became the drug of choice for the treatment of treatment-resistant schizophrenia and recurrent suicidal behavior in schizophrenia. Not too long after its widespread acceptance and use, its most debilitating side effect, agranulocytosis, began to surface.

When clozapine (Clozaril) fell out of favor, other drugs of the same class emerged, namely risperidone (Risperdal) and olanzapine (Zyprexa). Expert consensus agrees that atypical antipsychotics exhibit lower incidence of extrapyramidal effects and prolonged elevated prolactin levels. It blocks D4 at the mesolimbic pathway, accounting for its efficacy in managing psychiatric symptoms minus the extrapyramidal symptoms (EPS).

Clozapine (Clozaril) is a tricyclic benzodiapine with of 8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine. Its structure is shown below.



Clozapine (Clozaril) blocks weakly D2-receptor and D1-receptor. It primarily acts on the D4-receptors, a specificity that accounts for its lower incidence of EPS. It also exhibits of anticholinergic, antiserotoninergic, and antihitaminic activity. The latter is responsible for the adverse effects it has on sleep patterns.

Clozapine (Clozaril) has a 50-60% bioavailability following oral administration, reaching a peak plasma concentration of 102-771 ng/mL within 1.5-2.5 hours. It is excreted both in the urine and feces.

Risperidone (Risperdal) is another example of atypical antipsychotic drug. Its exact mechanism of action is not completely understood but studies show that it is also a serotonin and dopamine receptor antagonist. Its antidopaminergic and antiserotonergic activities stem from its blockade of the D2 and 5-HT2 receptors in the brain, respectively. Dopamine receptor blockade rarely results in neuroleptic malignant syndrome, a fatal neurological disorder characterized by muscle rigidity, fever and autonomic instability. Neuroleptic malignant syndrome is most commonly associated with the typical (older) antipsychotics.

Risperidone has also been found to possess antiadrenergic and antihistaminergic properties. Aside from schizophrenia, it is prescribed as an adjunct to lithium in patients with acute manic episodes associated with bipolar disorder [40, 41], and treatment of irritability and behavioral problems associated with autistic disorders [42].

The chemical formula of Risperidone is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

Its molecular formula is C23H27FN4O2 and its chemical structure is shown below.

Most drugs when passing the liver via the blood stream undergo the first pass effect or hepatic metabolism. Risperidone, when given orally, is almost completely absorbed. One/third of the drug undergoes hepatic metabolism, with its primary metabolite, paliperidone, exhibiting as much efficacy as its parent drug. This is the reason why the bioavailability of risperidone is close to 100%. Its mean half-life is between 19-23 hours; the diverse number is attributed to the variability in the CYP26D group of enzymes that metabolize it. It reaches steady state concentration within 5-6 days from the start of therapy. It is primarily excreted in the urine.

Initially, risperidone is given to adults in a dose of 2 mg/day (either once or twice daily tablet). The dosage can be increased to up to 4 mg on the second day with further increments as required. Severe side effects are expected with higher doses of the drug. Generally, doses above 10 mg/day have not been proven to be more efficacious than lower doses and since they are associated with serious side effects, they should only be administered when the clinicians deem its benefits to outweigh its risks.

Risperidone is the first antipsychotic approved by the FDA for the treatment of schizophrenia in adolescents aged 13-17. When used in the elderly, the starting dose should not be more than 1 mg/day. It carries a FDA black box warning because of its propensity to cause death in patients with dementia-related psychosis. Additionally, risperidone is best avoided in patients with renal and hepatic impairments. More than 900 medications are believed to interact with this drug and 46 of those have serious consequences. A detailed medication history should be taken to check for possible interactions prior to start of therapy.

Another novel atypical antipsychotic is quetiapine (Seroquel). Quetiapine is also indicated in the treatment of psychotic disorders. Anecdotal evidence points to its effectiveness in manic disorders as well, although, no multicenter control trials have been found to support it. It is considered a first line drug for bipolar disorders [43].

Quetiapine (Seroquel) is a diabenzothiazepine derivative that also possesses dopamine antagonistic effects responsible for its antimanic properties. Its antiserotonergic and antiadrenergic properties give this drug its antidepressant effects. Its molecular formula is C21H25N3O2S, and its chemical structure is shown below.



The drug is rapidly absorbed following oral administration and takes about 1.5 hours to reach peak plasma levels. Compared to risperidone (Risperdal), quetiapine (Seroquel) reaches steady state concentration faster i.e. approximately 2 days. The liver metabolizes Quetiapine extensively to produce inactive metabolites. Its average half-life is 2-3 hours.

Quetiapine (Seroquel) is given as a daily dose of 25 mg once or twice daily which can be increased up to a maximum of 400 mg per day. However, some clinical trials showed that doses above 300 mg/day did not exhibit superior efficacy to lower doses. Dosage adjustment is indicated in patients with hepatic impairment. Age, gender, ethnicity and smoking do not affect its pharmacokinetics. Like risperidone (Risperdal), quetiapine (Seroquel) has also been linked to early death in elderly patients with dementia [44] and likewise carries a black box warning on its label.

The black box warnings against the use of risperidone and quetiapine (Seroquel) in dementia-related psychosis in geriatric patients are due to their fatal adverse effects on the cardiovascular and respiratory systems. Patients have reportedly died suddenly because of heart failure and pneumonia.

In 2009, quetiapine (Seroquel) joined risperidone as an FDA-approved monotherapy for the treatment of schizophrenia in adolescents aged 13 to 17 years and as an adjunct to both lithium and divalproex (valproic acid) for acute manic episodes in children and adolescents aged 10 to 17 years with bipolar disorder.

The older (typical) antipsychotics first emerged in the 1950’s, some 40 plus years before clozapine (Clozaril) came into the picture. These drugs act on the dopamine receptors (D2) of the CNS, essentially blocking the endogenous dopamine from binding with them and exerting their normal physiological effects. The older antipsychotics initially fell out of favor because of their propensity to cause extrapyramidal symptoms (EPS). This adverse effect stems from the drug’s antidopaminergic action on the basal ganglia. EPS includes the following movement dysfunctions:


  • Akinesia

  • Akathisia

Additionally, typical antipsychotics also exhibit other adverse effects such as:

  • Parkinsonism (tremors, rigidity)

  • Bradykinesia

  • Erectile dysfunction

Haloperidol (Haldol) was developed in 1958 and approved for antipsychotic use by the FDA in 1967. It is also indicated for the treatment of schizophrenia and has been found to be effective in treating the vocal utterances in Tourette’s syndrome. It belongs to the butyrophenone class of drugs that include droperidol (Inapsine), a neuroleptanalgesic anesthesia and sedative and, domperidone (Motilium), an antiemetic. Its chemical structure is shown below.

Haloperidol (Haldol) is available in oral and injectable forms. The IM formulation contains the active drug haloperidol along with lactic acid, an excipients, used to stabilize the pH of the formulation. It is also given intravenously. As expected, its onset of action and response is very rapid with a bioavailability of 100%. When administered as an infusion, its pharmacological effects are sustained over a long period of time.

Haloperidol (Haldol) is believed to cause QT prolongation and should be given with extreme caution to patients suffering from conditions that cause prolonged QT intervals, patients who are receiving drugs that cause electrolyte imbalances, and critically ill patients [45]. Coadministration with carbamazepine (Tegretol) decreases its plasma concentration, thus, requiring dose adjustment in such cases [46]. Haloperidol (Haldol) is absolutely contraindicated in patients with stroke, cardiac conditions, known hypersensitivity to the drug, and severely intoxicated with alcohol and other central nervous system depressants. Just like the atypical antipsychotics, haloperidol carries the risk of early death in elderly patients with dementia-related psychosis.


Antidepressants

Antidepressants comprise a wide variety of drugs that are basically indicated to treat the various symptoms of depressive disorders. However, many off label indications for using antidepressants also exist and conditions such as anxiety, sleep disorders, obsessive compulsive disorders, eating disorders, neuropathic pain, ADHD, migraines and substance abuse benefit from its use.

Antidepressants are subdivided into the following classes:


  1. Selective serotonin reuptake inhibitors (SSRIs)

  2. Norepinephrine reuptake inhibitors (NERIs)

  3. Noradrenergic and specific serotonergic antidepressants (NaSSA)

  4. Serotonin–norepinephrine reuptake inhibitors (SNRIs)

  5. Serotonin antagonist and reuptake inhibitors (SARIs)

  6. Norepinephrine-dopamine reuptake inhibitors (NDRIs)

  7. Selective serotonin reuptake enhancers (SSREs)

  8. Norepinephrine-dopamine disinhibitors (NDDIs)

  9. Tricyclic antidepressants (TCAs)

  10. Monoamine oxidase inhibitors (MAOIs)

Selective Serotonin Reuptake Inhibitors (SSRIs)

The exact mechanism of action of SSRIs remains unclear to date; however, it is believed that these drugs inhibit the reuptake of serotonin from the synaptic cleft at the neuronal junctions, thus, maintaining high serotonin levels for binding with the postsynaptic 5-HT receptors. SSRIs are widely prescribed worldwide and its most famous member is fluoxetine (Prozac).

Fluoxetine (Prozac) or (±)-N-methyl-3-phenyl-3-[((alpha),(alpha),(alpha) -trifluoro-p-tolyl)oxy]propylamine hydrochloride has the empirical formula of C17H18F3NO·HCl and a chemical structure that is depicted below.

Fluoxetine (Prozac) is a white crystalline substance available as a tablet. Sustained release formulations are also available to facilitate easy administration of the drug and encourage patient compliance.

Fluoxetine (Prozac) is indicated in the following conditions:


  • Major depressive disorder (MDD)

  • Obsessive compulsive disorder (OCD)

  • Bulimia nervosa

  • Panic disorder (PD)

  • Premenstrual dysphoric disorder (PDD)

It is also used off label in:

  • Fibromyalgia

  • Migraine

  • Hot flashes

  • Reynaud’s phenomenon

For MDD, OCD, PD and PDD, an initial 20 mg is usually the preferred dose. Depending on patient needs, the dose can be gradually increased but should not exceed 80 mg/day. Peak plasma levels are achieved within 6-8 hours of administration. It undergoes extensive hepatic first pass metabolism, which produces one active metabolite, norfluoxetine, and multiple unidentified inactive metabolites. It is renally excreted. Variations in metabolism are seen in patient populations with reduced cytochrome P450 enzyme concentrations. However, the net pharmacodynamics in these patients was also observed to be the same, making it an efficacious drug of choice despite the said metabolic variations.

Prozac has a special formulation called Prozac Weekly, a delayed-release capsule that sustains the required plasma drug levels without the inconvenience of daily administration.

Patients with liver diseases may show impaired elimination of the drug and should be given it cautiously, and under close clinician supervision. A lower and less frequent dosing schedule should be followed in these patients. Similarly, since the metabolites may accumulate in patients with renal impairment, a similar dosing regimen is best adopted.

The efficacy of a 20 mg dose of fluoxetine (Prozac) has been established in both adult and pediatric patients suffering from major depressive disorders. In both cases, the drug was found to be significantly more potent than placebo in eliminating symptoms of the disease. Multiple clinical trials have demonstrated the efficacy of the drug in treating panic disorders, bulimia nervosa [47] and obsessive-compulsive disorders especially in combination with cognitive behavioral therapy in children as well as in adults.


Norepinephrine Reuptake Inhibitors (NERIs)

This class of antidepressants exclusively blocks the presynaptic membrane protein, norepinephrine transporter (NET). NERI’s are indicated in anxiety disorders, panic disorders, narcolepsy, ADHD and major depressive disorder.

Atomoxetine (Strattera) belongs to this class of drugs and received FDA approval in 2004 for the treatment of ADHD. Currently, it is the only drug approved for the treatment of ADHD in adults and the only non-stimulant drug approved for children and adults for the same indication. Although it was initially designed as an antidepressant, its clinical efficacy in depressed patients could not be established significantly. Following the results of such studies, it was proposed that atomoxetine (Strattera) exhibited a therapeutic potential in the treatment of ADHD patients.

Children under 6 however should not be given the drug since no guarantee of safety exists below this age group. The main reason for its popularity in ADHD treatment is that it is not a stimulant and therefore, do not have the abuse potential of the older stimulant medications. The drug is expected to take at least a week to show any therapeutic benefits and some studies suggest that the true potential of the drug can only be felt in about 6-8 weeks after which discontinuation should be proposed if no improvements are shown. Stimulant drugs (e.g. methylphenidate) are no longer recommended in ADHD patients with nervous disorders (e.g. spasms and tics). Atomoxetine (Strattera) become the drug of choice for these patients (48).

Its chemical name is (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride and its structure is shown below.

Atomoxetine (Strattera) is a white solid and usually marketed as a capsule formulation for oral administration. It is rapidly absorbed after oral administration. Its bioavailability is not significantly altered by food.

Serious drug interactions may occur when Atomoxetine (Strattera) is taken with a MAOI within 2 weeks of its discontinuation. The interaction can be fatal and caution should be taken in this regard. Patients with pheochromocytoma also need to be monitored closely when prescribed with it.


Noradrenergic and specific serotonergic antidepressants (NaSSA)

NaSSA exhibit its antidepressant effects by blocking a2-adrenergic receptors and certain subset of serotonin receptors, thereby enhancing noradrenergic and serotonergic neurotransmission. Because of the drug’s selective serotonin action, many of the unwanted serotonergic side effects associated with other antidepressants (e.g. TCAs and SSRIs) are prevented.

Mirtazapine (Remeron) is a prototype of the noradrenergic and specific serotonergic receptor antidepressants (NaSSA) that was initially marketed in the U.S. in the 1990’s. It is currently the only tetracyclic antidepressant to have received FDA approval for the treatment of depression. It belongs to the piperazinoazepine class with a chemical structure that is shown below.

Its designated chemical name is 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine and its empirical formula is C17H19N3.

Worldwide studies have shown mirtazapine (Remeron) to be superior to placebo in treating moderate to severe depression and having potentially less side effects than other antidepressants. It is often preferred as a first line treatment in these disorders. Mirtazapine (Remeron) is used off label for the treatment of post-traumatic stress disorder (PTSD).

Mirtazapine (Remeron) is also extensively metabolized in the liver by demethylation and hydroxylation into four metabolites, which then undergo glucuronide conjugation. These metabolites are less potent than the parent compound.


Serotonin norepinephrine reuptake inhibitors (SNRI)

SNRI’s are a class of antidepressants that have a dual action; they block the reuptake of the two neurotransmitters that have the most significant effect on moods – serotonin and norepinephrine, thereby increasing their levels in the postsynaptic junction. They are prescribed to patients who have not responded to SSRIs. Other approved uses of SNRIs are:


  • Neuropathic pain

  • Fibromyalgia

  • Appetite suppression

Venlafaxine (Effexor) was the first SNRI to gain FDA approval for depression. It is one of the most commonly prescribed SNRI and used in the treatment of major depressive disorder, and generalized anxiety disorder. It is also used in the treatment of panic disorders, social phobias and vasomotor symptoms.

It is structurally unrelated to other antidepressants (see picture below).


Venlafaxine (Effexor) is absorbed well and extensively metabolized in the liver to form its active metabolite, O-desmethylvenlafaxine (ODV) and two other inactive metabolites, N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. At least 92% of a single dose of venlafaxine is absorbed after 24 hours of administration and 87% of it is recovered in various forms in the urine.

At low doses i.e. less than 150 mg/day, venlafaxine (Effexor) acts only on the serotonergic neurotransmission. However, at slightly higher doses i.e. more than 150 mg/day, it affects both serotonergic and noradrenergic transmission. At doses above 300 mg/day, it also affects the dopaminergic transmission.

In patients with hepatic dysfunction, there is a significant reduction in the half-life elimination of venlafaxine (Effexor) that may require up to 50% dose adjustment. Patients with renal impairment are recommended to reduce their total daily dose as much as 25%. Similar to other antidepressants, its discontinuation requires a gradual tapering of the dose to avoid withdrawal symptoms.

Other serotonin norepinephrine reuptake inhibitors (SNRIs) approved in the U.S. are Duloxetine (Cymbalta) and Milnacipran (Savella). The latter was approved in 2009 for the sole indication of fibromyalgia, not depression. SNRIs carry the black box warning that cautions patients about its propensity to precipitate suicidal thoughts.


Serotonin antagonist and reuptake inhibitors (SARIs)

SARIs are antidepressants that stimulate 5-HT1A receptors by binding with 5-HT2A receptors and essentially block the 5-HT reuptake in the brain.

Trazodone (Oleptro) is a phenylpiperazine compound that belongs to the SARI class of antidepressants. It is structurally unrelated to other antidepressants such as the serotonin reuptake inhibitors and monoamine oxidase inhibitors. Its structural formula is 2-[3-[4-(m-Chlorophenyl)-1-piperazinyl]propyl]-s-triazolo[4,3-a]pyridin-3(2H)-one monohydrochloride and its chemical structure is shown below.

It does not affect norepinephrine and dopamine reuptake in the CNS. Its sedative activity stems from its blockade of alpha-adrenergic and histamine receptors (49). It is approved for the treatment of depression. It is also used off label for the following conditions:



  • Aggressive behavior

  • Alcohol withdrawal

  • Insomnia

  • Migraine prophylaxis

For major depressive disorder, the usual dose of trazodone (Oleptro) is 150 mg/day given once daily. An increment of 75 mg can be made 3 days after the start of therapy with a maximum dose not exceeding 375 mg/day.

Trazodone (Oleptro) is well absorbed after oral administration and extensively metabolized in the liver to form its major active metabolite, m-chlorophenylpiperazine (m-CPP). It is predominantly renally excreted, and after 72 hours up to 75% of the drug is found in the urine; the remaining 25% is found in the feces.

Safety of trazodone (Oleptro) has not been established in pediatric populations and should not be used. Additionally, short-term studies report an increase in suicidal thoughts associated with its use.


Norepinephrine dopamine reuptake inhibitors (NDRIs)

NDRIs block the dopamine and norepinephrine transporters, essentially inhibiting the reuptake of their neurotransmitters. The blockade increases the extracellular concentration of dopamine and norepinephrine, which results in an increase in their neurotransmission and mood elevation.

Bupropion (Wellbutrin) is a drug that falls under the NDRI category of antidepressants. Structurally, it is an aminoketone that is chemically unrelated to other groups of antidepressants. As such, it is a weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine. Moreover, bupropion (Wellbutrin) does not inhibit monoamine oxidase. Its chemical structure is shown below.

In major depressive disorder, 100 mg twice daily is the initial starting dose. By day 4, the dose can be increased to 100 mg three times daily, and increased up to 150 mg three times daily if no improvements are seen in the former regimen. Bupropion tablets taste bitter and produce local anesthetic effects in the oral mucosa.

After oral administration, it takes about 5 hours for the drug to reach its peak plasma levels. Sustained release formulations usually reach peak plasma levels within 3 hours. Bupropion (Wellbutrin) is extensively metabolized in the liver to form hydroxybupropion, its major metabolite that possesses 50% of its potency. The kidneys mainly excrete it and less than 0.5 % of it remains unchanged in the urine.

The drug is contraindicated in seizure disorders [50] and under no circumstances can be taken concomitantly with monoamine oxidase inhibitors.


Selective Serotonin Reuptake Enhancers (SSREs)

SSREs are structurally related to the TCAs but have an entirely different mechanism of action that is currently unclear to this date. Studies that have attempted to investigate their mechanisms of action suggest allosteric modulation of the serotonin transporter and modification of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor activity as possibilities.

Tianeptine is an SSRE approved in France for major depressive disorders. It is not approved for such an indication in either the U.S. or United Kingdom. It has strong anxiolytic and antidepressant properties but lacks the usual sedative affects associated with other antidepressants, making it an ideal drug for patients with a dual diagnosis of alcohol abuse and depression [51].


Norepinephrine dopamine disinhibitors (NDDIs)

NDDIs inhibit the 5-HT2c receptors in the frontal cortex region of the brain that releases dopamine and norepinephrine. Agomelatine (Valdoxan) is a relatively new compound that belongs to this category of antidepressants. In addition to its serotonergic actions, it is also a melatonergic agonist that resynchronizes circadian rhythm (proven in animal model studies). It is currently not available in the U.S.

Structurally speaking, agomelatine (Valdoxan), as the name suggests, is similar to the sleep-regulating hormone, melatonin. Its chemical structure is shown below.

In Australia, it is used for the treatment of major depressive disorder in adults. One of its advantages over other antidepressants is that it has minimal sexual adverse effects. The starting dose is 25-50 mg/day at bedtime.

Three of the six placebo controlled trials performed on agomelatine (Valdoxan) showed superior efficacy to placebo in the treatment of major depressive disorder [52]. The efficacy was observed as early as the first week of treatment. The studies also show no abuse potential. Its efficacy in children has not been proven and is not recommended for patients below the age of 18.

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants were introduced in the early 1950s and were the drugs of choice in the treatment of depressive disorders until SSRIs came into the picture with better side effect profile. The first TCA developed was chlorpromazine (Thorazine), followed by its derivatives, imipramine (Tofranil), desipramine (Norpramin) and clomipramine (Anafranil).

Currently, TCAs are only indicated when treatment with newer antidepressants failed to yield favorable results. Similar to SNRIs, TCAs block the serotonin and norepinephrine transporters to increase available serotonin and norepinephrine in the synapse.

Amitriptyline (Elavil) was the second TCA marketed in the US after chlorpromazine. It is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA) with an empirical formula of C20H23N·HCl. Its chemical structure is shown below.


Therapeutic effects can take up to one month to show up. Due to its strong anticholinergic activity, pediatric and geriatric patients may need to lower their doses. Oral administration results in only a 30-60% bioavailability due to the extensive hepatic metabolism. Its major active metabolite is nortriptyline. Peak plasma levels are achieved within 2-12 hours after oral and intramuscular administration. Studies show that 1/2 to 1/3 of the drug is excreted 24 hours after administration.

Amitriptyline (Elavil) is used off label for:


  • post-herpetic neuralgia

  • fibromyalgia

  • vulvodynia

  • ADHD

  • Migraine prophylaxis

  • Eating disorders

Monoamine oxidase inhibitors (MAOIs)

This is a class of antidepressants that inhibits the monoamine oxidase enzyme family. They are used in the treatment of depression but fell out of favor because of the strict dietary restrictions and severe interactions that accompany their use. They are often used as the last line of treatment, when all other treatments have failed.

Monoamine oxidase inhibitors are subdivided into classes according to the isoform of the enzyme they act on.


  • MAOI-A (e.g. tranylcypromine, isocarboxazid, phenelzine)

  • MAOI-B (e.g. selegiline)

Traditionally, only the MAOI-A are used for antidepressant treatment since they selectively deaminate the neurotransmitters primarily involved in mood and depression such as serotonin, dopamine and norepinephrine. Drugs that act on MAO-B are used in Parkinson’s disease as they selectively deaminate dopamine, the neurotransmitter implicated in the symptoms of Parkinson’s disease. Additionally, MAOIs have shown usefulness in the treatment of panic disorder, agoraphobia, sociophobia, anxiety, bulimia, post-traumatic stress disorder, borderline personality disorder and narcolepsy [53].

MAOIs function by inhibiting the enzyme that breaks down monoamine oxide, thereby increasing its availability in the synapse. Drugs that act on MAO-A irreversibly inhibit the enzyme permanently by degrading it. The body takes about 2 weeks to regenerate the enzyme, accounting for the long gap period required when starting on another class of antidepressant.

The drug that acts selectively on MAO-B, selegiline (Deprenyl) is used in Parkinson’s disease as an adjunct to levodopa. It prevents the degradation of levodopa by the MAO-B enzyme, thereby, prolonging and enhancing its effects on the brain.

The chemical structure of selegiline (Deprenyl) is shown below.


The FDA approved the use of the transdermal patch containing the active ingredient, selegiline in 2006. It is marketed under the trade name Emsam and indicated for the treatment of major depression.

The patch contains approximately 1 mg per cm2 of selegiline and delivers approximately 0.3 mg of selegiline per cm2. Different sizes of the patch deliver different doses. The patch is applied on dry intact skin on the upper torso, thigh or arm once in 24 hours. The usual indicated dose is 6 mg/day. After application and adhesion of dermal to intact skin, approximately 25-30% of the drug is delivered systemically over a period of 24 hours. The absorbed drug does not undergo first pass metabolism and exhibits 100% bioavailability. Patients with renal impairment do not require any dose adjustment.

It is very important that tyramine rich foods and beverages are avoided once patients initiate therapy with MAOIs. The same restriction applies to the patch at doses higher than 9 mg/day.


Anxiolytics and sedatives

Anxiolytics, as the name suggests, are medications that are used to curb anxiety. Anxiolytics basically include many of the drugs mentioned above and many other drugs that are not primarily indicated for anxiety but exhibit anxiolytic properties. Tricyclic antidepressants and monoamine oxidase inhibitors also relieve anxiety but are rarely prescribed because of their extensive side effect profile.

Barbiturates and benzodiazepines exhibit dose-dependent effects on the CNS, i.e. the higher the dose, the deeper the sedation-anxiolysis-anesthesia on the CNS. Benzodiazepines are primarily used for panic disorders and generalized anxiety disorder (54).

Benzodiazepines

Benzodiazepines are a class of psychoactive drugs used as anxiolytics, depressants, sedatives, anticonvulsants, and muscle relaxants. Their muscle relaxant and anxiolytic properties are useful in medical and dental procedures to relieve nervousness and dental phobia [55]. Due to their high abuse potential, most of the benzodiazepines are controlled medications and are not the first line drug for panic and anxiety disorders.

The chemical structure of benzodiazepines shows a characteristic fusion of the benzene rings and diazepine rings.

Benzodiazepines exert their pharmacological action by enhancing the activity of the inhibitory neurotransmitter, gamma amino butyric acid (GABA). They are divided into categories according to their duration and onset of action:


  • Short acting benzodiazepines

  • Intermediate acting benzodiazepines

  • Long acting benzodiazepines

Each category is used differently. The short and intermediate acting benzodiazepines are used in patients with insomnia before bedtime. Additionally, due to their short onset of action, short-acting benzodiazepines are used to provide symptomatic relief during panic episodes.

Diazepam (Valium) is one of the earliest benzodiazepines marketed and is used as an antiseizure, anxiolytic, sedative and muscle relaxant. Its empirical formula is C16H13ClN2O and its structural formula is shown below.



Diazepam (Valium) is well absorbed in the gut and achieves peak plasma concentration within 1-1.5 hours following oral administration. The absorption may be hampered if taken with a moderately fat meal. The drug is extensively metabolized in the liver to yield active metabolites such as desmethyldiazepam, temazepam and oxazepam. These metabolites cross the blood brain barrier and the placental barrier. Their excretion is mainly through the kidneys.

Another benzodiazepine that is commonly prescribed is alprazolam (Xanax). Its short onset and duration of action afford patients with generalized anxiety and panic disorders quick symptomatic relief. Its chemical structure is shown below.

It undergoes hepatic metabolism to form α-hydroxyalprazolam, which is also active.

Beta blockers

The non-selective beta blockers such as propranolol (Inderal), although not primarily indicated for anxiety, controls anxiety symptoms such as palpitations prior to surgery [56]. It is contraindicated in asthma patients.


Mood stabilizers

Mood stabilizers are a group of antipsychotic medications that are primarily used to treat the symptoms associated with mood shifts in bipolar disorder, schizoaffective disorders, and sometimes even borderline personality disorders. The main purpose of the drug is to stabilize the intense mood shifts between depressive and manic episodes.

The classic drug in this category is lithium carbonate (Eskalith). Its effectiveness in manic states is unclear but may be attributed to the following mechanisms:


  • Inhibition of glycogen synthase kinase 3 and inositol phosphatases

  • Modulation of glutamate receptors

Lithium has a strong side effect and toxicity profile, which is directly related to its plasma drug concentrations. It has a narrow therapeutic window, with the therapeutic dose overlapping with the toxicity dose in certain patient populations. Lithium should not be co-administered with diuretics because the renal sodium loss induced by the drug may lead to increased lithium levels in the body and consequently, toxicity. Similar effects may be seen when lithium is given with metronidazole.

Although monotherapy has been the ideal practice, it is often inadequate in meeting the realistic needs of many bipolar patients. Bipolar disorder requires pyschopharmacologic management combined evidence-based practice principles in order to reach optimal remission. The favorable side effect profiles and efficacy of atypical antipsychotics have made them ideal candidates to augment lithium in the management of manic disorders. Studies in the recent years have found them to be more effective than placebo in acute manic disorder and maintenance of bipolar disorder, and even more effective when combined with lithium or valproate. (206).

There are off-label uses for Lithium. For example, it is used for migraine and cluster headache prophylaxis.

Other mood stabilizers are the anticonvulsants carbamazepine (Tegretol) and valproic acid (Depakine). Carbamazepine (Tegretol) is used in refractory bipolar disorder. It may cause lupus reactions in women thereby, requiring close monitoring while on therapy.


Stimulants

Stimulants are psychoactive drugs that elevate mood and improve physical and mental functioning for a temporary period of time. They are used worldwide as prescription drugs and also have been widely abused as recreational substances.

Essentially, stimulants increase brain activity within the central nervous system and peripheral nervous system. They are used to treat lethargy, obesity, excessive appetite, narcolepsy, and improve concentration in ADHD patients.

There are many types of stimulants i.e. ampakines, amphetamine-related substances, eugeroics, norepinephrine reuptake inhibitors (NERIs), norepinephrine dopamine reuptake inhibitors (NDRIs), xanthine and caffeine-related drugs. Each type has a unique mechanism of action.

In this category of drugs, amphetamine derivatives (Adderall) are the most commonly prescribed psychostimulants for the management of ADHD and narcolepsy. They mimic NDRI’s mode of action by increasing the levels of norepinephrine and dopamine via reuptake inhibition. They are contraindicated in patients who are on MAOIs because of the risk of hypertensive crisis.

Another psychostimulant is methylphenidate (Concerta). It is similar to cocaine though with less potency and longer duration of action. It inhibits the reuptake of dopamine from the synapse. The main deterrent in the use of stimulants is their high risk for abuse [57].


Sedatives hypnotics

Sedatives or tranquilizers are a group of drugs that induces sleep by decreasing the excitatory mechanisms of the brain. Many of the drugs mentioned above have sedative effects, namely benzodiazepines. Barbiturates and antihistamines can all act as sedatives.

Sedatives, when used prior to medical surgeries, are called sedative-hypnotics because their effects on the CNS are dose-dependent i.e. at lower doses; they may act as anxiolytics but at higher doses, can induce unconsciousness. They are used to induce sleep and are adjuncts to general anesthesia.

Barbiturates

Just like benzodiazepines, barbiturates potentiate the inhibitory effects of GABA at its receptor. Additionally, they also block the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, a type of glutamate receptor, to effectively lower glutamate levels in the CNS.

Barbiturates were commonly used for their anxiolytic properties but have been largely replaced by benzodiazepines and nonbenzodiazepines for their better safety profile (lower risk of overdose). At lower doses, they exert anxiolytic effects and at higher doses, they exert total anesthesia. The ultra-short acting barbiturate, thiopental (Penthotal), is used as a general anesthetic.

Sedatives should not be used in combination with alcohol. Since both substances have a depressant effect on the central nervous system, their additive effects are fatal.

These drugs also cause anterogade amnesia and are often implicated in criminal activities (e.g. date rape) by combining them with alcohol or other drugs [58].



Miscellaneous drugs

In the last 10 years, herbal formulations have been gaining popularity in the U.S. for the treatment of psychiatric disorders. These supplements are widely purported by their manufacturers to exhibit fewer and lighter side effects compared to their counterparts that require prescription. The herbal supplement, St. John’s Wort, is one such example. It is obtained from the flowers and leaves of the herb, Hypericum perforatum. It is known by a number of other names including Tipton's weed, rosin rose, Amber, Amber Touch-and-Heal, goatweed, and Klamath weed.

Several studies propose the significant role of St. John’s Wort in the treatment of mild to moderate depression [59]. Some users have also reported experiencing therapeutic benefits in the treatment of anxiety and related disorders.

A study conducted in France showed that preparations of St. John’s Wort were superior to placebo in treating clinical depression. A total of 375 patients were enrolled in the study with the outcome measured by improvement in Hamilton scores [60]. Studies performed in Germany have also led to a similar conclusion; leading many experts in the field to postulate its effectiveness to be so superior that it may just become the first line treatment for depression in some countries. On the other hand, there are also many studies that contradict this assumption, showing a failed superiority over placebo in treating depression [61]. Large-scale studies are needed to establish the efficacy of this herbal supplement and its therapeutic value in the treatment of psychiatric disorders.

The exact mechanism of action of St. Johns Wort is not completely understood. Initial studies reported that the active components of the extracts exhibited weak inhibitory effects on the monoamine oxidase enzyme family. It has also been reported to inhibit the synaptosomal uptake of serotonin, dopamine and noradrenaline. Studies done on rat models have seen the drug cause a down regulation of the beta-adrenergic receptors and an up regulation of the serotonin receptors.

St. John’s Wort is notorious for its interaction with various medications. When it is administered with fexofenadine (Allegra), it causes an initial rise on the latter’s plasma levels. Continued co-administration leads to increased renal clearance of fexofenadine and a marked decrease in the peak plasma levels of the drug. When administered with amitriptyline, the herb decreases the plasma concentration of the antidepressant. The efficacy of the immunosuppressive agents, cyclosporine (Gengraf) and tacrolimus (Prograf), can be severely impaired when administered with St. John’s Wort. The interaction is reversible and cessation of herbal therapy generally results in restored efficacy of the drugs.

Additionally, St. John’s Wort significantly alters the pharmacodynamics of benzodiazepines, antihypertensive drugs, selective sinus node channel inhibitors and anticancer drugs such as imatinib mesylate (Gleevec). Most of these interactions occur via the P-glycoprotein and cytochrome P450 pathways.

Valerian is another herbal supplement with psychoactive properties. It is obtained from the perennial flowering herb, Valeriana officinalis, and used for its hypnotic and sedative properties in the treatment of insomnia, anxiety, depression, and migraines. It is known by a variety of other names such as All-Heal, Amantilla, Baldrian, Fragrant Valerian and Garden Heliotrope, just to name a few.

Studies have shown valerian to exert sedative effects by acting on the GABA receptors, the same receptors targeted by benzodiazepines. Small-scale placebo-controlled trials have reported this drug to be beneficial when given to elderly patients with sleep disturbance issues. Just like St. John’s Wort, there is an enormous amount of contradictory data on the effectiveness of Valerian as a sleep aid.

When it comes to safety, valerian is known to interact with a number of drugs, alcohol, and vitamin supplements and cause serious adverse effects. The active ingredients in valerian cause severe secondary effects when given with benzodiazepines as they enhance its inhibitory activity, thereby, producing an additive sedative effect. Published case reports showed an increased side effect profile when patients on lorazepam (Ativan) had self-medicated with over the counter preparations of valerian.

The widespread availability of herbal supplements makes them easy methods which allow dangerous interactions to take place when patients already on medications self-medicate with them. Because they are easily obtained, the general consensus is that they are safe, regardless of any food and medication that’s being taken with them. Reports have implicated this false sense of security in many emergency department visits over the years, some with fatal consequences.




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