Clinical Assessment and Goals of Therapy
CASE 83-9, QUESTION 3: What are the goals of treatment in this case, and how can D.D.’s symptoms be
and cognitions. In D.D.’s case, these target symptoms include nightmares, intrusive
memories, avoidance behaviors, irritability, hyperarousal, sleep difficulties, and
guilt. Improvements should begin within the first 2 weeks and gradually continue
over the course of 2 to 3 months. Secondary goals in this case include improving
D.D.’s stress resilience, decreasing her work- and marriage-related disability, and
improving her quality of life. Other general treatment goals in PTSD include
decreasing detrimental behaviors (use of alcohol or substances, risky activities,
violence) and treating comorbid psychiatric conditions.
Several different rating scales have been developed to assess response to
54 The most commonly used clinician-rated scales are the
Clinician Administered PTSD Scale and the Treatment Outcome PTSD Scale. The
Clinician Administered PTSD Scale is most often used in clinical PTSD trials. The
Sheehan Disability Scale is often used to assess functional impairment attributable to
Course and Duration of Treatment
Good treatment response in PTSD is more likely to occur when treatment is started
within 3 months of the trauma.
143,150 There is no well-established definition of
response in PTSD, but a decrease in symptoms by 30% to 50%, along with
substantial functional improvement, is commonly used in clinical trials. Full recovery
during treatment of PTSD is fairly uncommon, and partial responders to either
medication or psychosocial therapies may benefit from adding another treatment
modality. When an initial SSRI trial is ineffective, the patient may be switched to
another SSRI or another antidepressant shown to be effective in PTSD.
responders may benefit from the addition of a second medication, depending on
which core symptoms predominate (see Treatment of Post-traumatic Stress Disorder
For patients who respond, treatment should be continued for an additional 6 to 12
months for acute cases (when symptoms were present <3 months before treatment)
and 12 to 24 months for chronic cases (when symptoms lasted >3 months before
143 Long-term SSRI treatment can prevent relapse of PTSD, especially in
those who show good response during the first 3 months of therapy.
pharmacotherapy is discontinued, it should be withdrawn gradually over the course
OCD is characterized by repetitive thoughts (obsessions) that cannot be ignored or
suppressed voluntarily and/or repetitive behaviors (compulsions). The compulsions
are designed to reduce anxiety associated with obsessions or to prevent some future
event or situation; however, they are not actually connected to the obsessions in any
realistic way or are excessive. Obsessions and compulsions result in marked
distress, are time-consuming (greater than 1 hour/day), or significantly impair
1 Both obsessions and compulsions are unpleasant and disturbing to
the sufferer and are not associated with pleasure or gratification. This feature
distinguishes OCD from certain other behaviors (e.g., excessive gambling or
shopping) often described as “compulsive.”
OCD is a clinically heterogeneous disorder involving a broad range of symptoms
with four primary OCD symptom dimensions: symmetry obsessions and repeating,
counting, and ordering compulsions; contamination obsessions and cleaning
compulsions; hoarding obsessions and compulsions; aggressive, sexual, and religious
and related compulsions. Although specific symptoms in an individual may change
with time, they usually remain within the same dimension.
Epidemiology and Clinical Course
OCD is one of the least common mood–anxiety disorders with a lifetime risk and 12-
mo prevalence between 2% and 3%.
14 Although onset of illness ranges from very
early childhood to adulthood, the mean onset of illness is 20 years, which is later
than most anxiety disorders. Men tend to have an earlier onset of illness (childhood)
than women (adulthood). Approximately one-fourth of patients experience symptoms
by age 14, and onset after 30 years of age is rare.
1 Childhood onset OCD may be a
177 There is usually a gradual onset
of symptoms, although abrupt onset may occur during stressful periods and
The course and severity of OCD are highly variable and unpredictable. The
majority of patients with OCD will have a chronic course that waxes and wanes
rather than an intermittent or episodic course. Less than 10% of patients will have a
179 A 40-year naturalistic study found that although 83% of
patients were improved at the end of the follow-up period, only 20% experienced
OCD can have seriously detrimental effects on function such as abilities to
socialize, study, work, make friends, and maintain good relationships with family and
friends given the time spent obsessing and performing compulsions as well as
avoiding situational triggers.
It is estimated that each person with OCD loses an
average of 3 years’ wages during his or her lifetime.
180 Quality-of-life ratings in
OCD patients indicate marked impairments and are similar to those observed in
Although several effective treatments are currently available for OCD, there is an
average delay of 7.5 years between onset and seeking medical evaluation for OCD.
This may be because most OCD patients realize their symptoms are senseless, so
they attempt to hide their disorder because of embarrassment. People with OCD often
carry out their rituals privately and may be very successful at concealing their
symptoms from others. Initial treatment for OCD is commonly sought outside
psychiatric settings, and the obsessive–compulsive symptoms are often missed.
Clinicians across the healthcare system can incorporate four simple OCD screening
questions into their practice to improve detection: Do you have to wash your hands
over and over? Do you have to check things repeatedly? Do you have recurrent
distressing thoughts you cannot get rid of? Do you have to complete actions again and
Psychiatric Comorbidity and Obsessive–Compulsive
Identification of comorbid conditions with OCD is important because it can influence
treatment decisions. As with other anxiety disorders, OCD is often accompanied by
psychiatric comorbidity in 60% to 90% of patients with affective (e.g., depression,
bipolar disorder), anxiety, and tic disorders being common.
20% to 30% of OCD patients. These individuals believed to represent a distinct
subtype of illness where patients are more likely to be male, have an earlier onset
(before age 10 years), experience more severe symptoms, and have a poorer
response to SSRIs than those with OCD alone.
182 Distinguishing from obsessive–
compulsive personality disorder (OCPD), a personality pattern characterized by
rigid and inflexible preoccupation with rules, lists, order, and perfectionism, can be
difficult, and the two disorders co-occur in a small percentage of patients. OCPD,
however, does not involve distressing obsessions and compulsions.
OCD is no longer classified as an anxiety disorder in the DSM-5 but rather an
illness within a new obsessive–compulsive and related disorders.
disorders included are body dysmorphic disorder (preoccupation with an imagined
or slight defect in appearance), trichotillomania (recurrent impulses to pull out one’s
hair), excoriation disorder (skin-picking), and hoarding disorder. Like OCD, many
patients with these conditions have shown good response to treatment with
serotonergic antidepressants such as clomipramine and SSRIs.
Since OCD displays such clinical heterogeneity, there may be several distinct
etiologies for different subtypes of illness. Structural and functional brain imaging
suggests that OCD is a neurologic disorder characterized by a hyperfunctioning
circuit involving the frontal lobe and basal ganglia regions termed the frontostriatal
177 Abnormalities therein imply potential dysfunction in glutamatergic,
dopaminergic, and serotonergic neurotransmission. In support of this hypothesis,
these abnormalities normalize after successful treatment of OCD with SSRI
monotherapy and antipsychotic augmentation. Preliminary evidence with
glutamatergic agents suggests a role in treatment. Furthermore, neuromodulation
therapies (e.g., deep brain stimulation, cycloserine-enhanced CBT) and neurosurgical
techniques interrupting this circuit are often effective in the treatment of OCD.
Besides biologic factors, twin and family studies support genetic influences,
particularly in early-onset OCD cases.
17,184 Genetic studies have found associations
between OCD and specific polymorphisms in the glutamatergic (high-affinity
neuronal/epithelial excitatory amino acid transporters), dopaminergic
(catechol-O-methyltransferase and dopamine D4
-receptor genes), and serotonergic
(5-HT type 1Dβ and 5-HT type 2A receptor genes) pathways.
of OCD is estimated at 40% with the remaining variation purportedly mediated by
environmental factors (e.g., perinatal events, trauma, stress, neuroinflammation).
An example of this is the autoimmune disease, called PANDAS (pediatric
autoimmune neuropsychiatric disorders associated with streptococcal infection).
Reports describe children who developed sudden and severe tics and obsessive–
compulsive symptoms after strep throat infections.
188 These children may be better
treated with other medications and modalities (e.g., antibiotics, corticosteroids,
surgery). The possibility of a PANDAS correlation should be considered in any child
who develops abrupt onset of obsessive–compulsive symptoms and has a history of
pharyngitis within the past 6 months.
Treatment of Obsessive–Compulsive Disorder
Both medications and behavioral therapies are effective in the treatment of OCD.
Behavioral therapy is vitally important for OCD, and the combination of drugs plus
behavioral therapy provides optimal treatment. All medications consistently effective
as monotherapy are potent inhibitors of serotonin reuptake. These include the SSRIs,
clomipramine, and the SNRI venlafaxine.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND SEROTONIN
AND NOREPINEPHRINE REUPTAKE INHIBITORS
SSRIs are the only first-line medication treatments for OCD of which fluvoxamine,
fluoxetine, paroxetine, and sertraline are FDA-approved based on double-blind,
189 Citalopram and escitalopram also are effective but
with less evidence to support their use, particularly with the former. No single SSRI
is considered to be more effective than the others in treating OCD, but some patients
may respond to or tolerate one agent better than another.
dosages can be used in OCD, but at least 4 weeks should be allowed before
exceeding the targeted minimally effective dosages (fluvoxamine 200 mg/day,
fluoxetine 40 mg/day, paroxetine 40 mg/day, and sertraline 100 mg/day).
generally considered to have a dose–response relationship such that higher SSRI
doses may be required to effectively treat OCD.
25 Additionally, several controlled
studies support the efficacy of venlafaxine in the treatment of OCD.
SNRIs (duloxetine, desvenlafaxine, milnacipran, or levomilnacipran) may ultimately
in the treatment of OCD, no well-controlled studies have been conducted evaluating
Clomipramine was the first drug FDA-approved for OCD treatment and was
considered the standard treatment for several years until the SSRIs gained popularity.
Many large well-controlled studies have documented that clomipramine is superior
to placebo and significantly improves OCD symptoms in approximately 60% to 70%
179,190 Clomipramine is the only TCA recommended for OCD treatment as
others have not proven efficacious
20,25,113,179,192 although there is some evidence to the
193 This is attributed to its more potent effects on 5-HT reuptake inhibition
compared with other TCAs. Clomipramine is often referred to as a SRI (serotonin
reuptake inhibitor), not a SSRI (selective serotonin reuptake inhibitor), because its
major active metabolite, desmethylclomipramine, is a potent inhibitor of NE
reuptake. Clomipramine also blocks adrenergic, histaminergic, and cholinergic
receptors resulting in an adverse effect profile similar to other TCAs (see Chapter
Although direct comparison studies have shown clomipramine to be similar in
efficacy to various SSRIs in treating OCD, several meta-analyses have concluded
clomipramine is superior to SSRIs overall.
190,194 Nonetheless, clomipramine is
currently reserved as a second-line treatment option for patients who do not respond
adequately to SSRI/venlafaxine therapy given its poorer tolerability (e.g., sedation,
orthostatic hypotension, and anticholinergic side effects).
190 Details about the clinical
use of clomipramine are discussed in Case 83-11, Questions 1.
Other than venlafaxine, no other miscellaneous agents studied in OCD have
demonstrated impressive efficacy as monotherapy. However, several agents appear
to be useful as augmentation therapy to boost response to SSRIs or clomipramine in
195 The combination of an SSRI plus clomipramine is one such
option for patients who show partial response, although attention must be paid to
potential drug interactions, which may lead to clomipramine toxicity (see Case 83-
Antipsychotic agents are the most studied pharmacologic augmentation strategy in
OCD and may improve response in 30% of patients.
effective in four scenarios: treatment-refractory OCD, OCD with poor insight (often
treatment refractory), comorbid tic disorders, and comorbid schizophrenia.
Several meta-analyses have been conducted on antipsychotic effectiveness.
Risperidone (0.5–4 mg/day) is generally considered to have the highest evidence
base for antidepressant augmentation in OCD. Other reasonable agents include
aripiprazole and haloperidol (of which haloperidol is less tolerated compared to
second-generation antipsychotics). Conversely, quetiapine (up to 600 mg/day) and
olanzapine (2.5–20 mg/day) use is controversial based on inconsistent evidence
supporting their use in well-designed trials. Preliminary evidence suggests
paliperidone may not be more effective than placebo, and ziprasidone may be less
201,202 Recent evidence suggests antipsychotics are less
effective than augmenting with CBT with exposure–response prevention (ERP) and,
thus, may not be a preferred augmentation strategy.
203,204 Additionally, the use of
antipsychotics must be weighed against tolerability and safety concerns such as
metabolic dysfunction and extrapyramidal symptoms.
Anticonvulsants (e.g., topiramate, lamotrigine, pregabalin, gabapentin) may also
be considered as augmentation agents although the evidence is limited to lower
20,205 As such, this strategy should be one of last resort unless
otherwise clinically indicated.
Benzodiazepines, although typically useful in other anxiety disorders, are generally
not beneficial in treating OCD. There are several reports of clonazepam being
effective as adjunctive therapy or monotherapy which may be explained by its
serotonergic properties; however, double-blind placebo-controlled trials have been
206 As such, clonazepam is not recommended by treatment guidelines.
The MAOI phenelzine was one of the first medications studied for OCD. Early
case reports of its use were favorable, but more recent findings suggest phenelzine is
Cognitive Behavioral Therapies
CBT is an extremely important component of OCD treatment and should be
incorporated into the treatment plan whenever possible. The combination of
psychotherapy and medication is generally superior to pharmacotherapy alone but not
20,179 CBT alone may be appropriate for mild OCD or in cases in which
it is desirable to avoid medication (e.g., pregnancy, medical conditions). Treatment
gains achieved with CBT often are maintained long after its discontinuation, which is
an advantage versus pharmacotherapy, likely improving relapse prevention.
The cognitive therapy component of CBT is aimed toward changing the detrimental
thought patterns in OCD and is most helpful for obsessions such as scrupulosity,
moral guilt, and pathologic doubt. The behavioral therapy aspect, ERP, involves
exposure to feared objects or situations followed by prevention of the usual
compulsive response. This type of therapy is most beneficial for patients with
contamination fears, hoarding, and rituals involving symmetry, counting, or repeating.
Because ERP is anxiety provoking and can be very distressing, patients may refuse to
Neurosurgical treatment of OCD has been practiced since the 1950s and is
considered an option of last resort in treatment-refractory patients. Anterior
cingulotomy and anterior capsulotomy are the most commonly used surgical
procedures. Indications for neurosurgery include severe disability from symptoms
and failed treatments (drugs and behavioral therapies) that have been tried
systematically for at least 5 years.
208 Neurosurgery success rates range from 35% to
70%, complications (including potential infections, personality changes, cognitive
impairment, and epilepsy) appear to be rare, and limited long-term follow-up studies
indicate the benefit is maintained with mild-to-moderate impairments in
neuropsychological performance.
208,209 Deep brain stimulation involving bilateral
electrode implantation into the subthalamic nucleus and nucleus accumbens is gaining
popularity for treatment-refractory OCD. Although this procedure is still
experimental, overall preliminary results are positive.
Response to medication treatment in OCD is gradual and often delayed. Initial
improvements usually begin to appear within the first month. Patients with
unsatisfactory response by weeks 4 to 9 should have their SSRI dosages gradually
increased to the manufacturer’s recommended maximum. A trial of 8 to 12 weeks at
maximal tolerated medication dosages is recommended before assessing therapeutic
benefit and maximal response may take as long as 5 to 6 months..
Since complete elimination of symptoms is rare with current treatments, the
primary goal of OCD treatment is to minimize functional impact of symptoms.
clinical trials in OCD define clinical response as a 25% to 35% reduction in Yale–
Obsessive–Compulsive Symptom Checklist (Y-BOCS) scores. Therefore, even
those classified as responders may be left with 65% to 75% of their original
symptoms, and this may or may not result in significant improvements in functioning
or quality of life. The Y-BOCS is an objective tool in the initial evaluation of those
who present with symptoms of OCD. It is a 10-item scale with a maximal possible
score of 40; a score of more than 15 is generally considered to represent clinically
significant obsessive–compulsive symptoms.
212 This scale is a standard tool for
evaluating drug efficacy in OCD clinical trials and is often used in clinical practice
to assess response to treatments with a version designed for administration with
STRATEGIES FOR MANAGING NONRESPONSE AND PARTIAL
Approximately 40% to 60% of patients show clinically meaningful improvements
during an initial (SSRI or clomipramine) medication trial, but only a small
percentage exhibit marked response.
190 Predictors of poor response include poor
insight; hoarding, sexual, religious, and symmetry dimension symptoms; prepubertal
onset of illness; and presence of comorbid personality, mood, or eating disorders.
For nonresponsive patients, it is usually recommended to pursue a second SSRI trial,
as approximately 20% of initial nonresponders will respond with a subsequent trial.
efficacy in SSRI nonresponders.
181,190 Patients with partial response to an initial SSRI
trial may be better served by adding an augmentation agent to preserve therapy
benefits rather than switching to a new medication and risk losing any improvement
already gained. Additionally, using SSRI doses beyond those FDA-approved may be
beneficial for poor responders if tolerability is acceptable.
Clinical Presentation and Assessment
QUESTION 1: R.G. is a 25-year-old woman whose husband complains she spends 1.5 hours a day cleaning
features of OCD does R.G. display, and how can her symptoms be objectively evaluated?
R.G. displays many characteristic symptoms of OCD. The most commonly
encountered clinical presentation of OCD involves excessive fear of contamination
with dirt, germs, or toxins and repeated washing of hands or cleaning objects or
surroundings. These persons also typically avoid touching possibly dirty objects
(e.g., doorknobs, money) or shaking hands with people. Another common clinical
presentation of OCD is the patient with pathologic doubt who constantly worries
something bad will happen because of his or her negligence. Individuals can be
afraid they have failed to lock the door, turn off the stove, shut the refrigerator door,
or secure the medicine cabinet from children. As a result, they continuously check
R.G. displays obsessions of contamination and pathologic doubt, and compulsions
of excessive cleaning and washing. These symptoms are time-consuming, cause
significant distress, and have led to her unemployment and marital difficulties. As
seen in this case, most persons present with a mixture of various obsessions and
compulsions. R.G. also realizes her thoughts and behaviors are “silly,” which most
often is the case in OCD. This case also illustrates the onset of OCD during times of
stressful or significant life events. Pregnancy, death of a relative, and marital discord
have been identified as precipitating factors in the onset of OCD.
Selective Serotonin Reuptake Inhibitor Treatment of
CASE 83-10, QUESTION 2: On assessment, R.G.’s Y-BOCS score is found to be 33. Her physician
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
SSRIs such as fluvoxamine are considered the best choice of initial pharmacotherapy
for OCD. The primary differences between SSRIs involve pharmacokinetic
properties and potential for drug interactions (see Chapter 86, Depression). Because
there are no overall differences in SSRI efficacy, fluvoxamine is a suitable selection
for R.G. However, the prescribed dosing instructions for R.G. are not appropriate.
The initial recommended dosage for fluvoxamine in adults is 50 mg/day (25 mg in
children), and it is best taken in the evening because it tends to be sedating. Using
higher-than-necessary dosages can increase both adverse effects and medication
costs, and these factors can lead to early termination of therapy. The dosage can be
increased by 50-mg increments every 3 to 4 days according to patient tolerability, up
to the initial targeted dose of 200 mg/day and a maximum of 300 mg/day.
doses exceeding 100 mg should be given in two divided doses if once-daily dosing is
ADJUNCTIVE COGNITIVE BEHAVIORAL THERAPY
R.G.’s Y-BOCS score of 33 indicates a moderate-to-severe symptom severity, which
supports using a combined treatment approach. The overall efficacy of these
nonpharmacologic treatments is estimated to be 50% to 70% when used alone, and
their use to complement pharmacotherapy is considered vital.
therapy might involve covering her hands with dirt and not allowing her to wash them
for a certain time period. These behavioral techniques cause extreme anxiety and
discomfort, which often lead to dropout from therapy or noncompliance with
“homework assignments” (which involve continuation of the therapy principles
outside the clinical setting), but are highly effective if the patient can adhere to
SELECTIVE SEROTONIN REUPTAKE INHIBITOR ADVERSE EFFECTS
with the prescribed treatments?
All OCD patients beginning treatment should be counseled that medication
response occurs gradually and several weeks may elapse before beneficial effects
become noticeable. It is important to emphasize that maximal response may take 3
months or longer and complete elimination of all symptoms is unlikely. Inform
patients that a variety of other medications exist for those who do not respond
adequately to an initial trial.
R.G. should be educated about possible fluvoxamine side effects, including
nausea, sedation or insomnia, and headache. Medication should be taken with food to
decrease these effects. Side effects are most common during the initial weeks of
therapy, are usually dose-related, and often subside with continued treatment. Other
aspects of SSRI therapy, including additional adverse effects and their management
and drug–drug interactions, are discussed in Chapter 86, Depression. Patients should
be encouraged to report any problems to their treatment provider. The importance of
adhering to prescribed therapies, both pharmacologic and behavioral, should also be
CASE 83-10, QUESTION 4: After 4 weeks, R.G. is taking fluvoxamine 200 mg daily and tolerating the
action for R.G. at this point?
Switching to another medication is not recommended at this point because not
enough time has elapsed to assess fluvoxamine’s efficacy. R.G. is tolerating
fluvoxamine well and has shown a mild improvement, so this medication should be
continued for at least another 4 weeks. Additional counseling information should be
provided to R.G. to emphasize this fact. An increase in fluvoxamine dosage, up to
250 or 300 mg/day, may be considered after several more weeks because some
patients may respond better to higher dosages. If R.G.’s symptoms continue to cause
significant functional impairment after 10 to 12 weeks of higher-dose fluvoxamine
therapy, a change in treatment (e.g., switching to another SSRI or augmentation
R.G. should be encouraged to continue CBT to optimize the chance for successful
treatment. An anxiety response is integral to the therapeutic benefits of behavioral
therapies; because benzodiazepines can blunt this response, they may reduce their
efficacy. Therefore, alprazolam should be avoided, and a temporary reduction in the
intensity of behavioral therapy may be indicated instead. Fluvoxamine can also
inhibit the CYP3A4-mediated metabolism of alprazolam, resulting in more
pronounced effects from a given dose.
Course and Duration of Therapy
CASE 83-10, QUESTION 5: After 5 months of treatment, R.G. is happy to report her OCD is much
This case illustrates a common outcome of OCD treatment, in which some
symptoms persist (as evidenced by a Y-BOCS score of 11), but significant
improvements in functioning occur. It is currently recommended that effective
treatment for OCD be continued for at least 1 year after response to reduce the risk of
212,217 Therefore, continued drug treatment for at least 7 more months is
indicated. Results from several studies suggest decreased medication doses (with
SSRIs and clomipramine) during maintenance therapy are comparably as effective as
full doses in preventing relapse.
If R.G. was experiencing any fluvoxamine-related
problems, a decrease to the minimally effective dose (150 mg/day) during
maintenance therapy might be recommended.
After a 1-year maintenance period, discontinuation of medication may be
considered by carefully weighing the possible risks and benefits. When medication
therapy for OCD is withdrawn, the dosage should be gradually decreased by
approximately 25% every 1 to 2 months. Continuous monitoring for signs of relapse
is required during this period. Gradual discontinuation also lessens the chance of the
withdrawal syndrome often occurring after abrupt discontinuation of SSRI or TCA
therapy (see Chapter 86, Depression). Long-term or even lifelong maintenance
pharmacotherapy is usually recommended after two to four severe relapses or three
QUESTION 1: K.T. is an 18-year-old Asian man who was diagnosed with OCD 2 years ago and also suffers
patient? What recommendations can be made regarding initiation of clomipramine treatment?
Current guidelines recommend clomipramine be reserved for OCD patients who
fail at least two SSRI trials; therefore, its choice for this patient is appropriate.
One precaution relevant to this case is that clomipramine, like other TCAs, is highly
dangerous in overdose situations. Because K.T. is depressed, he should be evaluated
carefully for any suicidal thoughts before starting clomipramine. If suicidal ideation
is detected, it would be preferable to try another SSRI. This case also illustrates the
common comorbidity of depression with OCD. Fortunately, most effective treatments
for OCD are antidepressants, and drug treatment can be beneficial for both
conditions. Nevertheless, the responses of depression and OCD to treatment are
independent of one another, so depression may respond completely to a certain
medication while OCD symptoms persist.
Clomipramine should be initiated at a low dosage of 25 to 50 mg/day administered
with meals. Divided daily doses are sometimes used initially to minimize side
effects, but the total daily dose can be given at bedtime after dose titration given its
average elimination half-life of 24 hours.
The clomipramine dosage should be increased to an initial target range of 150 to
200 mg/day during 2 to 4 weeks, guided by patient tolerability. The maximal
recommended daily dosage of clomipramine is 250 mg/day because of the sharply
increased risk of seizures (2.1%–3.4%) with higher dosages as compared with the
risk with dosages less than 250 mg/day (0.24%–0.48%).
clomipramine therapy may also increase the risk of seizures. As such, use with
history of seizures, head injury, or other factors might lower the seizure threshold.
Side Effects and Monitoring Guidelines
CASE 83-11, QUESTION 2: What guidelines should be recommended for monitoring the outcomes (both
therapeutic and adverse) of clomipramine therapy?
Clomipramine is less well tolerated than the SSRIs and can cause a number of
significant adverse effects, especially during the first few weeks of therapy. The most
common side effects, reported in more than half of those taking clomipramine,
include sedation, dry mouth, dizziness, and tremor.
219 Constipation, nausea, blurred
vision, insomnia, and headache also occur frequently. K.T. should be advised these
usually subside with continued treatment.
Many patients receiving long-term clomipramine (and other TCA) therapy gain
substantial amounts of weight. As with the SSRIs, sexual dysfunction can be a
problem in both men and women. In men, clomipramine can cause ejaculation
abnormalities, which can impair fertility. Patients taking clomipramine should also
be counseled about the additive CNS depressant effects with alcohol and to be
cautious about the possible sedative effects while driving or performing other
potentially hazardous activities.
As with other TCAs, an ECG should be performed before starting clomipramine in
individuals at risk for heart disease and in pediatric patients. Elevations in liver
enzymes have been observed frequently during the first 3 months of clomipramine
treatment, and baseline liver function tests should also be obtained before initiating
treatment. The liver enzyme changes are reversible on discontinuation of
No therapeutic range for plasma drug concentrations has been firmly established
for clomipramine in OCD, but monitoring plasma levels may be clinically useful in
certain patients to guide dosing and minimize drug toxicity. Clomipramine
metabolism exhibits interpatient variability, and it is difficult to accurately predict
the resulting clomipramine level from any given dose. The initial hepatic metabolism
of tertiary TCAs such as clomipramine involves demethylation through various
isozymes, including CYP1A2, CYP2C19, and CYP3A4.
(clomipramine) and the primary active metabolite (N-desmethylclomipramine) then
undergo CYP2D6-mediated hydroxylation. Therefore, the metabolism of
clomipramine will be affected by combination with any agent inhibiting CYP1A2,
CYP2C19, CYP3A4, or CYP2D6. Clinically significant drug interactions are
possible with several of the SSRIs, including fluoxetine, paroxetine, fluvoxamine,
and sertraline (see Chapter 86, Depression).
Although various studies have failed to find a correlation between clomipramine
plasma level and clinical response, the ratio of clomipramine to
N-desmethylclomipramine may be important.
serotonergic, whereas N-desmethylclomipramine is more noradrenergic; higher
levels of N-desmethylclomipramine relative to clomipramine have been associated
with poorer clinical response. Factors impairing the CYP2D6-mediated elimination
of N-desmethylclomipramine (e.g., concurrent medications that are potent CYP2D6
inhibitors and CYP2D6 poor metabolizers) may possibly decrease the efficacy of
clomipramine by shifting the metabolic ratio in an undesired direction.
Asian patients such as K.T. have been found to have significantly decreased
clearance of clomipramine and higher clomipramine to N-desmethylclomipramine
ratios compared with whites, which may necessitate use of lower doses.
probably caused by a genetic polymorphism of either CYP2C19 or CYP2D6, which
results in decreased metabolic capacity via these metabolic pathways in the Asian
population. Careful monitoring for possible signs of toxicity should accompany dose
increases, and the clomipramine plasma level should be checked in those patients
(Asian or otherwise) who show unexpected effects with usual doses. An opposite
effect has been described in ultra-rapid CYP2D6 metabolizers, in which unusually
high clomipramine dosages may be required for therapeutic efficacy.
CASE 83-11, QUESTION 3: After 10 weeks of taking clomipramine 100 mg at bedtime, K.T. has shown
desmethylclomipramine; range 150–450 ng/mL).
223 The physician decides to add another drug to augment
treatment. Considering K.T.’s current medication regimen and the evidence supporting the different
augmentation strategies, which drug would be the best choice for K.T.?
When adding an SSRI to a TCA, the potential for drug interactions should always
be considered. Clomipramine is metabolized by CYP1A2, CYP3A4, CYP2C19, and
218,220,224,225 The CYP2D6 pathway is particularly important because it is the
rate-limiting metabolic pathway for elimination of both clomipramine and
desmethylclomipramine. Fluvoxamine, paroxetine, and fluoxetine are all strong
inhibitors of clomipramine metabolism, whereas sertraline is a weak–moderate
inhibitor. Alternatively, escitalopram and citalopram would not be likely to cause a
significant drug interaction, but evidence for escitalopram as an augmenting agent in
combination with clomipramine is lacking.
226 A combination less likely to be
rather than clomipramine. Nonetheless, antipsychotic augmentation with agents
demonstrating more consistent efficacy in well-designed trials (e.g., risperidone and
aripiprazole) is a reasonable strategy in patients requiring more improvement as
previously discussed. Haloperidol would not be the optimal choice in K.T. because
it inhibits clomipramine metabolism, and as a first-generation antipsychotic, it is
associated with numerous side effects. Unfortunately, most of the well-designed
studies are often small (15–45 patients).
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